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Miscellaneous treatments for antipsychotic‐induced tardive dyskinesia

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Referencias

Bucci 1971 {published data only}

Bucci L. The dyskinesias: a new approach. Diseases of the Nervous System 1971;32(5):324‐7. CENTRAL

Cai 1988 {published data only}

Cai N. A controlled study on the treatment of tardive dyskinesia using 1‐stepholidine. Chinese Journal of Neurology and Psychiatry 1988;21(5):281‐3. CENTRAL

Castro 2011 {published data only}

Castro F, Carrizo E, Prieto de Rincon D, Rincon CA, Asian T, Medina‐Leendertz S, et al. Effectiveness of melatonin in tardive dyskinesia. Investigación Clínica 2011;52(3):252‐60. CENTRAL

Emsley 2006 {published data only}

Elmsley R, Oosthuizen PP. Double‐blind, randomized, parallel‐group comparison of ethyl‐eicosapentaenoic acid (ethyl‐EP A) versus placebo as add‐on medication in 84 patients with established tardive dyskinesia. Stanley Foundation Research Programs2002. CENTRAL
Emsley R. A double‐blind, randomised, parallel‐group comparison of ethyl‐eicosapentaenoic acid (ethyl‐epa) versus placebo as add‐on medication in patients with established tardive dyskinesia. https://clinicaltrials.gov/ct2/show/NCT001145952005. CENTRAL
Emsley R. Ethyl eicosapentanoic acid for tardive dyskinesia. Stanley Foundation Research Programs2009. CENTRAL
Emsley R, Niehaus DJH, Koen L, Oosthuizen PP, Turner HJ, Carey P, et al. The effects of eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo‐controlled trial. Schizophrenia Research 2006;84(1):112‐20. [MEDLINE: 16632329]CENTRAL
Emsley R, Niehaus DJH, Oosthuizen PP, Koen L, Ascott‐Evans B, Chiliza B, et al. Safety of the omega‐3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo‐controlled trial. Psychiatry Research 2008;161(3):284‐91. CENTRAL

Gardos 1979 {published data only}

Gardos G, Granacher RP, Cole JO, Sniffin C. The effects of papaverine in tardive dyskinesia. Progress in Neuro‐Psychopharmacology & Biological Psychiatry 1979;3(5‐6):543‐50. CENTRAL

Glazer 1985 {published and unpublished data}

Glazer WM, Naftolin F, Morgenstern H, Barnea ER, MacLusky NJ, Brenner LM. Estrogen replacement and tardive dyskinesia. Psychoneuroendocrinology 1985;10(3):345‐50. CENTRAL

Glover 1980 {published data only}

Glover O. Alternative treatment modalities for drug induced psychomotor dysfunctions. PhD dissertation submitted to the Wright Institute1980:150. CENTRAL

Goff 1993 {published data only}

Goff DC, Renshaw PF, Sarid‐Segal O, Dreyfuss DA, Amico ET, Ciraulo DA. A placebo‐controlled trial of selegiline (L‐deprenyl) in the treatment of tardive dyskinesia. Biological Psychiatry 1993;33(10):700‐6. CENTRAL

Hajioff 1983 {published data only}

Hajioff J, Wallace M. Effect of Co‐dergocrine mesylate on tardive dyskinesia. A preliminary report. Psychopharmacology 1983;79(1):1‐3. CENTRAL

Kojima 1992 {published data only}

Kojima T, Yamauchi T, Miyasaka M, Isaki K, Nakane Y, Takahashi R, et al. Treatment of tardive dyskinesia with ceruletide: a double‐blind placebo‐controlled study. Saishin‐Igaku 1989;44(10):2177‐88. CENTRAL
Kojima T, Yamauchi T, Miyasaka M, Koshino Y, Nakane Y, Takahashi R, et al. Treatment of tardive dyskinesia with ceruletide: a double‐blind, placebo‐controlled study. Psychiatry Research 1992;43(2):129‐36. CENTRAL

Koshino 1979 {published data only}

Koshino Y, Kurata K, Hosokawa K, Yamaguchi N. Double‐blind trial of cyproheptadine on neuroleptic induced tardive dyskinesia. Clinical Psychiatry [Seishin Igaku] 1979;21(4):421‐6. CENTRAL

Koshino 1983 {published data only}

Koshino Y, Hiramatsu H, Isaki K, Yamaguchi N. A double‐blind clinical trial of dihydrogenated ergot alkaloids in antipsychotic‐induced tardive dyskinesia. Clinical Psychiatry [Seishin Igaku] 1983;25(6):627‐35. CENTRAL

Libov 2007 {published data only}

Anon. Piracetam reduces TD symptomstardive dyskinesia. Brown University Psychopharmacology Update 2007;18(11):3‐4. CENTRAL
Lerner V. Piracetam for tardive dyskinesia. Stanley Foundation Research Programs2009. CENTRAL
Libov I, Miodownik C, Bersudsky Y, Dwolatzky T, Lerner V. Efficacy of piracetam in the treatment of tardive dyskinesia in schizophrenic patients: a randomized, double‐blind, placebo‐controlled crossover study. Journal of Clinical Psychiatry 2007;68(7):1031‐7. [MEDLINE: 17685739]CENTRAL
NCT00190008. Therapeutic use of piracetam for treatment of patients suffering from tardive dyskinesia ‐ a double blind, placebo‐controlled crossover study. http://www.clinicaltrials.gov. 2005. CENTRAL

Mackay 1980 {published data only}

Mackay AVP, Sheppard GP, Saha BK, Motley B, Johnson L, Marsden CD. Failure of lithium treatment in established tardive dyskinesia. Psychological Medicine 1980;10(3):583‐7. CENTRAL

Matsunaga 1988 {published and unpublished data}

Matsunaga T, Ohyama S, Takehara S, Kabashima K, Moriyama S, Tsuzuki J, et al. The effect of ceruletide on tardive dyskinesia: a double‐blind placebo‐controlled study. Progress in Neuro‐Psychopharmacology and Biological Psychiatry 1988;12(4):533‐9. CENTRAL

Meco 1989 {published data only}

Meco G, Bedini L, Bonifati V, Sonsini U. Ritanserin in tardive dyskinesia: A double‐blind crossover study versus placebo. Current Therapeutics Research 1989;46(5):884‐94. CENTRAL

Mosnik 1997 {published data only}

Mosnik DM. Phenylalanine loading effects on tardive dyskinesia severity in schizophrenics. Master of Science dissertation submitted to the Finch University of Health Sciences, USA. 1994. CENTRAL
Mosnik DM, Spring B, Rogers K, Baruah S. Tardive dyskinesia exacerbated after ingestion of phenylalanine by schizophrenic patients. Neuropsychopharmacology 1997;16(2):136‐46. CENTRAL
Mosnik DM, Spring B, Rogers K, Baruah S, Waziri R. Phenylalanine loading effects on tardive dyskinesia severity in schizophrenics. Schizophrenia Research 1995;15(1, 2):208. CENTRAL

Mouret 1991 {published and unpublished data}

Mouret J, Khomais M, Lemoine P, Sebert P. Low doses of insulin as a treatment of tardive dyskinesia: conjuncture or conjecture?. European Neurology 1991;31(4):199‐203. CENTRAL

O'Brien 2014 {published data only}

Factor S, Hauser R, Mandri D, Castro‐Gayol J, Jimenez R, Siegert S, et al. A Phase 2 Study of valbenazine (NBI‐98854) for treatment of tardive dyskinesia: KINECT 2. Neurology 2016;86(16 SUPPL. 1):S27.007. CENTRAL
NCT01733121. Nbi‐98854 dose titration study for the treatment of tardive dyskinesia. http://ClinicalTrials.gov/show/NCT01733121 (accessed on 6 October 2017)2012. CENTRAL
O'Brien CF, Jimenez R, Hauser RA, Factor SA, Burke J, Mandri D, et al. NBI‐98854, A selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double‐blind, placebo‐controlled study. Movement Disorders 2015;30(12):1681‐7. CENTRAL
O'Brien CF, Jimenez R, Hauser RA, Factor SA, Mandri DF, Castro‐Gyol JC. Kinect 2: NBI‐98854 treatment of moderate to severe tardive dyskinesia. 18th International Congress of Parkinson's Disease and Movement Disorders, Stockholm, Sweden June 8‐12 2014;29:S305‐S306. CENTRAL

Rastogi 1982 {published data only}

Rastogi SC, Blowers AJ, Gibson AC. Co‐dergocrine (hydergine) in the treatment of tardive dyskinesia. Psychological Medicine 1982;12(2):427‐9. CENTRAL

Richardson 2003 {published data only}

Richardson MA, Bevans ML, Read LL, Chao HM, Clelland JD, Suckow RF, et al. Efficacy of the branched‐chain amino acids in the treatment of tardive dyskinesia in men. American Journal of Psychiatry 2003;160(6):1117‐24. CENTRAL

Shamir 2000 {published data only}

Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is melatonin treatment effective for tardive dyskinesia?. Journal of Clinical Psychiatry 2000;61(8):556‐8. CENTRAL

Shamir 2001 {published data only}

Shamir EZ, Barak F, Shalman I, Landon N, Zisapel N, Elizur A, et al. Melatonin treatment for tardive dyskinesia: a double‐blind, placebo‐controlled, cross‐over study. Annual Meeting of the American Psychiatric Association; 2001 May 5‐10; LA, USA. 2001. CENTRAL
Shamir EZ, Barak F, Shalman I, Landon N, Zisapel N, Elizur A, et al. Melatonin treatment for tardive dyskinesia: a double‐blind, placebo‐controlled, cross‐over study. Archives of General Psychiatry 2001;58:1049‐52. CENTRAL

Shi 2009 {published data only}

Shi X, Zhu F, Zhang X, Zjang J, Zhang X, Wei L, et al. Melatonin in treatment of schizophrenia with tardive dyskinesia: A comparison study of cognitive function. Linchuang Jingshen Yixue Zazhi 2009;19(6):391‐3. CENTRAL

UCB Pharma 2005 {published data only}

NCT00175955. An 8‐week exploratory, double‐blind, placebo controlled, randomized trial ‐ evaluation of the efficacy and safety of levetiracetam up to 3000 mg/day (250‐500 mg oral tablets in bid administration) on neuroleptic‐induced tardive dyskinesia in subjects with stable axis I psychiatric disorder, aged from at least 18 years to 80 years. https://clinicaltrials.gov/ct2/show/NCT001759552005. CENTRAL

Wolkin 1986 {published data only}

Wolkin A, Jordan B, Peselow E, Rubinstein M, Rotrosen J. Essential fatty acid supplementation in tardive dyskinesia. American Journal of Psychiatry 1986;143(7):912‐4. CENTRAL

Woods 2008 {published data only}

NCT00291213. Levetiracetam treatment of tardive dyskinesia. www.Clinical Trials.gov (https://clinicaltrials.gov/ct2/show/NCT00291213)2006. CENTRAL
Woods SW, Saksa JR, Baker CB, Cohen SJ, Tek C. Effects of levetiracetam on tardive dyskinesia: A randomized, double‐blind, placebo‐controlled study. Journal of Clinical Psychiatry 2008;69(4):546‐54. CENTRAL

Yang 1999 {published data only}

Yang X, Meng F, Cui Y, Yang P, Liu R, Ma L, et al. Promethazine treatment of tardive dyskinesia: a double blind placebo controlled study. Chinese Mental Health Journal 1999;13:365‐7. CENTRAL

Zeng 1995 {published data only}

Zeng Z‐X. Treatment of tardive dyskinesia with buspirone. Medical Journal of Chinese Civil Administration 1995;7:202‐3. CENTRAL

Zeng 1996 {published data only}

Zeng ZX. Pemoline in the treatment of tardive dyskinesia. Chinese Journal of New Drugs and Clinical Remedies 1996;15:240‐1. CENTRAL

Zhang 2011 {published data only}

NCT00672373. Extract of ginkgo biloba and tardive dyskinesia. www.ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT00672373?term=NCT00672373&rank=1)2008. CENTRAL
Zhang F, Bigos K, Weinberger D. Genome‐wide analysis of antipsychotic drug response in schizophrenia. Proceedings of the 50th Annual Meeting of the American College of Neuropsychopharmacology; 2011 Dec 4‐8; Waikoloa, Hawaii. 2011; Vol. 50:135. CENTRAL
Zhang WF, Tan YL, Zhang XY, Chan RC, Wu HR, Zhou DF. Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double‐blind, placebo‐controlled trial. Journal of Clinical Psychiatry 2011;72(5):615‐21. [DOI: 10.4088/JCP.09m05125yel]CENTRAL

Apseloff 2000 {published data only}

Apseloff G, Mullet D, Wilner KD, Anziano RJ, Tensfeldt TG, Pelletier SM, et al. The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium. British Journal of Clinical Pharmacology 2000;49(S1):61‐4S. CENTRAL

Bjorndal 1980 {published data only}

Bjorndal N, Casey DE, Gerlach J. Enkephalin, morphine, and naxoxone in tardive dyskinesia. Psychopharmacology 1980;69:133‐6. CENTRAL

Blum 1984 {published data only}

Blum I, Munitz H, Shalev A, Roberts E. Naloxone may be beneficial in the treatment of tardive dyskinesia. Clinical Neuropharmacology 1984;7(3):265‐7. CENTRAL
Blum I, Nisipeanu PF, Roberts E. Naloxone in tardive dyskinesia. Psychopharmacology Berlin 1987;93(4):538. CENTRAL

Bockenheimer 1976 {published data only}

Bockenheimer S, Lucius G. Deanol in tardive dyskinesia: a double‐blind study [Zur Therapie mit Dimethylaminoathanol (Deanol) bei neuroleptikainduzierten extrapyramidalen Hyperkinesen]. Archiv für Psychiatrie und Nervenkrankheiten 1976;222(1):69‐75. CENTRAL

Bowers 1979 {published data only}

Bowers MB, Moore D, Tarsy D. Tardive dyskinesia: a clinical test of the supersensitivity hypothesis. Psychopharmacology Berlin 1979;61(2):137‐1. CENTRAL

Casey 1981 {published data only}

Blum I, Nisipeanu PF, Roberts E, Casey DE, Korsgaard S, Gerlach J. Des‐tyr‐gamma‐endorphin in tardive dyskinesia. Proceedings of the 3rd World Congress of Biological Psychiatry 1981 Jun 28‐Jul 3; Stockholm, Sweden;93:538. CENTRAL
Casey DE, Korsgaard S, Gerlach J. Des‐tyr‐gamma‐endorphin in tardive dyskinesia. Proceedings of the World Congress of Biological Psychiatry; 1981 June 28‐ July 3rd; Stockholm, Sweden. 1981. CENTRAL
Casey DE, Korsgaard S, Gerlach J, Jorgensen A, Simmelsgaard H. Effect of des‐tyrosine‐gamma ‐endorphin in tardive dyskinesia. Archives of General Psychiatry 1981;38(2):158‐60. CENTRAL

Chaplin 2002 {published data only}

Chaplin R, Kent A. Informing patients about tardive dyskinesia: controlled trial of patient education. British Journal of Psychiatry 1998;172:78‐81. CENTRAL
Chaplin R, Timehin C. Informing patients about tardive dyskinesia: Four‐year follow up of a trial of patient education. Australian and New Zealand Journal of Psychiatry 2002;36(1):99‐103. [DOI: http://dx.doi.org/10.1046/j.1440‐1614.2002.00979.x]CENTRAL
Chaplin R, Zipursky RB. An educational session on tardive dyskinesia increased patients' knowledge at 6 months without affecting compliance or clinical stability. Evidence‐Based Medicine 1998;3:153. CENTRAL

Emsley 2002 {published data only}

Emsley R, Myburgh C, Oosthuizen P, Van Rensburg SJ. Randomized, placebo‐controlled study of ethyl‐eicosapentaenoic acid as supplemental treatment in schizophrenia. American Journal of Psychiatry 2002;159(9):1596‐8. CENTRAL

Fann 1973 {published data only}

Fann WE, Davis JM, Wilson IC. Methylphenidate in tardive dyskinesia. American Journal of Psychiatry 1973;130(8):922‐4. CENTRAL

Fudge 1991 {published data only}

Fudge RC, Thailer SA, Alpert M, Intrator J, Sison CE. The effects of electromyographic feedback training on suppression of the oral‐lingual movements associated with tardive dyskinesia. Biofeedback and Self‐Regulation 1991;16(2):117‐29. CENTRAL

Gardos 1978 {published data only}

Gardos G, Cole JO. Pilot study of cyproheptadine (Periactin) in tardive dyskinesia. Psychopharmacolgy Bulletin 1978;14(2):18‐20. CENTRAL

Gerlach 1975 {published data only}

Gerlach J, Thorsen K, Munkvad I. Effect of lithium on neuroleptic‐induced tardive dyskinesia compared with placebo in a double‐blind cross‐over trial. Pharmakopsychiatrie, Neuro‐Psychopharmakologie 1975;8(2):51‐6. [DOI: 10.1055/s‐0028‐1094443]CENTRAL

Goetz 2013 {published data only}

Goetz C, Stebbins G, Chung K, Hauser R, Miyasaki J, Nicholas A, et al. No PD dyskinesia scale protects against placebo responses: A comparison of multiple scales. Neurology 2013;80(7):Supplement P04.187. CENTRAL
Goetz CG, Stebbins GT, Chung KA, Hauser RA, Miyasaki JM, Nicholas AP, et al. No PD dyskinesia scale protects against placebo responses: A comparison of seven scales. Movement disorders 2013;28:S115‐6. CENTRAL

Huang 1981 {published data only}

Huang CC, Wang RIH, Hasegawa A, Alverno L. Evaluation of reserpine and alpha‐methyldopa in the treatment of tardive dyskinesia. Psychopharmacology Bulletin 1980;16:41‐3. CENTRAL
Huang CC, Wang RIH, Hasegawa A, Alverno L. Reserpine and alpha‐methyldopa in the treatment of tardive dyskinesia. Psychopharmacology 1981;73:359‐62. CENTRAL

Jus 1974 {published data only}

Jus K, Jus A, Gautier J, Villeneuve A, Pires P, Pineau R, et al. Studies on the action of certain pharmacological agents on tardive dykinesia and on the rabbit syndrome. International Journal of Clinical Pharmacology 1974;9(2):138‐45. CENTRAL

Jus 1978 {published data only}

Jus A, Villeneuve A, Gautier J, Jus C, Villeneuve P, Pires P, et al. Deanol, lithium and placebo in the treatment of tardive dyskinesia: A double‐blind crossover study. Neuropsychobiology 1978;4:140‐9. CENTRAL

Kabes 1982 {published data only}

Kabes J, Sikora J Pisvejc J Skoudia V. Piracetam action in neuroleptic induced extrapyramidal side‐effects. Proceedings of the 12th CINP congress; Supplement to Progress in Neuropsychopharmacology. Pergamon Press, 1980. CENTRAL
Kabes J, Sikora J, Pisvejc J, Hanzlicek L, Skondia V. Effect of piracetam on extrapyramidal side effects induced by neuroleptic drugs. International Pharmacopsychiatry 1982;17(3):185‐92. CENTRAL
Kabes J, Sikora J, Pisvejc J, Skoudia V. Piracetam action in neuroleptic induced extrapyramidal side‐effects. Proceedings of the 12th Collegium Internationale Neuro‐Psychopharmacologicum Congress; 1980 Jun 22‐26; Goteborg, Sweden. 1980. CENTRAL
Kabes J, Sikora J, Stary O, Piisvejc J, Hanzlicek L. Piracetam effectivity in tardive dyskinesia. A double‐blind placebo‐controlled cross‐over trial. Ceskoslovenska Psychiatrie 1983;79(5):339‐45. CENTRAL
Sikora J, Kabes J, Pisvejc J. Management of neuroleptic side‐effects with piracetam. Ceskoslovenska Psychiatrie 1981;77(2):137‐42. CENTRAL

Kabes 1985 {published data only}

Kabes J, Sikora J, Stary O, Pisvejc J. Dose‐dependent effect of piracetam in tardive‐dyskinesia ‐ double‐blind placebo controlled trial. Activitas Nervosa Superior 1985;27(1):64‐6. CENTRAL

Koller 1982 {published data only}

Koller WC, Barr A, Biary N. Estrogen treatment of dyskinetic disorders. Neurology 1982;32(5):547‐9. CENTRAL

Korsgaard 1981 {published data only}

Korsgaard S, Casey DE, Damgaard‐Pedersen NE, Jorgensen A, Gerlach J. Vasopressin in anergic schizophrenia: a cross‐over study with lysine‐8‐vasopressin and placebo. Psychopharmacology 1981;74(4):379‐82. CENTRAL

Lieberman 1987 {published data only}

Lieberman JA, Kane JM, Sarantakos S, Gadaleta D, Woerner M, Alvir J, et al. Prediction of relapse in schizophrenia. Archives of General Psychiatry 1987;44:597‐603. CENTRAL

Lieberman 1994 {published data only}

Lieberman JA, Alvir J, Geisler S, Ramos Lorenzi J, Woerner M, Novacenko H, et al. Methylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia. Neuropyschopharmacology 1994;11:107‐18. CENTRAL

Lindenmayer 1988 {published data only}

Lindenmayer JP, Gardner E, Goldberg E, Opler LA, Kay SR, Van Praag HM, et al. High‐dose naloxone in tardive dyskinesia. Psychiatry Research 1988;26(1):19‐28. CENTRAL

Moore 1980 {published data only}

Moore DC, Bowers MB. Identification of a subgroup of tardive dyskinesia patients by pharmacologic probes. American Journal of Psychiatry 1980;137(10):1202‐5. CENTRAL

Nasrallah 1986 {published data only}

Nasrallah HA, Dunner FJ, McCalley Whitters M, Smith RE. Pharmacologic probes of neurotransmitter systems in tardive dyskinesia: implications for clinical management. Journal of Clinical Psychiatry 1986;47(2):56‐9. CENTRAL

Peselow 1989 {published data only}

Peselow ED, Irons S, Rotrosen J, Alonso MT, Dorsey F. GM1 ganglioside as a potential treatment in tardive dyskinesia. Psychopharmacology Bulletin 1989;25(2):277‐80. CENTRAL
Sommer BR, Cohen BM, Satlin A, Cole JO, Jandorf L, Dorsey F. Changes in tardive dyskinesia symptoms in elderly patients treated with ganglioside GM1 or placebo. Journal of Geriatric Psychiatry and Neurology 1994;7:234‐7. CENTRAL

Prange 1973 {published data only}

Prange A, Wilson JC, Morris CE, Hall CD. Preliminary experience with tryptophan and lithium in the treatment of tardive dyskinesia. Psychopharmacology Bulletin 1973;9:36‐7. CENTRAL

Reda 1974 {published data only}

Reda FA, Escobar JJ, Scanlon JM. Lithium carbonate in the treatment of tardive dyskinesia. American Journal of Psychiatry 1975;132:560‐2. CENTRAL
Reda FA, Scanlon JM, Kem K, Escobar JJ. Treatment of tardive dyskinesia with lithium carbonate. New England Journal of Medicine 1974;291:850. CENTRAL

Reker 1982 {published data only}

Reker D, Anderson B, Yackulic C, Cooper TB, Banay‐Schwartz M, Leon C, et al. Naloxone, tardive dyskinesia, and endogenous beta‐endorphin. Psychiatry Research 1982;7(3):321‐4. CENTRAL
Volavka J, Anderson B, Koz G. Naloxone and naltrexone in mental illness and tardive dyskinesia. Annals of New York Academy of Sciences 1982;398:97‐102. CENTRAL

Shah 2012 {published data only}

Shah BB, Connolly B, Mestre TA, Prashanth LK, Miyasaki JM, Steeves T, et al. Famotidine for the treatment of levodopa‐induced dyskinesia: An ongoing "N‐of‐1'' Study. 26th Annual Symposium on Etiology, Pathogenesis and Treatment of Movement Disorders. 2012. CENTRAL

Simpson 1976 a {published data only}

Simpson GM, Branchey MH, Lee JH, Voitashevsky A, Zoubok B. Lithium in tardive dyskinesia. Pharmakopsychiatrie neuro‐psychopharmakologie 1976;9(2):76‐80. CENTRAL

Simpson 1976 b {published data only}

Simpson GM, Zoubok B, Lee JH. An early clinical and toxicity trial of EX 11‐582A in chronic schizophrenia. Current Therapeutic Research 1976;19(1):87‐98. CENTRAL

Tamminga 1983 {published data only}

Nguyen JA, Thaker GK, Tamminga CA. Gamma‐aminobutyric‐acid (GABA) pathways in tardive dyskinesia. Psychiatric Annals 1989;19(6):302‐9. CENTRAL
Tamminga CA, Thaker GK, Ferraro TN, Hare TA. GABA agonist treatment improves tardive dyskinesia. Lancet 1983;2:97‐8. CENTRAL
Tamminga CA, Thaker GK, Goldberg ST. Tardive dyskinesia: GABA agonist treatment. In: Usdin E, Carlsson A, Dahlstrom A, Engel J editor(s). Catecholamines: Neuropharmacology and Central Nervous System ‐ Therapeutic Aspects. New York: Alan R Liss, 1994. CENTRAL

Vaddadi 1989 {published data only}

Vaddadi KS, Courtney P, Gilleard CJ, Manku M. A double blind trial of essential fatty acid supplementation in patients with tardive dyskinesia. Psychiatry Research 1989;27(3):313‐23. CENTRAL
Vaddadi KS, Gileard CJ. Essential fatty acids, tardive dyskinesia, and schizophrenia. Pathophysiology and Roles in Clinical Medicine. Wiley‐Liss, 1990:333‐43. CENTRAL

Vaddadi 2002 {published data only}

Vaddadi KS, Soosai E, Chiu E, Dingjan P. A randomised, placebo‐controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Neuroreport 2002;13(1):29‐33. CENTRAL

Villeneuve 1970 {published data only}

Villeneuve A, Böszörményi Z. Treatment of drug‐induced dyskinesias. Lancet1970. CENTRAL

Villeneuve 1980 {published data only}

Villeneuve A, Cazejust T, Cote M. Estrogens in tardive dyskinesia in male psychiatric patients. Neuropsychobiology 1980;6(3):145‐51. CENTRAL

Volavka 1986 {published data only}

Volavka J, O'Donnell J, Muragali R, Anderson BG, Gaztanaga P, Boggiano W, et al. Lithium and lecithin in tardive dyskinesia: an update. Psychiatry Research 1986;19(2):101‐4. CENTRAL

Wonodi 2004 {published data only}

Wonodi I, Adami H, Sherr J, Avila M, Hong LE, Thaker GK. Naltrexone treatment of tardive dyskinesia in patients with schizophrenia. Journal of Clinical Psychopharmacology 2004;24(4):441‐5. CENTRAL

Fernandez 2016 {published data only}

EUCTR‐003135‐19‐PL. A randomized, double‐blind, placebo‐controlled, fixed‐dose study of sd‐809 (deutetrabenazine) for the treatment of moderate to severe tardive dyskinesia ‐ addressing involuntary movements in tardive dyskinesia (aim‐td) study. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014‐003135‐19‐PL2014. CENTRAL
Fernandez HH, Factor SA, Hauser RA, Jimenez‐Shahed J, Ondo W, LeDoux MS, et al. A randomized, double‐blind, placebo‐controlled trial of deutetrabenazine for the treatment of tardive dyskinesia (ARM‐TD). Movement Disorders 2016;31:S294. CENTRAL
NCT02195700. A randomized, double‐blind, placebo‐controlled study of SD‐809 (Deutetrabenazine) for the treatment of moderate to severe tardive dyskinesia. www.Clinicaltrials.gov2014. CENTRAL

Hauser 2016 {published data only}

Factor SA, Hauser RA, Siegert S, Liang GS, O'Brien CF. KINECT 3: A randomized, double‐blind, placebo‐controlled phase 3 trial of valbenazine (NBI‐98854) for tardive dyskinesia. Movement Disorders 2016;31:S692. CENTRAL
Grigoriadis D, Comella C, Remington G, Jimenez R, Burke J, Christopher O. Efficacy of Valbenazine (NBI‐98854) in in subjects with tardive dyskinesia: results of a long‐term extension study (KINECT 3 Extension). Neuropsychopharmacology 2016;41:S213‐4. CENTRAL
Hauser R, Factor S, Marder S, Knesevich MA, Ramirez PM, Jimenez R, et al. KINECT 3: A randomized, double‐blind, placebo‐controlled phase 3 trial of valbenazine (NBI‐98854) for tardivedyskinesia. Neurology. 68th American Academy of Neurology Annual Meeting, 2016; Vol. 86 (16 SUPPL. 1). CENTRAL
NCT02274558. A phase 3 study of NBI‐98854 for the treatment of tardive dyskinesia. https://clinicaltrials.gov/ct2/show/NCT02274558 (accessed on 6 October 2017)2014. CENTRAL

NCT01393600 2011 {published data only}

NCT01393600. Nbi‐98854 for the treatment of tardive dyskinesia in subjects with schizophrenia or schizoaffective disorder. www.Clinicaltrials.gov2011. CENTRAL

Pattojoshi 2016 {published data only}

Pattojoshi A, Khan AH, Lavania S. Effect of right DLPFC‐repetitive transcranial magnetic stimulation (rTMS) on tardive dyskinesia in patients with psychosis. Movement Disorders 2016;31:S691‐2. CENTRAL

Xu 2012 {published data only}

Xu X. A randomized controlled study of Ginkgo biloba extract on tardive dyskinesia [银杏叶提取物治疗迟发性运动障碍的随机对照研究]. Journal of Chinese Physician 2012;14(6):843‐845. CENTRAL

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Garcia G, Crismon ML. Double‐blind placebo controlled study using buspirone in the treatment of tardive dyskinesia. ASHP Midyear Clinical Meeting 1992;27:P‐91. CENTRAL

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ISRCTN14688109. Investigation of the potential beneficial effects of cannabidiol in the treatment of tardive dyskinesia. http://www.isrctn.com2015. CENTRAL

NCT00621634 2008 {published data only}

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NCT01391390 2011 {published data only}

NCT01391390. Melatonin treatment for tardive dyskinesia in schizophrenia. www.Clinicaltrials.gov2011. CENTRAL

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NCT01804920. D‐Serine treatment for tardive dyskinesia. www.Clinicaltrials.gov2013. CENTRAL

NCT02291861 2014 {published data only}

NCT02291861. Addressing involuntary movements in tardive dyskinesia. www.ClinicalTrials.gov2014. CENTRAL

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bucci 1971

Methods

Allocation: random, further details not reported.

Blindness: not reported.

Duration: 40 weeks.

Design: parallel.

Setting: outpatients, USA (probably).

Participants

Diagnosis: chronic schizophrenia treated with phenothiazine for several years and demonstrating obvious dyskinetic manifestations.

N = 20

Sex: 16 female and 4 male

Age: range 45‐62 years

History: at least two years of TD.

Interventions

1. Procyclidine (Anticholinergic), 5 mg twice a day + chlorpromazine, 100 mg three times a day N = 10.
2. Isocarboxazid (MAOI), 10 mg twice a day + chlorpromazine, 100 mg three times a day N = 10.

Continuous phenothiazine‐antiparkisonian treatment for at least 2 years. .

Other concomitant medication was not reported.

Outcomes

TD symptoms (clinical evaluation, scale not reported)

Leaving the study early

Adverse events

Unable to use ‐

Mental state (data not reported for both groups)

Notes

Sponsorship source: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“The patients were divided at random into groups of 10 each”, no further details reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Blinding of participants and personnel not reported.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Blinding of outcome assessment not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

“One male patient on chlorpromazine and isocarboxazid was discontinued after 6 weeks as he became increasingly tense, apprehensive and sleepless”

Selective reporting (reporting bias)

High risk

Adverse effects reported only as those related to treatment. Mental state data not reported for group 2. Unclear if all outcomes have been reported, a protocol is not available for verification.

Other bias

Unclear risk

Insufficient information to make a judgement

Cai 1988

Methods

Allocation: not reported.
Blinding: double‐blind.
Duration: 8 weeks.

Design: parallel

Setting: not reported.

Participants

Diagnosis: antipsychotic‐induced TD;

N = 57

Sex: 33 male and 24 female 24

Age: mean 39.5 (SD 10.3) years old, range 28‐59

History: Duration of TD on average 2.4 (SD 1.8) years. Patients assigned to the treatment group were stable to AP dose from 0.7 to 27 years, whereas patients assigned to the control group were stable to AP dose from 1 to 10 years before start of study.

Interventions

1. L‐stepholidine (SPD) Group: Management: L‐stepholidine was prescribed two tablets each time, three times per day for 8 weeks. N = 42

2. Placebo Group: The placebo with similar appearance to L‐stepholidine was prescribed two tablets each time, three times per day for 8 weeks. N = 15

All participants received stable AP and concomitant anticholinergic drug.

Other concomitant medication is not reported.

Outcomes

Clinical improvement on TD symptoms: no definition.
Clinical improvement on psychosis symptoms: no definition.
Mental state: BPRS
Adverse event: any adverse events

‐‐Unable to use
TESS, (the author did not report the data)
Blood routine examination, urine routine test and liver function test, electrocardiography. (the author only stated results of these tests were normal but did not report the data)

Notes

Twenty cases from the SPD group received blood routine examination, urine routine test and liver function test; five cases received electrocardiography. Ten cases in each group received BPRS and TESS measurements.

We attempted to contact the study author for information on randomisation, but were informed he had retired.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...randomized, parallel‐group..." no further details.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"double blind" "The placebo with similar appearance", Blinding of participants and key study personnel ensured.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"double blind" "The placebo with similar appearance", Blinding of participants and key study personnel ensured.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the trial.

Selective reporting (reporting bias)

High risk

The author did not report the outcome: TESS, Blood routine examination, urine routine test and liver function test, electrocardiography

Other bias

Unclear risk

No further details reported

Castro 2011

Methods

Allocation: randomised.
Blindness: "double blind".
Duration: 12 weeks.
Design: parallel.
Setting: inpatients and outpatients, Venezuela

Participants

Diagnosis: Psychiatric patients meeting DSM‐IV‐TR diagnostic criteria for the diagnosis of antipsychotic‐induced TD.

N = 13.
Sex: 4 female and 9 male
Age: mean (SD) 59.9 (2.7) years; range 46‐75 years.
History: Duration of TD not reported. Most of the patients have been receiving the same antipsychotic treatment for at least 3 years up to 10 years. Antipsychotics received were levomepromazine (9 patients), haloperidol (4), clozapine (2), aripiprazole (2), olanzapine (1), quetiapine (1) and risperidone (1).

Interventions

1. Melatonin: 20 mg/day. N = 7. Duration: 12 weeks.

2. Placebo: N = 6. Duration: 12 weeks.

All individuals who participated faithfully complied with antipsychotic treatment and maintained it throughout the study.

Other concomitant medication: The treatment with anticholinergics was maintained for ethical reasons. In each of the groups two patients received biperidine. Other treatments applied were, in the melatonin group, valproic acid (1 patient), carbamazepine (1 patient), alprazolam (1 patient), indapamide (1 patient); in the placebo group: carbamazepine (2 patients), chlorimipramine (2 patients) and lithium carbonate (1 patient). During the study there were no dosage adjustments.

Outcomes

Tardive dyskinesia: Brief Psychiatric Rating Scale (BPRS)

Tardive dyskinesia: symptoms: AIMS

Adverse events: other observed effects.
Leaving the study early

Notes

This study was supported by the Instituto Venezolano de Investigaciones Científicas (IVIC), Venezuela

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"The individuals selected were divided randomly into two groups", no further details.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"A group of 6 patients received placebo capsules, identical in appearance".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double blind". Blinding of outcome assessors not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the trial.

Selective reporting (reporting bias)

Unclear risk

Unclear if all pre‐defined outcomes were reported. A protocol is not available for verification.

Other bias

Low risk

The study seems to be free of other sources of bias.

Emsley 2006

Methods

Allocation: randomised.
Blindness: double‐blind.
Duration: 12 weeks.
Design: parallel.
Setting: inpatients and outpatients, South Africa.

Participants

Diagnosis: schizophrenia, schizoaffective disorder with TD (DSM‐IV).
N = 84.
Sex: 51 male and 26 female
Age: mean 42 years.
History: Duration of TD more than 5 years. Patients were stabilised for at least 6 months prior to trial.

Interventions

1. Ethyl‐eicosapentaenoic acid (omega‐3 fatty acid eicosapentaenoic acid derivative): dose 2 g/day + antipsychotics. N = 42.
2. Placebo + antipsychotics. N = 42.

Patients who were stabilised on other psychotropic medications (anxiolytic, hypnotic, antidepressant, mood stabilising) before entry to the trial were allowed to continue on these medications; anticholinergic medication for treatment‐emergent extrapyramidal symptoms (EPS); anxiolytic or hypnotic medication for treatment emergent insomnia or acute anxiety; any medication for physical conditions that was taken prior to the commencement of the trial could be continued; medication for other conditions that arose during the course of the trial, at the investigator's discretion. Other omega‐3 fatty acid preparations, additional antipsychotics or antidepressants were not permitted.

Outcomes

Extrapyramidal symptoms: ESRS

Mental state deterioration

Leaving the study early.
Unable to use ‐
Mental state: PANSS (no usable data).
Global state: CGI (no usable data)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...randomized, parallel‐group..." no further details.

Allocation concealment (selection bias)

Unclear risk

No details.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"...double‐blind..." "Subjects were randomly assigned to receive either an encapsulated ethyl‐EPA supplement 2 g/day... or an identical capsule containing placebo (medicinal liquid paraffin BP 2 g/day)... Trial supplies were packed by an independent contract clinical trials supplies company (DHP), who prepared the placebo and active packs for the entire trial and assigned the randomization numbers to the packs. The randomization code was broken after completion of the trial".

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessors for efficacy outcomes (TD symptoms and Mental State) not reported. Adverse events blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Overall drop‐out rate: 35%. 7/84 (8%) participants dropped out before the first post‐randomisation visit. 7/84 (8%) participants were not included in the analysis. "Data from... 77 patients were included in the final analysis". "The number of subjects who discontinued medication prematurely in the ethyl‐EPA group was 8 (19%) (consent withdrawal n=4; non‐compliance n=3; protocol violation n=1), and in the placebo group 14 (33%) (consent withdrawal n=9; non‐compliance n=3; adverse events n=2 (congestive cardiac failure; nose‐bleed) (Chisquare=2.2, df=1, p=0.1)."

It seems that these participants were included in the analysis.

Selective reporting (reporting bias)

High risk

Data for some outcomes stated in the protocol have not been reported (e.g. remission, CGI severity)

Other bias

Unclear risk

"The demographic characteristics and baseline PANSS scores in the two treatment groups were similar, but baseline ESRS dystonia subscale and TD CGI scores differed significantly".

Unclear if the differences (confounding variables) may be biased

Gardos 1979

Methods

Allocation: "randomised" unclear.
Blindness: single‐blind.
Duration: 12 weeks. (6 weeks then crossed over to another 6 weeks. Washout period unknown)
Design: cross‐over.

Setting: inpatients, USA

Participants

Diagnosis: psychogeriatric (23) and schizophrenic (18) patients with obvious TD.
N = 41
Sex: 28 female and 13 male.
Age: mean 64 years, range 32‐84 years.

History: Duration of TD not reported.

Interventions

1. Papaverine: dose 150 mg/day twice a day for the first week and 300 mg twice a day for the subsequent 5 weeks. N = 21.
2. No treatment: 6 weeks (followed by 6 weeks of papaverine). N = 20.

Concomitant medication: antipsychotics, antidepressants, anxiolytics, or no medication. No changes were made in psychotropic drug administration during the study.

Outcomes

TD symptoms: AIMS (only reported for Boston sample)

Unable to use (not reported for first treatment phase before cross‐over)

Leaving the study early

Adverse effects: Parkinsonism

Notes

Sponsorship source: Supported in part by a grant from the Drug Abuse and Mental Health Administration of HEW.

* Authors state that the two samples differed greatly in the incidence and severity of tardive dyskinesia prior to the study. The differences were to a large extent due to the differences in the two populations: Boston patients were older with longer duration of disability and hospitalizations and showed more extensive dyskinesia. In view of the major differences in the populations, data from the two groups were analysed separately.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"random order", further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

"single‐blind". As the participants were randomised to receive papaverine or not, neither the participants nor the study personnel could have been blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"A single blind design was used with blind raters and a 6‐weeks no drug control condition."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Although not clearly reported, it seems that 1/23 participants in the Boston sample and 0/18 participants in the Kentucky sample were withdrawn from the study.

Selective reporting (reporting bias)

Unclear risk

Unclear if all predefined outcomes have been reported. Also, the reason for not assessing TD symptoms using AIMS in the Kentucky sample is not reported.

Other bias

Unclear risk

The two samples were very different in their baseline characteristics. However, this was controlled by reporting data separately. Unclear if there might have been other confounding variables to affect bias.

Glazer 1985

Methods

Allocation: randomised.
Blindness: double‐blind.
Duration: 3 weeks.
Design: parallel.
Setting: Outpatients, Connecticut Mental Health Center, USA

Participants

Diagnosis: psychiatric disorder (no operational criteria) and Schooler&. Kane's criteria for TD
N = 12.
Sex: 12 females.
Age: 50‐65 years, mean 57 years.
History: Duration of TD on average 32.3 months (range 6‐60 months). Patients maintained their antipsychotic medication

Interventions

1. Oestrogen: 1.25 mg/day. N = 6.*
2. Placebo. N = 6.

Nine of the 10 patients were on medications other than antipsychotics; 7 were on psychiatric medication. Further details not provided.

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores .
Adverse events: other observed effects.
Leaving the study early.

Unable to use ‐
Adverse events: Parkinson scores (no data).
Mental state: BPRS (no data).

Notes

Sponsorship source: Supported by HD 13587 and Ayerst Pharmaceuticals

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomized". Details not reported

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind". Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

TD related and mental state outcomes: "double‐blind". "All ratings were administered without knowledge of the study status of the individual subject. Patients were videotaped during the research nurse's rating on visits 1 and 4. These tapes were subsequently rated by a senior psychiatric resident who administered the AIMS and counted the frequency of abnormal movements of the most severely affected anatomical region as determined by the study psychiatrist during the baseline assessment".

Details of blinding not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Twelve patients were admitted to the study, and 10 completed the 3‐week trial. One patient in the placebo group was hospitalized for congestive heart failure. One patient in the oestrogen group required psychiatric hospitalization after taking an overdose of medications; she had been depressed at the onset of the trial and became worse at the third visit during a period of severe marital discord."

Balance between groups, reasons reported.

Selective reporting (reporting bias)

High risk

TD symptoms data not reported as mean (SD) but rather as mean only (table 1). Data for Mental state (BPRS) not reported. Adverse effects reported only as adverse events leading to study discontinuation.

Other bias

High risk

"Although our study involved randomization and double‐blind drug procedures to prevent bias, the small sample size resulted in some imbalances between groups at the first visit. Thus, the conjugated oestrogen group had less exposure to antipsychotic medication and a shorter duration of TD. They also had higher mean baseline AIMS scores than did the placebo group, thereby leaving more possibility for improvement in scores. The small sample size does not allow statistical analysis to adjust for these differences. Although we found a positive but non‐significant association between duration of TD and decrease in AIMS score between visits 1 and 4, we doubt that TD duration is a confounding factor, since the direction of this association is the opposite of what we would have expected".

Glover 1980

Methods

Allocation: randomised.
Blindness: not mentioned.
Duration: 8 sessions.
Design: parallel.
Setting: Outpatients, USA

Participants

Diagnosis: Diagnosis of chronic schizophrenia; diagnoses of either acute extra pyramidal symptoms, TD, and/or pseudoparkinsonism.
N = 15.
Sex: 12 females and 3 males.
Age: mean 34.9 years.
History: Duration of TD not reported. Not reported whether patients were stabilised prior to study.

Interventions

1. Hypnosis: 8 sessions. N = 5.
2. Relaxation. 8 sessions. N = 5.

3. Treatment as usual (control group). 8 sessions. N = 5.

Psychotropic medication continued.

Outcomes

Leaving the study early: number of dropouts

Notes

Sponsorship source: Sponsorship source not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

"There was a total of fifteen subjects randomly selected". "I made the assumption that the order in which patients approached the clinic was not related in any way to their susceptibility or effectiveness of subsequent treatments. Based on these assumptions I assigned the first patient who came into the study to group 1, the second patient '"as assigned to group 2, and the third patient was assigned to Group 3; after every three assignments I started the assignments with group 1 again and continued until each treatment modality had a total of five"

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

As participants in group 1 received hypnosis, those in group 2 received relaxation training, and those in group 3, TAU without any other treatment, blinding could not be achieved

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome assessors not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

There were no refusals, or dropouts among the referrals.

Selective reporting (reporting bias)

Low risk

It seems that all outcomes have been reported. However data are not usable.

Other bias

Unclear risk

"(Tables 1, 2 and 3). Using a non‐parametric test for testing differences on demographic data between treatment groups yielded no significant difference among these groups (Table 7). With respect to the regimen of medication for each patient (Tables 4, 5, 6), there was close similarity in each group. The majority of patients in each group received either haloperidol or trifluoperazine; therefore any alternative treatment differences could not be influenced by medication. However, due to the formula which is used by physicians in dispensing medication, it was not possible to use a statistical procedure for testing the equality of the three groups in this study. The sample size, sex and marital status variables was so small to preclude a statistical test on these two variables."

Goff 1993

Methods

Allocation: "randomly assigned" unclear.
Blindness: double, (identical capsules).
Duration: 6 weeks.
Design: parallel.

Setting: outpatients, USA
Raters: "AIMS were videotaped and scored by a second rater unaware of the temporal sequence of examinations"

Participants

Diagnosis: antipsychotic‐induced TD according to DSM‐III‐R, Schooler and Kane criteria with a score of at least 3 (moderate) on a single item or 2 (mild) on at least two items of the AIMS and have a history of at least 6 months of exposure to a antipsychotic prior to onset of dyskinetic movements.
N = 33
Sex: 13 female and 20 male.
Age: mean 48.8 (SD 9.8) years

Duration TD: not reported.

Interventions

1. Selengiline (L‐Deprenyl): dose 5 mg (one capsule daily for the first week, then one twice daily thereafter) for 6 weeks. N = 17.
2. Placebo for 6 weeks. N = 16

Doses of antipsychotics and anticholinergic agents were stable for at least 4 months before the trial. Patients receiving depot antipsychotic were included only if injections were administered on a biweekly schedule.

Outcomes

TD symptoms: not significant clinically improved (defined as an improvement of more than 50%)

Leaving the study early

Unable to use:

Adverse effects: severity of parkinsonian symptoms and akathisia using SAS, Mental state: BPRS for positive, negative and depressive symptoms, Global assessment scale, Average change in severity of TD using AIMS

Notes

Sponsorship source: Supported by PHS grant

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomly assigned", further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"identical capsules containing either selegiline 5 mg or placebo." "double‐blind"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Examinations with the AIMS were videotaped and scored by a second rater unaware of the temporal sequence of examinations."

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Five subjects, all receiving selegiline, dropped out prior to the completion of week 1 and so were not included in analysis of outcome."

29% drop out in the active medications group, not ITT.

Selective reporting (reporting bias)

High risk

Data not reported for mental state (BPRS total and sub scales), severity of parkinsonian symptoms (SAS)

Other bias

Low risk

The study seems to be free of other sources of bias.

Hajioff 1983

Methods

Allocation: "randomly assigned", no further details.
Blindness: double‐blind
Duration: 14 weeks (2 week run‐in, 6 week treatment, 6 week no‐treatment follow‐up)
Design: parallel

Setting: Inpatients, UK (probably)

Participants

Diagnosis: schizophrenia (9), dementia (3 with paranoid features, 3 without), depression (3), pre‐senile dementia (1). and epileptic psychosis (1).
N = 20.
Sex: 10 female and 5 male.
Age: mean 65.4 (males)‐79.5 (females) years, range 60‐92 years

History: Duration of TD not reported. Seventeen patients were each receiving one antipsychotic drug, thioridazine (5), promazine (5), chlorpromazine (3), haloperidol (2), trifluoperazine (1) and chlomethiazole (1). Their dosage regimen had remained constant for at least 6 months. Two patients with chronic schizophrenia and one with depression were not taking any antipsychotic drugs for the same period.

Interventions

1. 4.5 mg co‐dergocrine mesylate once daily for 6 weeks. N = 10.
2. Placebo once daily for 6 weeks. N = 10.

Only two patients had never received anti‐Parkinsonian drugs, the remainder receiving therapy for various periods of time (3 months to 8 years). Two other patients were receiving anti‐Parkinsonian drugs at a constant dose during the study period. Details of medications, not reported.

Outcomes

The abbreviated dyskinesia scale of the Rockland Research Institute (ADS).

Death.
Leaving study early.

Notes

Sponsorship source not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly assigned", no further details.

Allocation concealment (selection bias)

Unclear risk

Details on allocation concealment were not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double blind", no further details.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Details on blinding of outcome assessment were not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One participant from the placebo group died in the second week of the study (run‐in phase) and was not part of the final analyses.

Selective reporting (reporting bias)

Unclear risk

No details.

Other bias

Unclear risk

No details.

Kojima 1992

Methods

Allocation: randomised, not described.
Blindness: double, not described.
Duration: 8 weeks.
Design: parallel.
Setting: Inpatients and outpatients, Japan

Participants

Diagnosis: schizophrenia (DSM‐III‐R).
N = 85.
Sex: 34 female and 32 male.
Age: 31‐75 years, mean 55.2 years.
History: antipsychotic‐induced TD (mean duration 5 years).

Interventions

1. Ceruletine IM: dose 0.8 mcg/kg/week for 3 weeks. N = 43.
2. Placebo. N = 42.

Previous background medication and treatment held constant throughout trial.

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms.
Adverse events: other observed effects.
Leaving the study early.

Notes

Data presented for 33 matched pairs only.

Sponsorship source: Sponsorship source not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...patients were randomized into matched pairs on the basis of age and sex, and of the severity and duration of TD symptoms." Details not reported

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐ blind", further details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double‐ blind", further details not reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Of the 85 patients who entered the study, eight were excluded from data analysis because of protocol violations (e.g., an insufficient severity of TD symptoms during the baseline period or missing observations)." One patient was discontinued due to adverse event (table 2). Actually, 19 participants were excluded from the analysis (66/85 participants, 33 in each group, were analysed. "Analyses were performed on the 33 pairs (i.e., 33 patients in the ceruletide group vs. 33 patients in the placebo group). p. 131, 1st paragraph.

Selective reporting (reporting bias)

High risk

Judgement Comment: "Of the 85 patients who entered the study, eight were excluded from data analysis because of protocol violations (e.g., an insufficient severity of TD symptoms during the baseline period or missing observations)." "Analyses were performed on the 33 pairs (i.e. 33 patients in the ceruletine group versus 33 patients in the placebo group)"

Other bias

Unclear risk

Insufficient information. Baseline information reported for participants included in the analyses but not for the participants who were not entered to the analysis due to "protocol violations"

Koshino 1979

Methods

Allocation: "randomly allocated", Details not reported.

Blindness: "double‐blind," Details not reported

Duration: 4 weeks

Design: Parallel

Setting: Inpatients in 4 psychiatric hospitals in Japan

Participants

Diagnosis: Schizophrenia (n = 35), others (n = 7), drug‐induced TD

N = 42

Sex: Male 13, Female 29

Age: 56.1 (SD: 8.69)

History: Duration of TD not reported.

Interventions

1. Cyproheptadine (12 mg/day to 24 mg/day Flexible, 4 week). N = 21
2. Placebo. N = 21

Concomitant medication not reported.

Outcomes

Tardive dyskinesia: Assessment scale developed by the researchers

Leaving the study early.

Adverse effects

Notes

Sponsorship source: Cyproheptadine and placebo tablets supplied by Merck‐Banyu Co.Ltd

Assessed and data extracted by Yusuke Ogawa.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated", Details not reported.

Allocation concealment (selection bias)

Low risk

Randomization was conducted by the third person (outside of the research group). Allocation codes were stored until the end of the study

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind," Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double‐blind," Details not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Forty‐two patients were admitted to the study, and 41 completed the 4‐week trial. One patient in the placebo group dropped out due to side effects. Reason reported.

Selective reporting (reporting bias)

Unclear risk

Unclear if all pre‐defined outcomes were reported. A protocol is not available.

Other bias

Unclear risk

Insufficient information to make a judgement.

Koshino 1983

Methods

Allocation: "randomly allocated", Details not reported.

Blindness: "double‐blind," Details not reported

Duration: 6 weeks

Design: Parallel

Setting: Inpatients in a psychiatric hospital in Japan

Participants

Diagnosis: antipsychotic‐induced TD, Schizophrenia

N = 28

Sex: Male 16, Female 12

Age: 59.3 (SD: 8.29)

History: Duration of TD not reported.

Interventions

1. Dihydrogenated Ergot Alkaloids (6 mg/day, 6 week). N = 14
2. Placebo. N = 14

Concomitant medication not reported.

Outcomes

Tardive dyskinesia: Not clinically improved

Tardive dyskinesia: Not any improved

Tardive dyskinesia: Simpson scale

Tardive dyskinesia: Deterioration

Mental state: Not any change in general mental state

Adverse effects general

Leaving the study general

Leaving the study Due to side effect

Notes

Sponsorship source: Dihydrogenated Ergot Alkaloids and placebo tablets supplied by Sandoz

Assessed and data extracted by Yusuke Ogawa.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly allocated", Details not reported.

Allocation concealment (selection bias)

Low risk

Randomization was conducted by the third person (outside of the research group). Allocation codes were stored until the end of the study

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind," Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double‐blind," Details not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Twenty‐eight patients were admitted to the study, and all of them completed the 4‐week trial.

Selective reporting (reporting bias)

Unclear risk

Unclear if all pre‐defined outcomes were reported. A protocol is not available.

Other bias

Unclear risk

Insufficient information to make a judgement.

Libov 2007

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 9 weeks.
Design: cross‐over, 4 weeks treatment one week wash out.
Setting: Inpatients, Be'er Sheva Mental Health Center, Israel.

Participants

Diagnosis: schizophrenia, schizoaffective disorder (DSM‐IV).
N = 40.
Sex: 27 male, 23 female.
Age: 26‐69 years; mean 44.9 (SD 12.4) years.
History: Duration of TD at least 1 year. Patients were stabilised at least one month prior to entry. Antipsychotic medication was not altered.

Interventions

1. Piracetam: dose 4800 mg/day + conventional antipsychotics. N = 21
2. Placebo. N = 19

Twenty‐four patients received various mood stabilisers (lithium, carbamazepine, or valproate) in combination with antipsychotic agents

Outcomes

Tardive dyskinesia: Extrapyramidal System Rating Scale (ESRS).

TD symptoms: not any improvement
Adverse events: other observed effects.
Leaving the study early.

Notes

Sponsorship source: Supported by a Clinical Trials Grant from the Stanley Medical Research Institute, Bethesda, Md.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"subjects were randomized to receive either piracetam or placebo." Details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Both patients and raters were blinded to group allocation." further details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"raters were blinded to group allocation"

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Of the 40 randomly assigned patients, 5 subjects (4 taking placebo and 1 taking piracetam) did not comply with the treatment regimen following the first 2 weeks of the study and were not included in the statistical analysis. Therefore, 35 patients completed phase I, and, of these, 4 patients (2 receiving placebo and 2 receiving piracetam) did not agree to continue to phase II, resulting in 31 patients completing both phases of the crossover protocol. The main reason for patient dropout was the large size and number of the capsules that they were required to take."

In the first phase there was a 12.5% dropout while in the completed cross‐over trial 22.5% dropout. Patients who dropped out were not included in the analysis

Selective reporting (reporting bias)

Low risk

Outcomes defined in the Protocol have been reported. NCT00190008

Other bias

Low risk

The study seems to be free of other sources of bias.

Mackay 1980

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 5 weeks treatment per arm separated by 6 week washout.
Design: cross‐over.
Setting: Chronic inpatients, UK

Participants

Diagnosis: schizophrenia (7), bipolar affective illness (3), depressive psychosis (1) (no diagnostic criteria).
N = 11.
Sex: not described.
Age: 56‐70 years, median 59 years.
History: antipsychotic‐induced TD for at least one year and not pre‐dating antipsychotic treatment; treatment with antipsychotics for a period of at least 2 years.

Interventions

1. Lithium: dose not specified. N = 6.
2. Placebo. N = 5.

Previous background medication and treatment continued throughout trial, patients were receiving a variety of antipsychotic and anxiolytic drugs: 4 patients received no antipsychotic medication.

Outcomes

Tardive dyskinesia: improved/not improved, deterioration in symptoms, Rockland TD scale score.
Adverse events: other observed effects ‐ parkinsonian and drowsiness.
Leaving the study early.

Unable to use ‐
Tardive dyskinesia: SAS (no data).
Mental state: BPRS (no data).
Behavioiur: NOSIE (no data).

Notes

Sponsorship source: Sponsorship source not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"A random Li (Camcolit QDS)/placebo cross‐over design", further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Raters, nurses and patients were blind to treatment. Two non‐blind 'coordinators'... adjusted the oral dose of Li carbonate to aim at a serum concentration between 0.8 and 1.3 mM. Adjustment of U dosage was mirrored by a similar change for the 'placebo twin'" "At completion of the study, the patients, a psychiatrist and nursing staff involved in ratings were asked to guess the nature of the treatment block. There was a choice of 3 alternative answers: inactive tablets, active drug or uncertain. "Analysis of the guesses made by staff and patients as to the sequence of treatments showed that correct guesses occurred randomly. Thus, despite inevitable cues from side‐effects, it seemed that the double‐blind nature of the study was preserved".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Raters, nurses and patients were blind to treatment." "At completion of the study, the patients, a psychiatrist and nursing staff involved in ratings were asked to guess the nature of the treatment block. There was a choice of 3 alternative answers: inactive tablets, active drug or uncertain. "Analysis of the guesses made by staff and patients as to the sequence of treatments showed that correct guesses occurred randomly. Thus, despite inevitable cues from side‐effects, it seemed that the double‐blind nature of the study was preserved".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1/11 participants (in the lithium first group) did not complete the study. Reason not reported.

Selective reporting (reporting bias)

High risk

Mental State and behaviour outcome data not reported. TD symptoms scale scores data not reported.

Other bias

Unclear risk

"Patients were divided, as far as possible into matched for age, sex, severity of TD, duration of psychiatric illness and duration of neuroleptic treatment. Matching for sex was exact and the maximum discrepancies between members for any pair for other variables were as follows: age ± 4 years, total Rockland TD scores ±17, duration of illness ±11years, duration of neuroleptic treatment ±5 years"

Unclear of a discrepancy of ±17 on the total Rockland TD scores is significant.

Matsunaga 1988

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 4 weeks.
Design: parallel group.
Setting: inpatient, Japan

Participants

Diagnosis: chronic psychotic inpatients with TD
N = 47
Sex: 22 female and 15 male
Age: 59 (SD 8.8) years
History: antipsychotic‐induced TD from 7 months to 20 years. Patients stabilised at least 3 weeks prior to entry.

Interventions

1. Ceruletide: 0.8 mcg/kg/week. N = 19.
2. Placebo. N = 18.

Background medication and treatment continued throughout trial.

Outcomes

Tardive dyskinesia: AIMS improved/ not improved, deterioration in symptom.
Adverse events: other observed effects.
Leaving study early.

Notes

Sponsorship source: Shionogi & Co., Ltd., Japan supplied Ceruletide

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"The patients were assigned at random". Details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind" Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double blind" Details not reported.

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Of the original 47 patients, one patient dropped out of the study because of fever of unknown origin. Nine patients in whom assessment of TD symptoms was unreliable either due to the erratic variation in symptomatology or to the emotional or situational effect unrelated to the drug treatment, were excluded from the final analyses before opening of the key code. Thus, 37 patients were available for analysis, 19 receiving Ceruletide and 18 receiving placebo".

Data not reported for 21% of the participants.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to make a judgement. A protocol is not available to verify all outcomes defined prior to study.

Other bias

Low risk

The study seems to be free of other sources of bias.

Meco 1989

Methods

Allocation: randomised.
Blindness: double‐blind.
Design: cross‐over.

Setting: inpatients, Italy.
Duration: 30 days (then crossed over to another 30 days).

Participants

Diagnosis: Chronic schizophrenia (DSM‐III‐R criteria) and suffering from antipsychotic‐induced TD previously untreated with other drugs.
N = 10.
Age: mean 57 years, range 33‐72 years.
Sex: 5 Male and 5 Female
History: Duration of TD ranging from 0.5 to 3 years; Eight patients received anticholinergic drugs before TD; Duration of antipsychotic therapy ranging from 4 to 15 years.

Interventions

No washout period was reported before trial entry.

1. Ritanserin: dose 10 mg three times a day for 30 days. N = 4.

2. Placebo for 30 days. N = 6.

Concomitant medication: The patients continued receiving their basic treatment for the psychosis (i.e. haloperidol, lorazepam, haloperidol decanoate, chlorpromazine, clotiapine, thioridazine)

Outcomes

TD symptoms (AIMS): not clinically improved, not improved, deteriorated

Mental state: BPRS

Notes

Sponsorship source: Sponsorship source not reported

Results are presented for each phase

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Six patients, chosen at random (patients 1‐6; group A), first received the placebo and then ritanserin; the other four patients (patients 7 ‐10; group B) received treatment in the reverse order"

Further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind" Details not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double‐blind" Details not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Participant flow through the study is not clearly reported. However, full data for all participants have been reported for all visits including post intervention.

Selective reporting (reporting bias)

Unclear risk

All outcomes seem to have been reported. However, a protocol is not available for verification.

Other bias

Low risk

The study seems to have been free of other sources of bias.

Mosnik 1997

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 2 days (1 day/single dose crossed over to another day/single dose)
Design: cross‐over.
Setting: Inpatients and outpatients, USA.

Participants

Diagnosis: schizophrenia (DSM‐III‐R).
N = 18.
Sex: 18 male.
Age: 28‐65 years, mean 44 (SD 11.8) years.
History: currently receiving antipsychotics, clinically significant TD. Duration of TD nor reported. Patient stabilisation prior to study entry not reported.

Interventions

1. Phenylalanine: 100 mg/kg body weight (day 1) followed by placebo (day 2). N = 10.
2. Placebo: (day 1) followed by phenylalanine 100mg/kg body weight (day 2). N = 8.

Background medication and treatment continued throughout trial.

Outcomes

Leaving the study early.

Unable to use ‐
Tardive dyskinesia: AIMS endpoint score (not reported for placebo group or not reported for the first treatment phase before crossing over to the next treatment)

Cognitive ability: Rey Auditory Verbal Learning Test (AVLT) (not reported for the first treatment phase before crossing over to the next treatment)

Mental state: SANS & SAPS (modified version of scales used).
Cognitive ability: Edinburgh Inventory test (no data)

Notes

Sponsorship source: Supported in part by a VA Merit Review grant to one of the authors by The National Institute of Mental Health Grants to a second author, and a NARSAD Young Investigator Award to a third author.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomized..." Details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Drinks were prepared by an assistant and administered by the first author in a double blind manner". "The fine white L‐phenylalanine powder could not be tasted or detected visually when mixed with the bright orange colored powder." Thus, patients may have been blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"TD ratings were performed double‐blind". No further details are reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"One subject in the group who received phenylalanine on the first day, left the hospital against medical advice after completing only 1 day of the study; however, his data were included in the analyses"

Selective reporting (reporting bias)

Unclear risk

Not all data are fully reported. Some data are reported partially. No protocol are available

Other bias

Low risk

The study seems to be free of other sources of data

Mouret 1991

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 12 weeks.
Design: parallel.
Setting: inpatients, Morocco

Participants

Diagnosis: schizophrenia (DSM‐III).
N = 20.
Sex: 7 female and 13 male
Age: 20‐67 years, mean 38.3 years.
History: chronic with antipsychotic‐induced TD. Duration of TD from 1 to 9 years. The antipsychotic therapy was maintained at the same dose but it is not clear the duration of stabilisation prior to study entry.

Interventions

1. Insulin, 'standard' type: 10 units/day for 15 days administered at 10:00am; weekly for 5 weeks thereafter. N = 10.
2. Placebo. N = 10.

Background medication and treatment continued throughout trial.

Anticholinergics were withdrawn at least 2 weeks prior to the beginning of the study

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores.
Leaving the study early.

Notes

Sponsorship source: Standard Insulin or placebo supplied by Novo Industry.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"They were randomly assigned..." Details not reported.

Allocation concealment (selection bias)

Unclear risk

Judgement Comment: Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"...double‐blind... " "The patients and the rater were blind to treatment conditions" Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"...double‐blind... " "The patients and the rater were blind to treatment conditions". Details not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Attrition information has not been reported. However, as end of trial data had been individually reported for all randomised participants, it is assumed that all participants completed the trial

Selective reporting (reporting bias)

Unclear risk

Insufficient information to make a judgement. A protocol is not available to verify all outcomes defined prior to study.

Other bias

Unclear risk

"At day 0, all 20 patients had severe orofacial dyskinesia and the two groups of patients did not differ in scores, age, duration of disease. Neuroleptic treatment was however significantly (p=0.037) longer in the placebo group than in the insulin group".

Unclear if this could have influenced bias.

O'Brien 2014

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 6 weeks.
Design: parallel.
Setting: inpatients/outpatients, USA

Participants

Diagnosis: schizophrenia or schizoaffective disorder, mood disorder,or gastrointestinal disorder + antipsychotic‐induced TD
N = 78.
Sex: not reported
Age: 18‐85 years

History: Duration of TD at least 3 months prior to study. Patient stabilisation was minimum of 30 days before study start. Participants who were not using antipsychotic medication had stable psychiatric status.

Interventions

1. NBI‐98854 (VMAT2 inhibitor): dose 25mg/d‐75mg/d for 6 weeks. N = 39.
2. Placebo for 6 weeks. N = 49.

Concomitant medication not reported.

Outcomes

Tardive dyskinesia: AIMS. CGI‐TD and a patient‐reported scale were also reported for TD symptoms but not included in the review.
Adverse events.

Leaving the study early

Notes

Sponsorship source: Neurocrine Biosciences

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated block randomisation.

Allocation concealment (selection bias)

Low risk

Central interactive web response system.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

""double‐blind, "blinded physician investigator,"

Personnel blinded, details not reported for participants but we judge that participants were likely to be blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Movement Disorder Neurologists as blinded central AIMS raters"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Early discontinuation rates were comparable (5 subjects each, placebo and active)."

Active 13% and placebo 10% dropouts. Reasons were reported.

Selective reporting (reporting bias)

Unclear risk

Results for some scales to assess safety were not fully reported.

Other bias

Low risk

Appears to be free from other sources of bias.

Rastogi 1982

Methods

Allocation: "randomly allocated"
Blindness: double‐blind, unclear.
Duration:12 weeks (6 weeks intervention and 6 weeks post intervention follow‐up).
Design: parallel

Setting: Inpatients, UK

Participants

Diagnosis: Schizophrenia (29), dementia (5), depressive psychosis (3), oligophrenia (2), bipolar affective psychosis (1). Presence of persistent involuntary movements predominantly in the orofacial region and unrelated to drug‐induced Parkinsonian movements.
N = 40.
Sex: 22 female and 18 male.
Age: mean 69.9 years.

History: Duration of TD at least 1 year..

Interventions

1. Co‐dergocrine (hydergine): dose 4.5 mg/day for 6 weeks. N = 19.
2. Placebo for 6 weeks. N = 21

Background antipsychotic and antiparkinsonian medication was held constant throughout the study.

Outcomes

TD symptoms: AIMS combined with abbreviated Rockland Tardive Dyskinesia Rating Scale

Notes

Sponsorship source: Sponsorship source not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomly allocated to two groups"

Further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"[...], one of which received co‐dergocrine, 4.5 mg tablets once daily for 6 weeks, and the other received an identical placebo tablet for the same period. The 2 raters, ward staff and patients were blind to the treatment procedure."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Details not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Attrition information not reported.

Selective reporting (reporting bias)

Unclear risk

Unclear if all outcomes have been reported.

Other bias

Unclear risk

Baseline characteristics, except for age, sex, and TD scores, not reported per intervention group.

Richardson 2003

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 3 weeks.
Design: parallel.
Setting: Inpatients and outpatients, USA

Participants

Diagnosis: Psychiatric patients with long histories of antipsychotic treatment
N = 68.
Sex: 68 male
Age: mean 44.6(SD 9.9).

History: Duration of TD: "presumably long‐standing tardive dyskinesia".

Patients stable for 2 weeks prior to entry. Patients who began the trial with stable doses of medication but who had changes in antipsychotic antiparkinson, antidepressant, or anticonvulsant drug doses during the trial were dropped from the study.

Interventions

1. Branched‐chain amino acids: low dose 56 mg/kg of body weight for 3 weeks. N = not reported
2. Branched‐chain amino acids: medium dose 167 mg/kg of body weight for 3 weeks. N = not reported

3. Branched‐chain amino acids: high dose 222 mg/kg of body weight for 3 weeks. N = 25

4. Placebo for 3 weeks. N = 27

Only results from the high dose and placebo groups were reported.

Concomitant medication not reported

Outcomes

Tardive dyskinesia: Simpson Abbreviated Dyskinesia Scale: improvement, deterioration, scale scores.
Leaving the study early.

Notes

Sponsorship source: Supported by NIMH grant MH‐44153, institutional support from the New York State Office of Mental Health, and a grant and product support from Scientific Hospital Supplies International, Ltd.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Patients were randomly assigned" Details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind," Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Movement frequencies were counted from the videotapes by the first author, who was blind to the patients’ treatment status and the chronological order of the videotapes."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Participants treated with low and medium dose were not entered to the analysis. ITT was conducted for 41 participants who were treated with high‐dose aminoacid or placebo.

Selective reporting (reporting bias)

High risk

Outcome data not reported for low‐ and medium‐dose treatment. Patient recruitment of these two groups was stopped after interim analysis. Full details of interim analysis results not reported.

Other bias

Unclear risk

The authors state that there were no differences between participants treated with high dose and placebo. However, details of the two other groups randomised to the trial have not been reported.

Shamir 2000

Methods

Allocation: randomised.
Blindness: double‐blind.
Duration: 3 weeks.
Design: cross‐over (2 week washout)
Setting: Inpatients, Israel

Participants

Diagnosis: Chronic schizophrenia (DSM‐IV criteria)
N = 19.
Sex: 13 female and 6 male
Age: range 62‐91 years, mean 73 years (SD 9.9).

History: Duration of TD for a minimum of 5 years. Patient stabilisation duration was unclear but "all patients continued to receive antipsychotic treatment during the trial and treatment was unchanged throughout the study".

Interventions

1. Melatonin: dose 2 mg/day for 4 weeks. N = 9

2. Placebo for 4 weeks. N = 10

Concomitant medication not reported.

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores.
Leaving the study early.

Adverse effects

Notes

Sponsorship source: Melatonin (Circadin) and placebo tablets supplied by Neurim Pharmaceuticals, Tel Aviv, Israel.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"randomly assigned". Although details of randomisation have not been reported. As allocation was done by the hospital pharmacy, it is assumed that random sequence generation was not biased.

Allocation concealment (selection bias)

Low risk

"Both patients and physicians were blinded to the group allocation and all medications were dispensed by the center's pharmacy and added to the patients' regular treatment regimens".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"The patients were randomly assigned to receive placebo or melatonin 2mg/day, supplied in identical tablet form by Neurim Pharmaceuticals...Both patients and physicians were blinded to the group allocation and all medications were dispensed by the center's pharmacy and added to the patients' regular treatment regimens".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

TD symptoms' outcomes: "The patients were randomly assigned to receive placebo or melatonin 2mg/day, supplied in identical tablet form by Neurim Pharmaceuticals...Both patients and physicians were blinded to the group allocation and all medications were dispensed by the center's pharmacy and added to the patients' regular treatment regimens". "The same investigator... rated the individual patients throughout the trial."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"All 19 patients completed the 10‐week study."

Selective reporting (reporting bias)

Unclear risk

Unclear if all outcomes previously stated were reported. A protocol is not available for verification. Also, although stated that "Prior to separating the data into the 2 treatment groups, the data were examined according to order...No carryover effects were demonstrated and baseline values did not differ significantly", data not reported per period.

Other bias

Unclear risk

Insufficient information to make a judgement.

Shamir 2001

Methods

Allocation: randomised.
Blindness: double‐blind.
Duration: 16 weeks.
Design: cross‐over (4 week washout)
Setting: inpatient (probably), Israel

Participants

Diagnosis: Schizophrenia (Structured Clinical Interview for DSM‐IV); antipsychotic‐induced TD (DSM‐IV criteria)
N = 24 (2 were discharged after randomisation, but before initiation of treatment, and were not included).
Sex: 6 female and 6 male
Age: range 28‐82 years, mean 64.2 years (SD 14.3).

History: Duration of TD not reported. Patient stabilisation duration unclear but "the antipsychotic medication regimens remained unchanged throughout the study".

Interventions

1. Melatonin: dose 10 mg/day for 6 weeks. N = 12

2. Placebo for 6 weeks. N = 10

Concomitant medications: "anticholinergics 12 patients; benzodiazepines, 5 patients; antidepressants, 4 patients; and mood stabilizers, 5 patients. The regimens of these additional medications also remained unchanged throughout the study"

Outcomes

Leaving the study early.

Adverse effects

Unable to use ‐

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores (not reported separately for the first treatment phase before cross‐over to the next treatment).

Notes

Sponsorship source: Sponsorship source not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"randomized," Although details of randomisation have not been reported, as allocation was done by the hospital pharmacy, it is assumed that random sequence generation was not biased.

Allocation concealment (selection bias)

Low risk

"Medication and placebo were dispensed by the hospital’s pharmacy and added to the patients’ ongoing treatment regimen."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"using sealed envelopes."...tablets identical in appearance..."...unblinding code following database lock..."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details are provided.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"Two female patients were discharged from the hospital before initiation of the study and are not included in the analysis." Participants were randomised; 2/24(8%) were withdrawn before first dose of medication. It seems that the two withdrawn participants were originally randomised to the placebo group.

Selective reporting (reporting bias)

Unclear risk

Unclear if all outcomes previously stated were reported. A protocol is not available for verification.

Other bias

Unclear risk

Insufficent information to make a judgement.

Shi 2009

Methods

Allocation: “randomly assigned”
Blinding: not reported.
Duration: 12 weeks.

Design: parallel

Setting: inpatient (probably) China

Participants

Diagnose: Antipsychotic‐induced TD.

N = 76

Sex: male 26, female 50.

Age: mean 56.1 (SD 9.12) years old

History: Duration of TD not reported. Patient were stabilised before entry to trial but the duration is not reported.

Interventions

1. Melatonin Group: dose: 9 mg melatonin, oral taken before sleep for 12 weeks. N = 39

2. Control Group: no medication control group for 12 weeks. N = 37

Concomitant medication not reported.

Outcomes

Cognitive function: Wechsler Adult Intelligence Scale (WAIS)
Cognitive function: Wechsler Memory Scale (WMS)
Cognitive function: Vocabulary fluency scale (VFS)
Adverse events: Treatment Emergent Symptom Scale (TESS)

‐‐Unable to use (These outcomes were not predefined by this review and data were translated)
WAIS subscale‐score (verbal scale, verbal IQ, performance scale, performance IQ, and full scale IQ).

VFT subscale‐score: animal, fruits, making words.

RBANS, subscale‐score. The author did not report the total score and other subscales scores excluding the subscale‐semantic fluency; because a significant difference was only observed on the latter subscale.

Notes

Funding source: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“ randomly assigned…” The author did not state the method of randomisation

Allocation concealment (selection bias)

Unclear risk

No information about allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

It’s not possible that the participants and personnel could be blinded. As the control group did not receive intervention in addition to antipsychotics.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information about blinding outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants completed the study

Selective reporting (reporting bias)

Low risk

The authors reported all measured outcomes.

Other bias

Unclear risk

Insufficent information to make a judgement.

UCB Pharma 2005

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 8 weeks.
Design: parallel.
Setting: inpatient (probably), Belgium and Bulgaria.

Participants

Diagnosis: antipsychotic‐induced TD
N = 70.
Sex: 35 female and 35 male
Age: 18‐80 years, mean 53.92 (SD 10.83) years.
History: Duration of TD at least one month. Patient stabilised for at least 1 month prior to entry.

Interventions

1. Levetiracetam: dose: 1500 mg twice a day (stable dose) for 8 weeks. N = 34.
2. Placebo for 8 weeks. N = 36.

Concomitant medication not reported.

Outcomes

Tardive dyskinesia: mean change of symptoms (hyperkinesia subscale of the St Hans rating scale).
Leaving the study early.

Adverse events

Notes

Sponsorship source: Sponsored by UCB Pharma

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"...randomized ..." Clinical Study Summary (CSS). Details not reported

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

" ...double blind..." Clinical Study Summary (CSS). Details not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

" ...double blind..." Clinical Study Summary (CSS). Details not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

"All data are presented on the intent‐to‐Treat population (all randomized subjects who took at least one dose of study medication). ". Clinical Study Summary (CSS) The authors actually performed modified ITT.

Selective reporting (reporting bias)

High risk

Outcome data for 2/3 secondary outcomes (antipsychotic‐induced akathisia and other extrapyramidal symptoms, effect on the primary psychiatric disorder) not reported. Only summary data from Sponsor is available.

Other bias

Unclear risk

Insufficient information to make a judgement.

Wolkin 1986

Methods

Allocation: randomised, not described.
Blindness: double‐blind, not described.
Duration: 6 weeks.
Design: parallel.
Setting: Inpatients and outpatients, USA.

Participants

Diagnosis: schizophrenia* (no operational criteria).
N = 16.
Sex: male.
Age: mean 54 (SD 9) years.
History: Duration of TD at least 1 year. Individual antipsychotic regimens (including no antipsychotic drugs in three patients) were kept constant from at least 1 month before the study through termination. Chronic with antipsychotic‐induced TD.

Interventions

1. Gamma‐Linolenic acid supplementation (oil of evening primrose) 600 mg/day for 6 weeks. N = 8.
2. Placebo for 6 weeks. N = 8.

Background medication and treatment continued throughout trial.

1 patient was on lithium carbonate. Other concomitant medications not reported.

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores.
Mental state: BPRS scale scores.
Leaving the study early**.

Notes

Sponsorship source: Supported in part by Efamol, Ltd., and by the VA

* one participant might have been bipolar.

** assume loss is 0 as all AIMS scores available after 6 weeks.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Subjects were assigned on a random, double‐blind basis" Details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment details not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double‐blind". Details not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double‐blind". Details not reported.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Although attrition details have not been reported, as end of trial data are reported individually for all randomised participants, it is assumed that all participants completed the trial.

Selective reporting (reporting bias)

Unclear risk

Indufficent information to make a judgement. As a protocol is not available, it is not possible to verify if all outcomes defined prior to study have been reported. (e.g. adverse events have not been reported) .

Other bias

Low risk

The study seems to be free of other sources of bias.

Woods 2008

Methods

Allocation: "assigned at random", not described.
Blindness: double‐blind, not described.
Duration: 12 weeks.
Design: parallel
Setting: outpatients, USA

Participants

Diagnosis: schizophrenia/schizoaffective disorder (45), affective disorder (4), other psychiatric diagnosis (1) (DSM‐IV); and TD (Glazer‐Morgenstem criteria, i.e., total AIMS score ≥3, with at least 1 body area rated ≥2).
N = 50.
Sex: 21 female and 29 male.
Age: mean 47.4 (SD 9.6) years.

History: Duration of TD in the levetiracetam group is 7.5 ± 8.4 years, whereas in the placebo group is 9.0±7.3 years. "sufficiently stable psychiatrically that their CMHC clinician indicated that changes in prescribed antipsychotic medication drug or dosage were not anticipated in the next 3 months". "Changes in the prescribed concomitant antipsychotic medications or their doses during the randomised phase occurred in 3 levetiracetam patients (12%) versus 5 placebo patients (20%)..."

Interventions

1. Levetiracetam: maximum dose 1500 mg* twice a day for 12 weeks. N = 25

2. Placebo for 12 weeks. N = 25

* side effects permitting and assuming lack of complete response, the dose was recommended to be escalated weekly by 500 mg/day to the maximum dose of 3000 mg/day, given in 2 divided doses.

Concomitant medication: baseline anticholinergics (52%, levetiracetam group; 48% placebo group). Changes occurred in 2 placebo patients and none of the active patients.

Outcomes

Tardive dyskinesia: AIMS
Leaving the study early.

Adverse effects.

Unable to use () ‐

Mental State: Positive and Negative Syndrome Scale (PANSS); Young Mania Scale (YMRS); Montgomery‐Asberg Depression Rating Scale (MADRS); Hamilton Rating Scale for Anxiety (HAM‐A)

Notes

Sponsorship source: Supported by a grant from UCB Pharma.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Eligible patients who gave written informed consent were assigned at random", further details not reported.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"double blind phase" no further details.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"double blind phase" no further details.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Completion rates (64% [N = 16] for the levetiracetam group and 80% [N = 20] for the placebo group, P = 0.345), reasons for discontinuation did not differ significantly between treatment groups. Data were reported for all participants randomized to the two groups (mixed‐effects model).

Selective reporting (reporting bias)

High risk

Primary outcome, total AIMS scores reported. However the authors stated that: "In addition to the principal analyses of the AIMS total score, we also investigated the relative rates at which subjects achieved remission, defined a priori as no longer meeting the Glazer‐Morgenstern TD entry criteria. " Remission data only reported as "...Group differences did not achieve statistical significance." Also, although not stated in the Protocol, the publication reported that: "At each study visit, patients were weighed and underwent an AIMS examination and symptom ratings using the Positive and Negative Syndrome Scale (PANSS); Young Mania Rating Scale (YMRS), Montgomery Asberg Depression Rating Scale (MADRS), and the Hamilton Rating Scale for Anxiety (HAM‐A) administered via a structured interview guide. Adverse events were rated using the Systematic Assessment for Treatment Emergent Events, general inquiry method. Complete blood counts were obtained at baseline and at 6, 12". Only baseline data for these outcomes have been reported.

Other bias

Low risk

"...none of the interactions with baseline were statistically significant...Further analyses revealed that the small age difference at baseline did not confound the levetiracetam treatment effect, nor did the small baseline differences in years of education, antipsychotic chlorpromazine equivalent dose, antipsychotic type at baseline (only atypical vs. any conventional), or gender."

Yang 1999

Methods

Allocation: "randomly assigned”.
Blinding: double‐blind, outcome assessor was blinded.

Design: parallel.

Setting: inpatients, China.

Duration: 12 weeks.

Participants

Diagnosis: Antipsychotics‐induced TD (Research Diagnosis Criteria for TD, RD‐TD)

N = 36 (2 participants left the study early due to discharge)

Sex: male 18 , female 16

Age: mean 50.2 years old, SD 13.4 years old.
History: mean˜ 8.9 years (SD˜ 7.3years) TD; mean˜ 17.7years (SD˜ 9.22 years) schizophrenia.

Interventions

1. Promethazine Group: (n = 18)

Management: 50 mg promethazine was administrated by IM, twice per day for 2 weeks following with a 2‐week period of IV drip (50 mg promethazine dissolved in 500 mL normal saline, once per day). This 4‐week treatment regimen was conducted three circles in 12 weeks.

2. Placebo Group: (n = 16)

Management: The same treatment regimen as promethazine. The placebo drug was 2 mL normal saline with same appearance as promethazine.

All participants received antipsychotics as usual but were not allowed to use clozapine, anticholinergic drug, vitamin E or calcium channel blocker.

Outcomes

TD symptoms: improvement, AIMS
Global state: CGI
Mental state: BPRS
Extrapyramidal side effects: RSESE (rating scale for extrapyramidal side effects)
Adverse events: TESS (Treatment Emergent Symptom Scale)

Notes

*defined by the 4‐level clinical response standard, recovery, obvious improvement, improvement, no clinical response.

Funding source: not reported.

Paper in Chinese, assessed and data extracted by Sai Zhao.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

”randomly assigned”, no further details. Although the author did not state the method of randomisation, we have rated selection bias as low: because central allocation was used, it is very likely that an adequate randomisation sequence was generated.

Allocation concealment (selection bias)

Low risk

Central allocation, pharmacy‐controlled randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double blind", no details of blinding of participants and personnel.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

”The outcome assessor was blinded”

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants competed the study.

Selective reporting (reporting bias)

Low risk

The author reported all measured outcomes.

Other bias

Low risk

None obvious.

Zeng 1995

Methods

Allocation: "randomly assigned…"
Blinding: double‐blind study. Details are provided
Duration: 6 weeks

Design: parallel

Setting: inpatients

Participants

Diagnose: Antipsychotics‐induced TD

Total: N = 42

Sex: male 28, female 14

Age: mean˜32.5 years old, SD˜10.3years old.

Length of illness (schizophrenia): mean˜ 7.5 years, SD ˜3.4 years
History: Duration of TD on average 5.4 ± 4.2 years in active group, whereas 5.7 ± 4.5 years in control group.

Interventions

1. Buspirone Group: (n = 21)

Management: The initial dosage, one capsule each day, was titrated to 6‐12 capsules each day within 10 days.

2. Placebo Group: (n = 21)

Management: The initial dosage, one capsule each day, was titrated to 6‐12 capsules each day within 10 days.

All participants received stable AP and concomitant anticholinergic drug.

Outcomes

Clinical response*
Tardive dyskinesia: AIMS (Abnormal Involuntary Movement Scale)

Adverse events: dizziness, headache, nausea, vomiting

‐‐Unable to use
Blood routine examination, urine routine test and liver function test, electrocardiography, electroencephalogram (the author only stated results of these tests were normal but did not report the data)

Notes

Funding source: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly assigned…" The author did not state the method of randomisation.

Allocation concealment (selection bias)

Unclear risk

The author did not state the method of allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"double blind study , the interventions were coded as intervention A or B by the researcher in pharmacy ". "Participants and personnel did not know the allocation result. The two drugs were contained in capsules with same appearance"

Blinding of participants and key study personnel ensured.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants competed the study.

Selective reporting (reporting bias)

Low risk

The author reported all measured outcomes.

Other bias

Low risk

None obvious.

Zeng 1996

Methods

Allocation: "randomly assigned…."
Blinding: "double blind". Details are provided.
Duration: 6 weeks.

Design: parallel

Setting: inpatients

Participants

Diagnosis: Antipsychotic induced TD.

N = 46

Sex: male 30, female 16.

Age: mean ˜33 years old, SD˜10 years old.

History: Duration of TD on average 2.2 years (SD˜1.7 years). Patients stabilised prior to study for 5 ± 4 years.

Interventions

1. Pemoline Group: (n = 23)

Management: two capsules per day for six days per week, oral taken before breakfast.

2. Placebo Group: (n = 23)

Management: two capsules per day for six days per week, oral taken before breakfast.

All participants received stable AP and concomitant anticholinergic drug.

Outcomes

Clinical response*
Tardive dyskinesia: AIMS (Abnormal Involuntary Movement Scale)
Adverse events: dizziness and headache; nausea and anorexia

‐‐Unable to use

Blood routine examination, urine routine test and liver function test, electrocardiography, electroencephalogram (the author only stated results of these tests were normal but did not report the data)

Notes

Funding source: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"randomly assigned". The author did not state the method of randomisation.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind study), the interventions were coded as intervention I or II by the researcher in pharmacy. “Participants and personnel did not know the allocation result. The two drugs were contained in capsules with same appearance.”

Blinding of participants and key study personnel ensured.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants competed the study.

Selective reporting (reporting bias)

Low risk

The author reported all measured outcomes.

Other bias

Low risk

None obvious.

Zhang 2011

Methods

Allocation: "randomized", described.
Blindness: double‐blind, described.
Duration: 12 weeks.
Design: parallel
Setting: inpatients, China

Participants

Diagnosis: DSM‐IV diagnosis of schizophrenia; diagnosis of TD based on the Schooler‐Kane criteria.
N = 157.
Sex: 157 male.
Age: mean 45.2 (SD 6.7) years.

History: Duration of TD at least 1 year. "A stable dose of antipsychotics for at least 4 weeks prior to trial entry".

Interventions

1. EGb‐761 (standardised extract of Ginkgo biloba leaves that has antioxidant properties as a free radical scavenger): dose 80 mg, three times a day for 12 weeks. N = 78

2. Placebo for 12 weeks. N = 79

Patient regular antipsychotic medication. Antipsychotics and all other medications remained fixed throughout the double‐blind period (i.e. clozapine, risperidone, aripiprazole, olanzapine, quetiapine, chlorpromazine, haloperidol, sulpiride). Their chlorpromazine‐equivalent doses were 429.3 mg/day and 440.2 mg/day in the EGb‐761 and placebo groups, respectively. Anticholinergics were allowed during the trial. Twenty‐seven patients (12 in the EGb‐761 group and 15 in the placebo group) were treated with anticholinergics for a long time prior to entering the study; however, anticholinergic treatment was stable during the clinical trial. No new use of anticholinergic drugs was allowed.

Outcomes

Tardive dyskinesia: AIMS improved/not improved, deterioration in symptoms, AIMS scale scores.
Mental state: PANSS; Cognitive performance Continuous Performance Test‐37 (CBT‐37)

Leaving the study early.

Notes

Sponsorship source: Supported by the National Basic Research Program of China and the National Natural Science Foundation of China. Statistical analysis was funded by Glaxo Smith Kline.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Patients had an equal probability of being assigned to the 2 groups. An independent third party placed them in either the active or placebo group according to a computer‐generated randomization list compiled through simple randomization"

Allocation concealment (selection bias)

Low risk

"To ensure the concealment of allocation, this third party used a protected computer database for the randomization list."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"After the run‐in period, patients were randomly assigned to receive either capsulized EGb‐761... or an identically capsulized placebo in a double‐blind manner". "All of the study personnel and participants were blinded to the treatment assignment for the duration of the double‐blind period, except 1 study staff member in the pharmacy, who remained unblinded to provide the placebo and EGb‐761 treatments"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All efficacy outcomes: "Each subject was assessed by the same investigator, who was blind to treatment status". Cognitive tests: computer assessments.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

"intention‐to‐treat analysis for the 2 groups of randomly assigned patients, with last‐observation‐carried‐forward imputation."

Selective reporting (reporting bias)

High risk

Side effects and Adverse Events data not reported. "Systemic side effects were evaluated by means of routine physical and neurologic examinations and laboratory tests and reviewed by applying the UKU Side Effect Rating Scale. These systemic side effects were all mild and brief. For none of the subjects were the routine blood cell count, chemistry, urinalysis, or electrocardiogram parameters significantly affected by the experimental treatment (data not shown)". Also, Change in Simpson‐Angus Rating Scales for EPS not reported.

Other bias

Low risk

The study seems to be free from other sources of bias.

AIMS ‐ Abnormal Involuntary Movement Scale
AVLT ‐ Rey Auditory and Verbal Learning Test
BPRS ‐ Brief Psychiatric Rating Scale
CGI ‐ Clinical Global Impression
DSM ‐ Diagnostic and Statistical Manual of Mental Disorders
EPS ‐ extrapyramidal symptoms
ESRS ‐ Extrapyramidal System Rating Scale
IM ‐ intramuscular
ITT ‐ intention‐to‐treat
IV ‐ intravenous
MAOI ‐ monoamine oxidase inhibitor
mcg ‐ microgram
NOSIE ‐ Nurses Observation Scale for Inpatient Evaluation
PANSS ‐ Positive and Negative Syndrome Scale
Rockland TD ‐ Rockland Tardive Dyskinesia Rating Scale
SANS ‐ Scale for the Assessment of Negative Symptoms
SAPS ‐ Scale for the Assessment of Positive Symptoms
SAS ‐ Simpson Angus Scale
SD ‐ Standard deviation
TAU ‐ treatment as usual
TD ‐ tardive dyskinesiaTESS ‐ Treatment Emergent Symptoms Scale
VMAT ‐ vesicular monoamine transporter 2

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Apseloff 2000

Allocation: randomised.
Participants: healthy, non‐smoking males, not TD.

Bjorndal 1980

Allocation: not randomised.

Blum 1984

Allocation: not randomised.

Bockenheimer 1976

Allocation: randomised

Participants: TD

Intervention: Deanol vs placebo, not relevant for this review, included in Cholinergics review

Bowers 1979

Allocation: not randomised.

Casey 1981

Allocation: not randomised.

Chaplin 2002

Allocation: randomised.
Participants: schizophrenia (40), schizoaffective disorder (11), bipolar disorder (5); not TD at baseline.

Emsley 2002

Allocation: randomised.
Participants: people with schizophrenia, but not specifically TD.

Fann 1973

Allocation: randomised.

Participants: TD.

Interventions: Methylphenidate vs placebo.

Outcomes: No outcome data have been provided for the first phase before cross‐over. Author was contacted but no information was received and this over 40 years old study was excluded.

Fudge 1991

Allocation: randomised.

Participants: schizophrenia (DSM‐III‐R) and TD.

Interventions: Electromyographic biofeedback vs noncontingent "false" feedback (placebo).

Outcomes: No useable data were extractable. Study author was contacted but no information was received and this 25 years old study was excluded.

Gardos 1978

Allocation: not randomised.

Gerlach 1975

Allocation: randomised.

Participants: Psychiatric inpatients with a BLM syndrome induced by antipsychotic treatment; psychiatric‐neurological condition stable and pharmacological treatment unchanged for at least 2 months.

Interventions: Lithium vs placebo.

Outcomes: All data unusable. Unable to extract from the fist phase of cross‐over. We were unable to find up‐to‐date contact details for the study authors of this over 40 years old study; it was excluded.

Goetz 2013

Allocation: unclear if randomised.

Participants: people with Parkinson's disease and not TD symptoms at baseline

Huang 1981

Allocation: randomised

Participants: TD

Intervention: Alpha‐methyldopa vs. reserpine vs. placebo, not relevant for this review, included in the Non‐antipsychotics review.

Jus 1974

Not randomised, controlled clinical trial.
Benztropine vs diazepam vs diphenylhydantoin vs DL tryptophan.
No placebo control.

Jus 1978

Allocation: randomised.
Participants: people with TD. N = 29.
Interventions: deanol versus lithium carbonate versus placebo.
Outcomes: AIMS, TD symptom rating scale, CGI, BPRS, NOSIE, vital signs, lab values.
Trial used cross‐over design. Impossible to extract data from segment before cross‐over. One of authors contacted to confirm lack of additional data.

Kabes 1982

Allocation: randomised
Population: antipsychotic‐induced extrapyramidal side effects: (i) akathisia, (ii) tremor, (iii) muscle rigidity and (iv) dyskinesia.

Interventions: Piracetam versus placebo administered IV in 1‐hour intervals.

Outcomes: not useable, measured 30 mins after intervention.

Kabes 1985

Allocation: randomised
Population: patients suffering from TD and receiving antipsychotic treatment.

Interventions: Piracetam 2.4 g/d vs Piracetam 4.8 g/d vs Piracetam 10 g/d vs placebo for 4 weeks.

Outcomes: no usable data. We were unable to find up‐to‐date contact details for the study authors of this over 30 years old study; it was excluded.

Koller 1982

Allocation: randomised.

Participants: Various dyskinesias and movement disorders, including TD.

Interventions: Oestrogen vs. placebo

Outcomes: No usable data since they are reported in figures with no variability measures.

No reply from author. Study is over 30 years old and was excluded.

Korsgaard 1981

Allocation: not randomised.

Lieberman 1987

Allocation: randomised
Population: not TD

Lieberman 1994

Allocation: randomised

Participants: not TD, participants classified as TD or not TD only during measuring outcomes after intervention

Lindenmayer 1988

Allocation: randomised.

Participants: DSM‐III diagnoses were predominantly schizophrenia (N = 16) and included four cases of major affective disorder. All participants had TD for at least 1 year.

Interventions: Nalaxone 20g vs Nalaxone 40 g vs placebo.

Outcomes: No outcome data have been provided for the first period before cross‐over. Author was contacted but no information was received and this over 25 years old study was excluded.

Moore 1980

Allocation: not randomised.

Nasrallah 1986

Allocation: randomised.

Participants: Psychiatric patients; Schooler and Kane criteria for persistent TD.

Interventions: AMPT vs L‐DOPA vs Cholone chloride vs Valproic acid vs Hydroxytryptophan.

Outcomes: No outcome data has been provided for the first period before cross‐over. Author was contacted but no information was received and this 30 years old study was excluded.

Peselow 1989

Allocation: randomised.

Participants: people with chronic schizophrenia with multiple hospitalisations and averaged 5.5 years of TD.

Interventions: Monosialotetrahexosylganglioside (GM1) versus placebo.

Outcomes: All data unusable. Authors were contacted and confirmed data were inaccessible.

Prange 1973

Allocation: not randomised.

Reda 1974

Allocation: not randomised.

Reker 1982

Allocation: not randomised.

Shah 2012

Allocation: randomised.

Participants: Parkinson's disease, not TD.

Simpson 1976 a

Allocation: not randomised.

Simpson 1976 b

Allocation: not randomised.

Tamminga 1983

Allocation: randomised.

Participants: chronic schizophrenia patients with symptoms of TD.

Interventions: Muscimol vs placebo.

Outcomes: No useable data were extractable. Study author was contacted but no information was received and this over 30 years old study was excluded.

Vaddadi 1989

Allocation: randomised
Population: psychiatric patients (DSM‐II criteria) with established movement disorders who had been exposed to antipsychotics over a long period of time; TD (Schooler and Kane criteria).

Interventions: Efamol (essential fatty acid) + Vitamin E vs liquid paraffin + vitamin E.

Outcomes: No outcome data have been provided for the first period before cross‐over. Study author was contacted but no information was received and this over 25 years old study was excluded.

Vaddadi 2002

Allocation: randomised
Population: Huntington's disease, not TD

Villeneuve 1970

Allocation: not randomised.

Villeneuve 1980

Allocation: not randomised.

Volavka 1986

Allocation: not randomised.

Wonodi 2004

Allocation: randomised
Population: schizophrenia patients; treated by antipsychotics; TD (Schooler and Kane).

Interventions: Naltrexone vs placebo and Naltrexone + clonazepam vs placebo + clonazepam.

Outcomes: No outcome data have been provided for the first phase before cross‐over. Study author was contacted but no information was received and this over 10 years old study was excluded.

AIMS: Abnormal involuntary Movement Scale
CGI ‐ Clinical Global Impression
DSM ‐ Diagnostic and Statistical Manual of Mental Disorders
TD = tardive dyskinesia
IV = intravenous

Characteristics of studies awaiting assessment [ordered by study ID]

Fernandez 2016

Methods

Allocation: randomised.
Blindness: double‐blind
Duration: 12 weeks
Design: parallel.
Setting: USA, Czech Republic, Poland, Slovakia

Participants

Diagnosis: History of using a dopamine receptor antagonist for at least 3 months; clinical diagnosis of tardive dyskinesia and has had symptoms for at least 3 months prior to screening; participants with underlying psychiatric diagnosis are stable and have no change in psychoactive medications

N = 117

Sex: male and female

Age:18 to 75 years old

Interventions

1. SD‐809 (deutetrabenazine) tablets taken twice daily for 12 weeks, includes a dose titration period and maintenance period. N = 58

2. Placebo tablets taken twice daily for 12 weeks. N = 59

Outcomes

Change in AIMS score from baseline to week 12.

Quality of life; Treatment success based on Patient Global Impression of Change (PGIC) questionnaire; Percentage reduction in AIMS score; Proportion of responders based on AIMS change from baseline

Notes

Other study ID: SD‐809‐C‐18

Sponsor: Auspex Pharmaceuticals, Inc.

From 2017 update search, conference abstract with limited details, awaiting more detailed data.

Hauser 2016

Methods

Allocation: randomised.
Blindness: double‐blind
Duration: 6 weeks + 42 weeks extension
Design: parallel
Setting: USA, Canada, Puerto Rico

Participants

Diagnosis: schizophrenia, schizoaffective disorder, or mood disorder (for at least 3 months prior to screening); a clinical diagnosis of antipsychotic‐induced TD for at least 3 months prior to screening; if using maintenance medication(s), be on stable doses; negative drug screen for amphetamines, barbiturates, benzodiazepines, phencyclidine, cocaine, opiates, or cannabinoids

N = 240

Sex: male and female

Age: 18 to 85 years old

Interventions

1. NBI‐98854 administered orally as one 40 mg capsule and one placebo capsule for 6 weeks. At the end of week 6, participants will enter a double‐blind NBI‐98854 treatment period and continue with their current dose N = 80

2. Participants randomised to the NBI‐98854 80 mg dose will receive NBI‐98854 40 mg for the first week (administered orally as one 40 mg capsule and one placebo capsule), followed by NBI‐98854 80 mg administered orally as two 40 mg capsules for 5 weeks. At the end of week 6, participants will enter a double‐blind NBI‐98854 treatment period and continue with their current dose. N = 80

3. Placebo administered orally as two placebo capsules 6 weeks. At the end of Week 6, participants will enter a double‐blind NBI‐98854 treatment period and be randomised to either a 40 mg or 80 mg dose. N = 80

Outcomes

Severity of TD symptoms assessed by AIMS, change from baseline

Clinical Global Impression of Change ‐ TD (CGI‐TD);

Tardive Dyskinesia Impact Scale (TDIS);

Patient Global Impression of Change (PGIC);

Percentage of participants classified as responders based on AIMS dyskinesia total score % change from baseline;

Percentage of participants classified as responders based on CGI‐TD

Notes

Study ID: NCT02274558
Sponsor: Neurocrine Biosciences

From 2017 update search, conference abstracts, poster, and online trial registration record with limited details, awaiting more detailed data.

NCT01393600 2011

Methods

Allocation: randomised
Blindness: double‐blind
Duration: 1 month
Design: cross‐over
Setting: USA

Participants

Diagnosis: schizophrenia or schizoaffective disorder and a clinical diagnosis of antipsychotic‐induced TD (DSM‐IV) for at least 3 months prior to screening; stable dose of antipsychotic medication for a minimum of 30 days before study start; participants not using antipsychotic medication must have stable psychiatric status; the doses of concurrent medications and the conditions being treated be stable for a minimum of 30 days before study start and be expected to remain stable during the study.

N = 37

Sex: male and female

Age: 18 to 65 years old

Interventions

1. 12.5 mg NBI‐98854 once daily dose for days 1‐14 and placebo once daily dose for days 15‐28 (participants will be randomly assigned to receive one of these treatment sequences)

2. Placebo once daily dose for days 1‐14 and 50 mg NBI‐98854 once daily dose for days 15 mg to 28 mg or 50 mg NBI‐98854 once‐daily dose for days 1‐14 and placebo once‐daily dose for days 15‐28 (participants will be randomly assigned to receive one of these treatment sequences)

Outcomes

Treatment efficacy (AIMS)

Efficacy of 12.5 mg or 50 mg doses of NBI‐98854 administered once daily for the treatment of TD symptoms using CGI‐TD and PGIC questionnaire

Safety and tolerability for adverse events

Notes

Other study ID: NBI‐98854‐1101
Sponsor: Neurocrine Biosciences

Online trial registration record, results are provided for combined groups in this cross‐over study, awaiting separate data.

Pattojoshi 2016

Methods

Randomised, double‐blind, sham‐controlled study, 22 months duration.

Participants

Diagnosis: psychosis with TD (Schooler and Kane criteria).

Interventions

10 right dorsolateral prefrontal cortex‐repetitive transcranial magnetic stimulation (rTMS) sessions versus 10 sham rTMS sessions, total n = 30.

Outcomes

AIMS, MMSE, CPRS.

Notes

From 2017 update search, conference abstract with limited details, awaiting more detailed data.

Xu 2012

Methods

Randomised controlled trial, 12 weeks duration.

Participants

Diagnosis: schizophrenia (CHMD‐3) with tardive dyskinesia.

Interventions

Ginkgo biloba extract (n = 42) versus standard treatment (n = 40).

Outcomes

AIMS, TESS.

Notes

From 2017 update search, article in Chinese, awaiting translation.

AIMS ‐ Abnormal involuntary Movement Scale
CGI ‐ Clinical Global Impression
CHMD‐3 ‐ Chinese Classification of Mental Disorders Version 3
CPRS ‐ Comprehensive Psychopathological Scale
DSM IV ‐ Diagnostic and Statistical Manual of Mental Disorders
MMSE ‐ Mini Mental State Examination
PGIC ‐ Patient Global Impression of Change
rTMS ‐ right dorsolateral prefrontal cortex‐repetitive transcranial magnetic stimulation
TD ‐ tardive dyskinesia
TESS ‐ Treatment Emergent Symptom Scale

Characteristics of ongoing studies [ordered by study ID]

Garcia 1992

Trial name or title

Double‐blind placebo controlled study using buspirone in the treatment of tardive dyskinesia

Methods

Allocation: randomised.
Blindness: double‐blind.
Duration: 12 weeks.
Design: cross‐over.
Setting: USA.

Participants

Diagnosis: TD patients, criteria not reported.
N = 20.
Sex: not reported.
Age: not reported

Interventions

1. Buspirone: Not reported, increasing dose. N = 20.
2. Placebo. N = 20.

Outcomes

AIMS score

Starting date

Contact information

Notes

Abstract of a study protocol, there are no data to be extracted.

ISRCTN14688109 2015

Trial name or title

Investigation of the potential beneficial effects of cannabidiol in the treatment of tardive dyskinesia

Methods

Allocation: randomised

Blindness: double‐blind (no further details)

Duration: 1 year

Design: parallel

Setting: Nigeria

Participants

Diagnosis: ICD‐10 diagnosis of a psychotic disorder, verified with the MINI‐PLUS questionnaire; clinical diagnosis of TD confirmed with the AIMS; currently receiving treatment for a psychotic disorder and be on either the atypical or conventional antipsychotics.

N = 56

Sex: male and female

Age: at least 18 years old

Interventions

1. High cannabidiol extract Nabidiolex® (CBD) (300 mg) administered orally in capsules twice a day for six weeks as an adjunctive treatment alongside their usual antipsychotic medication. N = 28
2. Vitamin E (400 IU) administered daily for six weeks as an adjunctive treatment alongside their usual antipsychotic medication N = 28

Outcomes

Primary: Improvement in symptoms of TD measured using the Abnormal Involuntary Movement Scale (AIMS).

Secondary: Side effects of CBD; improvement in psychotic symptoms.

Starting date

December 2015

Contact information

Dr Jaiyeola Kajero, +234 08037140976, [email protected], Nigeria

Notes

Sponsor: South Africa Research Chair in PTSD, Stellenbosch University

NCT00621634 2008

Trial name or title

Efficacy of docosahexaenoic acid on tardive dyskinesia

Methods

Allocation: randomised.
Blindness: double‐blind (Participant, Investigator, Outcomes Assessor).
Duration: 12 weeks.
Design: parallel.
Setting: Canada

Participants

Diagnosis: chronic schizophrenia; under long‐term antipsychotic drug treatment, stable for at least 3 months before study entry; presence of TD following Schooler‐Kane research criteria (mild intensity (2/4 points) in at least two body segments, or moderate intensity (3/4 points) for at least one body segment).

N = 40

Sex: male and female

Age: 30‐75 years

Interventions

1. Omega‐3 fish oil capsules (including docosahexaenoic acid): Fish oil capsules of 1000 mg each, including DHA 460 mg‐540 mg/capsule; dose: 6 capsules per day; N = 20.

2. Placebo: Corn/Soybean placebo 1000 mg capsules; dose: 6 capsules per day; N = 20.

Outcomes

Primary: Clinical rating scales (AIMS, St.Hans)

Secondary: Quantitative motor testing (kinematic parameters); Monitoring of psychopathology (Neuro‐Psychiatric Inventory, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia); Erythrocyte membrane phospholipid profile (gas chromatography)

Starting date

February 2008

Contact information

Pierre J. Blanchet, MD, PhD, (514) 890‐8123, [email protected]

Notes

Sponsor: Université de Montréal, National Alliance for Research on Schizophrenia and Depression

Study IDs: NCT00621634; HD06.067

NCT01391390 2011

Trial name or title

Melatonin treatment for tardive dyskinesia in schizophrenia.

Methods

Allocation: randomised
Blindness: double‐blind (Subject, Investigator)
Duration: 12 weeks
Design: parallel
Setting: China

Participants

Diagnosis: diagnosis of both schizophrenia and TD; duration of TD symptoms longer than 1 year; on stable doses of antipsychotic drug for at least 6 months.

N = 120

Sex: male and female

Age: 18 to 70 years old

Interventions

1. Melatonin (other Name: APRD00742)10mg/day, 12‐week treatment. N = 60.

2. Placebo 10mg/day, 12‐week treatment. N = 60

Outcomes

Primary: AIMS at 12 weeks

Secondary: the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); the Positive and Negative Syndrome Scale (PANSS); the Simpson‐Angus Scale for extrapyramidal side effects (SAS)

Starting date

September 2008

Contact information

Lian Y Cao, MD, Beijing Hui‐Long‐Guan Hospital

Notes

Sponsor: Beijing HuiLongGuan Hospital, Stanley Medical Research Institute
Other study ID: BJ‐7072035

NCT01688037 2012

Trial name or title

NBI‐98854 for the for the treatment of tardive dyskinesia in subjects with schizophrenia or schizoaffective disorder (KINECT study)

Methods

Allocation: randomised
Blindness: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Duration: 6 weeks
Design: parallel
Setting: USA, Puerto Rico

Participants

Diagnosis: Clinical diagnosis of schizophrenia or schizoaffective disorder and a clinical diagnosis of antipsychotic‐induced TD for at least 3 months prior to screening;receiving a stable dose of antipsychotic medication for a minimum of 30 days before study start; participants not using antipsychotic medication must have stable psychiatric status;the doses of concurrent medications and the conditions being treated be stable for a minimum of 30 days before study start and be expected to remain stable during the study.

N = 109

Sex: male and female

Age: 18 to 65 years old

Interventions

1. NBI‐98854 50 mg administered as two 25 mg capsules by mouth, taken every morning for 6 weeks. N = NR

2. NBI‐98854 100 mg and 50 mg. NBI‐98854 100 mg administered as two 50 mg capsules taken every morning between for 2 weeks. After 2 weeks, NBI‐98854 50 mg administered by two 25 mg capsules by mouth, taken every morning for remaining 4 weeks. N = NR

3. Placebo capsule containing no active substance, manufactured to mimic NBI‐98854 25 mg and 50 mg capsules. N = NR

Outcomes

Primary:

Severity of TD symptoms assessed by AIMS

Secondary:

CGI‐TD; Number of participants with adverse events following dosing with NBI‐98854; Evaluation of plasma concentrations of NBI‐98854 and metabolites following repeated daily doses (50 mg and 100 mg) of NBI‐98854

Starting date

September 2012

Contact information

Principal Investigator: Chris O'Brien, MD

Notes

Other study ID: NBI‐98854‐1201
Sponsor: Neurocrine Biosciences

NCT01804920 2013

Trial name or title

D‐Serine treatment for tardive dyskinesia

Methods

Allocation: randomised
Blindness: double‐blind (Subject, Investigator, Outcomes Assessor)
Duration: 8 weeks
Design: parallel
Setting: Israel

Participants

Diagnosis: Diagnosis of schizophrenia/schizoaffective disorder according to DSM‐IV criteria; history of at least 3 months antipsychotic drugs treatment and present stable dose antipsychotic treatment for at last 4 weeks; fulfilment of Schooler‐Kane TD research criteria on a first evaluation performed 2‐12 weeks prior to study entrance and on a subsequent evaluation performed prior to allocation to experimental treatment.

N = 60

Sex: male and female

Age: 18 to 70 years old

Interventions

1. D‐Serine (amino acid) 4 g/dN for 8 weeks. N = 30

2. Placebo adjuvant treatment for 8 weeks. N = 30

Outcomes

Primary: Change in AIMS total score

Starting date

January 2013

Contact information

Contact: Uriel Heresco‐Levy, MD, +972‐2‐5316906, [email protected]

Notes

Other Study ID Numbers: 1600

NCT02291861 2014

Trial name or title

Addressing involuntary movements in tardive dyskinesia (AIM‐TD)

Methods

Allocation: randomised.
Blindness: double‐blind (Subject, Investigator, Outcomes Assessor).
Duration: 12 weeks
Design: parallel.
Setting: USA, Czech Republic, Germany, Hungary, Poland, Slovakia

Participants

Diagnosis: History of using a dopamine receptor antagonist for at least 3 months; clinical diagnosis of TD and has had symptoms for at least 3 months prior to screening, participants with underlying psychiatric diagnosis are stable and have no change in psychoactive medications.

N = 288

Sex: male and female

Age: 18 to 80 years old

Interventions

1. SD‐809 12 mg tablets dose titrated for 4 weeks to target randomised dose. The dose is maintained for an additional 8 weeks. N = 72

2. SD‐809 24 mg tablets dose titrated for 4 weeks to target randomised dose. The dose is maintained for an additional 8 weeks. N = 72

3. SD‐809 36 mg tablets dose titrated for 4 weeks to target randomised dose. The dose is maintained for an additional 8 weeks. N = 72

4. Placebo tablets taken twice daily for 12 weeks. N = 72

Outcomes

Primary: Change in AIMS score from Baseline to Week 12

Secondary:Quality of Life; treatment success based on Patient Global Impression of Change (PGIC) questionnaire; percentage reduction in AIMS score; proportion of responders based on AIMS score change from baseline.

Starting date

October 2014

Contact information

Teva US Medical Information (+1‐800‐896‐5855)

Notes

Auspex Pharmaceuticals, Inc.
Other Study ID Numbers: SD‐809‐C‐23

AIMS ‐ Abnormal Involuntary Movement Scale
CGI ‐ Clinical Global Impression
DHA ‐ docosahexaenoic acid
DSM ‐ Diagnostic and Statistical Manual of Mental Disorders
ICD ‐ International Classification of Diseases
PGIC ‐ Patient Global Impression of Change
TD = tardive dyskinesia

Data and analyses

Open in table viewer
Comparison 1. ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.97]

Analysis 1.1

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.5 [0.23, 1.09]

Analysis 1.2

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.55]

Analysis 1.3

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term Show forest plot

1

28

Mean Difference (IV, Fixed, 95% CI)

‐2.80 [‐12.25, 6.65]

Analysis 1.4

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term.

5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term Show forest plot

2

59

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.31 [‐0.83, 0.20]

Analysis 1.5

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term.

5.1 AIMS+RTDS

1

40

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.31 [‐0.93, 0.32]

5.2 ADS

1

19

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.33 [‐1.24, 0.57]

6 Mental state: Deterioration ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.5 [0.05, 4.90]

Analysis 1.6

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 6 Mental state: Deterioration ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 6 Mental state: Deterioration ‐ medium term.

7 Adverse events ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

2.33 [0.75, 7.23]

Analysis 1.7

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 7 Adverse events ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 7 Adverse events ‐ medium term.

8 Leaving the study early ‐ medium term Show forest plot

2

48

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.02, 7.32]

Analysis 1.8

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 8 Leaving the study early ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 8 Leaving the study early ‐ medium term.

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Comparison 2. ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.35, 0.82]

Analysis 2.1

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term Show forest plot

1

20

Mean Difference (IV, Fixed, 95% CI)

‐4.5 [‐7.60, ‐1.40]

Analysis 2.2

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term.

3 Adverse events: any adverse events ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 2.3

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 3 Adverse events: any adverse events ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 3 Adverse events: any adverse events ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 2.4

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

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Comparison 3. ALKALOID ‐ PAPAVERINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

22

Mean Difference (IV, Fixed, 95% CI)

0.51 [‐1.18, 2.20]

Analysis 3.1

Comparison 3 ALKALOID ‐ PAPAVERINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 3 ALKALOID ‐ PAPAVERINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

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Comparison 4. AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.63, 1.00]

Analysis 4.1

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

2 Tardive dyskinesia: 1. Not any improvement ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.36, 1.11]

Analysis 4.2

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ short term.

3 Tardive dyskinesia: 2. Deterioration ‐ short term Show forest plot

1

36

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.07, 1.19]

Analysis 4.3

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 3 Tardive dyskinesia: 2. Deterioration ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 3 Tardive dyskinesia: 2. Deterioration ‐ short term.

4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term Show forest plot

1

41

Mean Difference (IV, Fixed, 95% CI)

‐92.9 [‐167.57, ‐18.23]

Analysis 4.4

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term.

5 Leaving the study early ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.37, 1.92]

Analysis 4.5

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 5 Leaving the study early ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 5 Leaving the study early ‐ short term.

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Comparison 5. AMINO ACID ‐ PHENYLALANINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Leaving the study early ‐ short term Show forest plot

1

18

Risk Ratio (M‐H, Fixed, 95% CI)

2.45 [0.11, 53.25]

Analysis 5.1

Comparison 5 AMINO ACID ‐ PHENYLALANINE versus PLACEBO, Outcome 1 Leaving the study early ‐ short term.

Comparison 5 AMINO ACID ‐ PHENYLALANINE versus PLACEBO, Outcome 1 Leaving the study early ‐ short term.

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Comparison 6. ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

33

Risk Ratio (M‐H, Fixed, 95% CI)

1.37 [0.96, 1.94]

Analysis 6.1

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Leaving the study early ‐ medium term Show forest plot

1

33

Risk Ratio (M‐H, Fixed, 95% CI)

10.39 [0.62, 173.97]

Analysis 6.2

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 2 Leaving the study early ‐ medium term.

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 2 Leaving the study early ‐ medium term.

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Comparison 7. ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.24 [0.08, 0.71]

Analysis 7.1

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term.

2 Tardive dyskinesia: 1. Not any improvement ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.14 [0.03, 0.64]

Analysis 7.2

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ long term.

3 Adverse effects ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 65.90]

Analysis 7.3

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 3 Adverse effects ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 3 Adverse effects ‐ long term.

4 Leaving the study early ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 65.90]

Analysis 7.4

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 4 Leaving the study early ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 4 Leaving the study early ‐ long term.

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Comparison 8. ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: No clinically important improvement (short term) Show forest plot

1

10

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.70, 1.43]

Analysis 8.1

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (short term).

2 Tardive dyskinesia: Not any improvement (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.28 [0.02, 4.66]

Analysis 8.2

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (short term).

3 Tardive dyskinesia: Deterioration (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.47 [0.02, 9.26]

Analysis 8.3

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 3 Tardive dyskinesia: Deterioration (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 3 Tardive dyskinesia: Deterioration (short term).

4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term) Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐2.0 [‐5.93, 1.93]

Analysis 8.4

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term).

5 General mental state: Deterioration (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.47 [0.02, 9.26]

Analysis 8.5

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 5 General mental state: Deterioration (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 5 General mental state: Deterioration (short term).

6 General mental state: Average change score (BPRS, high=poor) (short term) Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐0.80 [‐3.10, 1.50]

Analysis 8.6

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 6 General mental state: Average change score (BPRS, high=poor) (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 6 General mental state: Average change score (BPRS, high=poor) (short term).

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Comparison 9. ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term Show forest plot

1

50

Mean Difference (IV, Fixed, 95% CI)

‐2.18 [‐3.65, ‐0.71]

Analysis 9.1

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term.

2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term Show forest plot

1

69

Mean Difference (IV, Fixed, 95% CI)

0.13 [‐0.73, 0.99]

Analysis 9.2

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term.

3 Leaving the study early ‐ medium term Show forest plot

2

119

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.46, 2.22]

Analysis 9.3

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ medium term.

4 Adverse effects ‐ medium term Show forest plot

1

69

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.25, 1.04]

Analysis 9.4

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 4 Adverse effects ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 4 Adverse effects ‐ medium term.

5 Mental state: deterioration ‐ medium term Show forest plot

1

50

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.12, 3.65]

Analysis 9.5

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

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Comparison 10. ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.27, 1.08]

Analysis 10.1

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. Not any improvement ‐ short term.

2 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.74]

Analysis 10.2

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Deterioration ‐ short term.

3 Adverse events ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.04, 2.95]

Analysis 10.3

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 3 Adverse events ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 3 Adverse events ‐ short term.

4 Leaving the study early ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.74]

Analysis 10.4

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 4 Leaving the study early ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 4 Leaving the study early ‐ short term.

Open in table viewer
Comparison 11. ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: No clinically important improvement (medium term) Show forest plot

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

0.24 [0.11, 0.55]

Analysis 11.1

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (medium term).

2 Tardive dyskinesia: Not any improvement (medium term) Show forest plot

1

34

Risk Ratio (IV, Fixed, 95% CI)

0.06 [0.01, 0.43]

Analysis 11.2

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (medium term).

3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐7.10 [‐9.53, ‐4.67]

Analysis 11.3

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term).

4 General mental state: Average endpoint score (BPRS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

0.70 [‐3.77, 5.17]

Analysis 11.4

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 4 General mental state: Average endpoint score (BPRS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 4 General mental state: Average endpoint score (BPRS, high=poor) (medium term).

5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐0.53, 0.33]

Analysis 11.5

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term).

6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐0.5 [‐1.36, 0.36]

Analysis 11.6

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term).

7 Global state: Average endpoint score (CGI, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐1.00 [‐3.78, ‐2.22]

Analysis 11.7

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 7 Global state: Average endpoint score (CGI, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 7 Global state: Average endpoint score (CGI, high=poor) (medium term).

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Comparison 12. ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.33, 0.84]

Analysis 12.1

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.15, 0.75]

Analysis 12.2

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

42

Mean Difference (IV, Fixed, 95% CI)

0.0 [‐1.45, 1.45]

Analysis 12.3

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 12.4

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

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Comparison 13. COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

‐0.70 [‐4.30, 2.90]

Analysis 13.1

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

2.5 [‐4.73, 9.73]

Analysis 13.2

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

3 Leaving the study early ‐ short term Show forest plot

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.03, 1.85]

Analysis 13.3

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ short term.

4 Global state: Average endpoint score (CGI, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

0.20 [‐0.35, 0.75]

Analysis 13.4

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 4 Global state: Average endpoint score (CGI, high=poor) ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 4 Global state: Average endpoint score (CGI, high=poor) ‐ short term.

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Comparison 14. COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.29, 0.77]

Analysis 14.1

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.13, 0.66]

Analysis 14.2

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

46

Mean Difference (IV, Fixed, 95% CI)

‐3.90 [‐5.47, ‐2.33]

Analysis 14.3

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 14.4

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

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Comparison 15. ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

92

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.46, 0.86]

Analysis 15.1

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term Show forest plot

1

89

Mean Difference (IV, Fixed, 95% CI)

‐2.5 [‐2.00, ‐1.00]

Analysis 15.2

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term.

3 Adverse events ‐ medium term Show forest plot

1

100

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [0.92, 2.45]

Analysis 15.3

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 3 Adverse events ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 3 Adverse events ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

102

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.31, 3.25]

Analysis 15.4

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

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Comparison 16. FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.57, 1.18]

Analysis 16.1

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term.

2 Mental state: deterioration ‐ medium term Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.49 [0.05, 5.14]

Analysis 16.2

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 2 Mental state: deterioration ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 2 Mental state: deterioration ‐ medium term.

3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐1.17, 1.77]

Analysis 16.3

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

‐0.35 [‐0.58, ‐0.12]

Analysis 16.4

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

‐0.04 [‐0.30, 0.22]

Analysis 16.5

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

6 Leaving the study early ‐ medium term Show forest plot

1

84

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.27, 1.22]

Analysis 16.6

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

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Comparison 17. FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.69, 1.45]

Analysis 17.1

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.24, 2.33]

Analysis 17.2

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

1.5 [0.34, 6.70]

Analysis 17.3

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

16

Mean Difference (IV, Fixed, 95% CI)

‐0.20 [‐3.10, 2.70]

Analysis 17.4

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term.

5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐6.0 [‐15.99, 3.99]

Analysis 17.5

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term.

6 Leaving the study early ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 17.6

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

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Comparison 18. HERB ‐ GINKGO BILOBA versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.81, 0.96]

Analysis 18.1

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.41, 0.65]

Analysis 18.2

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

157

Mean Difference (IV, Fixed, 95% CI)

‐2.06 [‐2.94, ‐1.18]

Analysis 18.3

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.25 [0.03, 2.22]

Analysis 18.4

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

5 Mental state: deterioration ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.16]

Analysis 18.5

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term Show forest plot

1

157

Mean Difference (IV, Fixed, 95% CI)

‐3.30 [‐6.51, ‐0.09]

Analysis 18.6

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term.

7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term Show forest plot

1

119

Mean Difference (IV, Fixed, 95% CI)

‐0.02 [‐0.10, 0.06]

Analysis 18.7

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term.

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Comparison 19. HORMONE ‐ OESTROGEN versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.76, 1.83]

Analysis 19.1

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.05, 2.37]

Analysis 19.2

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

10

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.01, 3.35]

Analysis 19.3

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐1.2 [‐4.18, 1.78]

Analysis 19.4

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term.

5 Adverse effects ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.02, 6.86]

Analysis 19.5

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 5 Adverse effects ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 5 Adverse effects ‐ short term.

6 Leaving the study early ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.08, 12.56]

Analysis 19.6

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

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Comparison 20. HORMONE ‐ INSULIN versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.29, 0.96]

Analysis 20.1

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.06 [0.00, 0.90]

Analysis 20.2

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.45]

Analysis 20.3

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

20

Mean Difference (IV, Fixed, 95% CI)

‐6.20 [‐10.53, ‐1.87]

Analysis 20.4

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

5 Leaving the study early ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 20.5

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 5 Leaving the study early ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 5 Leaving the study early ‐ medium term.

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Comparison 21. HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement Show forest plot

2

32

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.71, 1.12]

Analysis 21.1

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement.

1.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.83, 1.21]

1.2 Medium term

1

13

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.44, 1.23]

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.47, 2.60]

Analysis 21.2

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.22 [0.01, 4.05]

Analysis 21.3

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

13

Mean Difference (IV, Fixed, 95% CI)

‐2.38 [‐6.58, 1.82]

Analysis 21.4

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

5 Adverse effects Show forest plot

3

54

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 21.5

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 5 Adverse effects.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 5 Adverse effects.

5.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Medium term

2

35

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Leaving the study early Show forest plot

3

54

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 21.6

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 6 Leaving the study early.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 6 Leaving the study early.

6.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Medium term

2

35

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Cognitive function: Average scale score ‐ medium term Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 21.7

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 7 Cognitive function: Average scale score ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 7 Cognitive function: Average scale score ‐ medium term.

7.1 WAIS

1

76

Mean Difference (IV, Fixed, 95% CI)

15.83 [4.61, 27.05]

7.2 WMS

1

76

Mean Difference (IV, Fixed, 95% CI)

3.77 [‐8.21, 15.75]

8 Mental state: deterioration ‐ medium term Show forest plot

1

13

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 21.8

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 8 Mental state: deterioration ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 8 Mental state: deterioration ‐ medium term.

Open in table viewer
Comparison 22. MOOD STABILISER ‐ LITHIUM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

1.59 [0.79, 3.23]

Analysis 22.1

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

4.29 [0.25, 72.90]

Analysis 22.2

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

4.29 [0.25, 72.90]

Analysis 22.3

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

0.63 [‐5.23, 6.49]

Analysis 22.4

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term.

5 Adverse events ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

6.0 [0.38, 94.35]

Analysis 22.5

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 5 Adverse events ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 5 Adverse events ‐ short term.

6 Leaving the study early ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

2.57 [0.13, 52.12]

Analysis 22.6

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

Open in table viewer
Comparison 23. POLYPEPTIDE ‐ CERULETIDE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Not any improvement Show forest plot

2

132

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.65, 1.07]

Analysis 23.1

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Not any improvement.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Not any improvement.

1.1 Short term

1

47

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.50, 1.06]

1.2 Medium term

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.64, 1.27]

2 Tardive dyskinesia: 2. Deterioration Show forest plot

2

103

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.14, 6.80]

Analysis 23.2

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Deterioration.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Deterioration.

2.1 Short term

1

37

Risk Ratio (M‐H, Fixed, 95% CI)

2.85 [0.12, 65.74]

2.2 Medium term

1

66

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.90]

3 Adverse effects Show forest plot

2

122

Risk Ratio (M‐H, Fixed, 95% CI)

1.32 [0.74, 2.36]

Analysis 23.3

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 3 Adverse effects.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 3 Adverse effects.

3.1 Short term

1

37

Risk Ratio (M‐H, Fixed, 95% CI)

3.79 [0.47, 30.77]

3.2 Medium term

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

1.13 [0.61, 2.07]

4 Leaving the study early ‐ medium term Show forest plot

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.49, 2.40]

Analysis 23.4

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Open in table viewer
Comparison 24. HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.94]

Analysis 24.1

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 3.81]

Analysis 24.2

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 3.81]

Analysis 24.3

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

4 Leaving the study early ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Analysis 24.4

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 4 Leaving the study early ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 4 Leaving the study early ‐ medium term.

4.1 Short term

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Message from one of the participants of the Public and patient involvement consultation of service user perspectives on tardive dyskinesia research.
Figuras y tablas -
Figure 1

Message from one of the participants of the Public and patient involvement consultation of service user perspectives on tardive dyskinesia research.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figuras y tablas -
Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Study flow diagram for 2015 and 2017 searches.
Figuras y tablas -
Figure 4

Study flow diagram for 2015 and 2017 searches.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 1.1

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 1.2

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.
Figuras y tablas -
Analysis 1.3

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 1.4

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 1.5

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 6 Mental state: Deterioration ‐ medium term.
Figuras y tablas -
Analysis 1.6

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 6 Mental state: Deterioration ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 7 Adverse events ‐ medium term.
Figuras y tablas -
Analysis 1.7

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 7 Adverse events ‐ medium term.

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 8 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 1.8

Comparison 1 ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO, Outcome 8 Leaving the study early ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 2.1

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 2.2

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 3 Adverse events: any adverse events ‐ medium term.
Figuras y tablas -
Analysis 2.3

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 3 Adverse events: any adverse events ‐ medium term.

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 2.4

Comparison 2 ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 3 ALKALOID ‐ PAPAVERINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 3.1

Comparison 3 ALKALOID ‐ PAPAVERINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.
Figuras y tablas -
Analysis 4.1

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ short term.
Figuras y tablas -
Analysis 4.2

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 3 Tardive dyskinesia: 2. Deterioration ‐ short term.
Figuras y tablas -
Analysis 4.3

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 3 Tardive dyskinesia: 2. Deterioration ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term.
Figuras y tablas -
Analysis 4.4

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term.

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 5 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 4.5

Comparison 4 AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO, Outcome 5 Leaving the study early ‐ short term.

Comparison 5 AMINO ACID ‐ PHENYLALANINE versus PLACEBO, Outcome 1 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 5.1

Comparison 5 AMINO ACID ‐ PHENYLALANINE versus PLACEBO, Outcome 1 Leaving the study early ‐ short term.

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 6.1

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 2 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 6.2

Comparison 6 ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO, Outcome 2 Leaving the study early ‐ medium term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term.
Figuras y tablas -
Analysis 7.1

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ long term.
Figuras y tablas -
Analysis 7.2

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 2 Tardive dyskinesia: 1. Not any improvement ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 3 Adverse effects ‐ long term.
Figuras y tablas -
Analysis 7.3

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 3 Adverse effects ‐ long term.

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 4 Leaving the study early ‐ long term.
Figuras y tablas -
Analysis 7.4

Comparison 7 ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE, Outcome 4 Leaving the study early ‐ long term.

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (short term).
Figuras y tablas -
Analysis 8.1

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (short term).
Figuras y tablas -
Analysis 8.2

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 3 Tardive dyskinesia: Deterioration (short term).
Figuras y tablas -
Analysis 8.3

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 3 Tardive dyskinesia: Deterioration (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term).
Figuras y tablas -
Analysis 8.4

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 5 General mental state: Deterioration (short term).
Figuras y tablas -
Analysis 8.5

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 5 General mental state: Deterioration (short term).

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 6 General mental state: Average change score (BPRS, high=poor) (short term).
Figuras y tablas -
Analysis 8.6

Comparison 8 ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO, Outcome 6 General mental state: Average change score (BPRS, high=poor) (short term).

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 9.1

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term.
Figuras y tablas -
Analysis 9.2

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 9.3

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 4 Adverse effects ‐ medium term.
Figuras y tablas -
Analysis 9.4

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 4 Adverse effects ‐ medium term.

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.
Figuras y tablas -
Analysis 9.5

Comparison 9 ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. Not any improvement ‐ short term.
Figuras y tablas -
Analysis 10.1

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Deterioration ‐ short term.
Figuras y tablas -
Analysis 10.2

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 3 Adverse events ‐ short term.
Figuras y tablas -
Analysis 10.3

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 3 Adverse events ‐ short term.

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 4 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 10.4

Comparison 10 ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO, Outcome 4 Leaving the study early ‐ short term.

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (medium term).
Figuras y tablas -
Analysis 11.1

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 1 Tardive dyskinesia: No clinically important improvement (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (medium term).
Figuras y tablas -
Analysis 11.2

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 2 Tardive dyskinesia: Not any improvement (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term).
Figuras y tablas -
Analysis 11.3

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 4 General mental state: Average endpoint score (BPRS, high=poor) (medium term).
Figuras y tablas -
Analysis 11.4

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 4 General mental state: Average endpoint score (BPRS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term).
Figuras y tablas -
Analysis 11.5

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term).
Figuras y tablas -
Analysis 11.6

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term).

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 7 Global state: Average endpoint score (CGI, high=poor) (medium term).
Figuras y tablas -
Analysis 11.7

Comparison 11 ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO, Outcome 7 Global state: Average endpoint score (CGI, high=poor) (medium term).

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 12.1

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 12.2

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 12.3

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 12.4

Comparison 12 ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term.
Figuras y tablas -
Analysis 13.1

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term.
Figuras y tablas -
Analysis 13.2

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 13.3

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 3 Leaving the study early ‐ short term.

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 4 Global state: Average endpoint score (CGI, high=poor) ‐ short term.
Figuras y tablas -
Analysis 13.4

Comparison 13 COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO, Outcome 4 Global state: Average endpoint score (CGI, high=poor) ‐ short term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 14.1

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 14.2

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 14.3

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 14.4

Comparison 14 COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 15.1

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 15.2

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 3 Adverse events ‐ medium term.
Figuras y tablas -
Analysis 15.3

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 3 Adverse events ‐ medium term.

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 15.4

Comparison 15 ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 16.1

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 2 Mental state: deterioration ‐ medium term.
Figuras y tablas -
Analysis 16.2

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 2 Mental state: deterioration ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term.
Figuras y tablas -
Analysis 16.3

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.
Figuras y tablas -
Analysis 16.4

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.
Figuras y tablas -
Analysis 16.5

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term.

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 16.6

Comparison 16 FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 17.1

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 17.2

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.
Figuras y tablas -
Analysis 17.3

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 17.4

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 17.5

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term.

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 17.6

Comparison 17 FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO, Outcome 6 Leaving the study early ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 18.1

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 18.2

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 18.3

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 18.4

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.
Figuras y tablas -
Analysis 18.5

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 5 Mental state: deterioration ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 18.6

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term.

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term.
Figuras y tablas -
Analysis 18.7

Comparison 18 HERB ‐ GINKGO BILOBA versus PLACEBO, Outcome 7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.
Figuras y tablas -
Analysis 19.1

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.
Figuras y tablas -
Analysis 19.2

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.
Figuras y tablas -
Analysis 19.3

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term.
Figuras y tablas -
Analysis 19.4

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 5 Adverse effects ‐ short term.
Figuras y tablas -
Analysis 19.5

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 5 Adverse effects ‐ short term.

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 19.6

Comparison 19 HORMONE ‐ OESTROGEN versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 20.1

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 20.2

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.
Figuras y tablas -
Analysis 20.3

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 20.4

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 5 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 20.5

Comparison 20 HORMONE ‐ INSULIN versus PLACEBO, Outcome 5 Leaving the study early ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement.
Figuras y tablas -
Analysis 21.1

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.
Figuras y tablas -
Analysis 21.2

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.
Figuras y tablas -
Analysis 21.3

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.
Figuras y tablas -
Analysis 21.4

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 5 Adverse effects.
Figuras y tablas -
Analysis 21.5

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 5 Adverse effects.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 6 Leaving the study early.
Figuras y tablas -
Analysis 21.6

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 6 Leaving the study early.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 7 Cognitive function: Average scale score ‐ medium term.
Figuras y tablas -
Analysis 21.7

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 7 Cognitive function: Average scale score ‐ medium term.

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 8 Mental state: deterioration ‐ medium term.
Figuras y tablas -
Analysis 21.8

Comparison 21 HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT, Outcome 8 Mental state: deterioration ‐ medium term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.
Figuras y tablas -
Analysis 22.1

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.
Figuras y tablas -
Analysis 22.2

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.
Figuras y tablas -
Analysis 22.3

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term.
Figuras y tablas -
Analysis 22.4

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 5 Adverse events ‐ short term.
Figuras y tablas -
Analysis 22.5

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 5 Adverse events ‐ short term.

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.
Figuras y tablas -
Analysis 22.6

Comparison 22 MOOD STABILISER ‐ LITHIUM versus PLACEBO, Outcome 6 Leaving the study early ‐ short term.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Not any improvement.
Figuras y tablas -
Analysis 23.1

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 1 Tardive dyskinesia: 1. Not any improvement.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Deterioration.
Figuras y tablas -
Analysis 23.2

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 2 Tardive dyskinesia: 2. Deterioration.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 3 Adverse effects.
Figuras y tablas -
Analysis 23.3

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 3 Adverse effects.

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 23.4

Comparison 23 POLYPEPTIDE ‐ CERULETIDE versus PLACEBO, Outcome 4 Leaving the study early ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.
Figuras y tablas -
Analysis 24.1

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.
Figuras y tablas -
Analysis 24.2

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 2 Tardive dyskinesia: 2. Not any improvement ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.
Figuras y tablas -
Analysis 24.3

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 3 Tardive dyskinesia: 3. Deterioration ‐ medium term.

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 4 Leaving the study early ‐ medium term.
Figuras y tablas -
Analysis 24.4

Comparison 24 HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL, Outcome 4 Leaving the study early ‐ medium term.

Table 3. Suggestions for design of future study

Methods

Allocation: randomised, with sequence generation and concealment of allocation clearly described.
Blindness: double, tested.
Duration: 12 months beyond end of intervention at least.
Raters: independent.

Participants

People with antipsychotic‐induced tardive dyskinesia.*
Age: any.
Sex: both.
History: any.
N = 300.**

Interventions

1. Active intervention. N = 150.
2. Placebo: N = 150.

Outcomes

Tardive dyskinesia: any clinically important improvement in TD, any improvement, deterioration.***
Adverse effects: no clinically significant extrapyramidal adverse effects ‐ any time period***, use of any antiparkinsonism drugs, other important adverse events.
Leaving the study early.
Service outcomes: admitted, number of admissions, length of hospitalisation, contacts with psychiatric services.
Compliance with drugs.
Economic evaluations: cost‐effectiveness, cost‐benefit.
General state: relapse, frequency and intensity of minor and major exacerbations.
Social confidence, social inclusion, social networks, or personalised quality of life: binary measure
Distress among relatives: binary measure.
Burden on family: binary measure.

Notes

* This could be diagnosed by clinical decision. If funds were permitting all participants could be screened using operational criteria, otherwise a random sample should suffice.

** Size of study with sufficient power to highlight about a 10% difference between groups for primary outcome.
*** Primary outcome. The same applies to the measure of primary outcome as for diagnosis. Not everyone may need to have operational criteria applied if clinical impression is proved to be accurate.

Figuras y tablas -
Table 3. Suggestions for design of future study
Summary of findings for the main comparison. ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO for antipsychotic‐induced tardive dyskinesia

DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 59‐80 (mean) years old patients with antipsychotic‐induced tardive dyskinesia
Settings: inpatients in Japan and the UK
Intervention: dihydrogenated ergot alkaloids (co‐dergocrine mesylate) (4.5 mg/day to 6 mg/day) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

DIHYDROGENATED ERGOT ALKALOIDS

Tardive dyskinesia: No clinically important improvement
follow‐up: 6 weeks

786 per 1000

354 per 1000
(165 to 762)

RR 0.45
(0.21 to 0.97)

28
(1 RCT)

⊕⊕⊝⊝
low1,2

Tardive dyskinesia: Deterioration of symptoms

follow‐up: 6 weeks

71 per 1000

24 per 1000
(1 to 539)

RR 0.33
(0.01 to 7.55)

28
(1 RCT)

⊕⊝⊝⊝
very low1,3

Adverse effects ‐ any adverse effect

follow‐up: 6 weeks

214 per 1000

499 per 1000
(161 to 1000)

RR 2.33
(0.75 to 7.23)

28
(1 RCT)

⊕⊝⊝⊝
very low1,3

Acceptability of treatment (measured by participants leaving the study early)

follow‐up: 6 weeks

42 per 1000

14 per 1000
(1 to 305)

RR 0.33
(0.02 to 7.32)

48
(2 RCTs)

⊕⊝⊝⊝
very low1,3,4

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for risk of bias: randomisation procedure and allocation concealment were not adequately described.
2 Downgraded one step for imprecision: very small sample size and few events reported.
3 Downgraded two steps for imprecision: very small sample size and very few events reported with the 95% CI around the effect estimate indicating both appreciable benefit for dihydrogenated ergot alkaloids and no effect.
4 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings for the main comparison. ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 2. ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO for antipsychotic‐induced tardive dyskinesia

LEVETIRACETAM versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 47‐54 years old (mean) patients with various psychiatric conditions and antipsychotic‐induced tardive dyskinesia
Settings: in‐ and outpatients in Belgium, Bulgaria, and the USA
Intervention: levetiracetam (1500 mg twice per day) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

LEVETIRACETAM

Tardive dyskinesia: No clinically important improvement ‐ not reported

This outcome was not reported.

Tardive dyskinesia: Deterioration of symptoms ‐ not reported

This outcome was not reported.

Adverse effects ‐ any adverse effect

follow‐up: 8 weeks

457 per 1000

233 per 1000
(114 to 475)

RR 0.51
(0.25 to 1.04)

69
(1 RCT)

⊕⊕⊝⊝
low1,2

Acceptability of treatment (measured by participants leaving the study early)
follow‐up: 8‐12 weeks

167 per 1000

168 per 1000
(77 to 370)

RR 1.01
(0.46 to 2.22)

119
(2 RCTs)

⊕⊝⊝⊝
very low1,2,3

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for risk of bias: randomisation procedure, allocation concealment and blinding were not adequately described.
2 Downgraded one step for imprecision: small sample size and few events reported with the 95% CI around the effect estimate indicating both appreciable benefit for levetiracetam and no effect.
3 Downgraded one step for inconsistency: substantial heterogeneity (I2 = 73%).

Figuras y tablas -
Summary of findings 2. ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 3. ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO for antipsychotic‐induced tardive dyskinesia

BUSPIRONE versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 33‐year old (mean) patients with schizophrenia and antipsychotic‐induced tardive dyskinesia
Setting: inpatients, China
Intervention: Buspirone versus placebo.

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with buspirone

Tardive dyskinesia: No clinically important improvement
follow‐up: 6 weeks

905 per 1,000

480 per 1,000
(299 to 760)

RR 0.53
(0.33 to 0.84)

42
(1 RCT)

⊕⊕⊝⊝
low1,2

Tardive dyskinesia: Deterioration of symptoms ‐ not reported

This outcome was not reported.

Adverse effects ‐ not reported

This outcome was not reported.

Acceptability of treatment (measured by participants leaving the study early)
follow‐up: 6 weeks

not estimable

not estimable

RR not estimable

42
(1 RCT)

⊕⊝⊝⊝
very low1,3

No events were reported.

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded one step for risk of bias: randomisation procedure, allocation concealment and blinding were not adequately described.

2 Downgraded one step for imprecision: very small sample size and few events reported.

3 Downgraded two steps for imprecision: effect could not be estimated due to very small sample size with no events reported.

Figuras y tablas -
Summary of findings 3. ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 4. ENZYME INHIBITOR ‐ VMAT2‐INHIBITOR (valbenazine) versus PLACEBO for antipsychotic‐induced tardive dyskinesia

VMAT2‐inhibitor compared to placebo for antipsychotic‐induced tardive dyskinesia

Patient or population: 18 to 85 year‐old patients with schizophrenia, schizoaffective disorder, mood disorder, or gastrointestinal disorder + antipsychotic‐induced tardive dyskinesia
Settings: in‐ and outpatients in the USA
Intervention: Valbenazine (NBI‐98854) (25mg to 75mg/day) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

VMAT2‐inhibitor

Tardive dyskinesia: 1. No clinically important improvement
Follow‐up: 6 weeks

826 per 1000

520 per 1000
(380 to 710)

RR 0.63
(0.46 to 0.86)

92
(1 study)

⊕⊕⊕⊝
moderate1

Adverse effects ‐ any adverse effect
Follow‐up: 6 weeks

327 per 1000

490 per 1000
(300 to 800)

RR 1.50
(0.92 to 2.45)

100
(1 study)

⊕⊕⊝⊝
low2

Leaving the study early
follow‐up: 6 weeks

98 per 1000

98 per 1000
(30 to 319)

RR 1.00
(0.31 to 3.25)

102
(1 study)

⊕⊝⊝⊝
very low2,3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for imprecision: small sample size and few events reported
2 Downgraded two steps for serious imprecision: small sample size and very few events reported with the 95% CI around the effect estimate indicating both appreciable benefit for valbenazine and no effect.
3 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings 4. ENZYME INHIBITOR ‐ VMAT2‐INHIBITOR (valbenazine) versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 5. FATTY ACID ‐ ETHYL‐EPA versus PLACEBO for antipsychotic‐induced tardive dyskinesia

ETHYL‐EPA versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 42 (mean) years old patients with schizophrenia or schizoaffective disorder and antipsychotic‐induced tardive dyskinesia
Settings: in‐ and outpatients in South Africa
Intervention: ethyl‐EPA (omega‐3 fatty acid eicosapentaenoic acid derivative) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

ETHYL‐EPA

Tardive dyskinesia: No clinically important improvement ‐ not reported

This outcome was not reported.

Tardive dyskinesia: Deterioration of symptoms ‐ not reported

This outcome was not reported.

Adverse effects: EPS: parkinsonism

measured by average ESRS change scores

follow‐up: 12 weeks

mean: ‐1.1 (3.3)

The mean change in ESRS: parkinsonism scale score in the ethyl‐EPA group was
0.3 points higher
(1.17 lower to 1.77 higher)

MD 0.30

(‐1.17 to 1.77)

75

(1 RCT)

⊕⊕⊝⊝
low1,2

Adverse effects: EPS: dystonia

measured by average ESRS change scores

follow‐up: 12 weeks

mean: 0.4 (0.5)

The mean change in ESRS: dystonia scale score in the ethyl‐EPA group was
0.35 points lower
(0.58 to 0.12 lower)

MD ‐0.35

(‐0.58 to ‐0.12)

75

(1 RCT)

⊕⊕⊝⊝
low1,2

Adverse effects: EPS: akathisia

measured by average ESRS change scores

follow‐up: 12 weeks

mean: ‐0.06 (0.7)

The mean change in ESRS: akathisia scale score in the ethyl‐EPA group was
0.04 points lower
(0.3 lower to 0.22 higher)

MD ‐0.04

(‐0.30 to 0.22)

75

(1 RCT)

⊕⊝⊝⊝
very low1,3

Acceptability of treatment (measured by participants leaving the study early)

follow‐up: 12 weeks

548 per 1000

214 per 1000
(115 to 406)

RR 0. 57
(0.2 7 to 1.22)

84
(1 RCT)

⊕⊝⊝⊝
very low1,2,4

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; EPS: extrapyramidal symptoms; ESRS: Extrapyramidal Symptom Rating Scale; ethyl‐EPA: ethyl‐eicosapentaenoic acid; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for risk of bias: randomisation procedure, allocation concealment and blinding were not adequately described.
2 Downgraded one step for imprecision: small sample size.
3 Downgraded two steps for serious imprecision: small sample size with the 95% CI around the effect estimate indicating both appreciable benefit for ethyl‐EPA and no effect.
4 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings 5. FATTY ACID ‐ ETHYL‐EPA versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 6. HERB ‐ GINKGO BILOBA versus PLACEBO for antipsychotic‐induced tardive dyskinesia

GINKGO BILOBA versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: male 45.2 (mean) years old patients with schizophrenia and antipsychotic‐induced tardive dyskinesia
Settings: inpatients in China
Intervention:GINKGO BILOBA (EGb‐761, standardised extract of Ginkgo biloba leaves) versus PLACEBO

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

GINKGO BILOBA

Tardive dyskinesia: No clinically important improvement
follow‐up: 12 weeks

987 per 1000

869 per 1000
(800 to 948)

RR 0.88
(0.81 to 0.96)

157
(1 RCT)

⊕⊕⊕⊝
moderate1

Tardive dyskinesia: Deterioration of symptoms ‐ not reported

This outcome was not reported.

Adverse effects ‐ not reported

This outcome was not reported.

Acceptability of treatment (measured by participants leaving the study early)
follow‐up: 12 weeks

51 per 1000

13 per 1000
(2 to 112)

RR 0.25
(0.03 to 2.22)

157
(1 RCT)

⊕⊝⊝⊝
very low2,3

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for imprecision: small sample size and few events reported.
2 Downgraded two steps for serious imprecision: small sample size and very few events reported with the 95% CI around the effect estimate indicating both appreciable benefit for Ginkgo biloba and no effect.
3 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings 6. HERB ‐ GINKGO BILOBA versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 7. HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT for antipsychotic‐induced tardive dyskinesia

MELATONIN versus PLACEBO OR NO TREATMENT for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 28 to 91 years old patients with antipsychotic‐induced tardive dyskinesia
Settings: in‐ and outpatients in Israel and Venezuela
Intervention: melatonin (2‐20 mg/day) versus placebo or no treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo/no treatment

MELATONIN

Tardive dyskinesia: No clinically important improvement
follow‐up: 3‐12 weeks

1000 per 1000

890 per 1000
(710 to 1000)

RR 0.89
(0.71 to 1.12)

32
(2 RCTs)

⊕⊕⊝⊝
low1,2

Tardive dyskinesia: Deterioration of symptoms

follow‐up: 3 weeks

200 per 1000

44 per 1000
(2 to 810)

RR 0.22
(0.01 to 4.05)

19
(1 RCT)

⊕⊕⊝⊝
low3

Adverse effects

follow‐up: 3‐12 weeks

See comment

See comment

Not estimable

54
(3 RCTs)

⊕⊕⊝⊝
low3

No events were reported.

Acceptability of treatment (measured by participants leaving the study early)
follow‐up: 3‐12 weeks

See comment

See comment

Not estimable

54
(3 RCTs)

⊕⊝⊝⊝
very low3,4

No events were reported.

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for inconsistency: substantial heterogeneity (I2 = 46%).
2 Downgraded one step for imprecision: small sample size and few events reported with the 95% CI around the effect estimate indicating both appreciable benefit for melatonin and no effect.
3 Downgraded two steps for imprecision: very small sample size and no or very few events reported.
4 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings 7. HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT for antipsychotic‐induced tardive dyskinesia
Summary of findings 8. POLYPEPTIDE ‐ CERULETIDE versus PLACEBO for antipsychotic‐induced tardive dyskinesia

CERULETIDE versus PLACEBO for antipsychotic‐induced tardive dyskinesia

Patient or population: female and male 55‐59 year old (mean) patients with various psychiatric conditions and antipsychotic‐induced tardive dyskinesia
Settings: in‐ and outpatients in Japan
Intervention: ceruletide (0.8 microgram/kg/week) versus placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

CERULETIDE

Tardive dyskinesia: No clinically important improvement ‐ not reported

This outcome was not reported.

Tardive dyskinesia: Deterioration of symptoms

follow‐up: 4‐8 weeks

20 per 1000

19 per 1000
(3 to 133)

RR 0.97
(0.14 to 6.80)

103
(2 RCTs)

⊕⊕⊝⊝
low1,2

Adverse effects ‐ any adverse effect

follow‐up: 4‐8 weeks

233 per 1000

308 per 1000
(173 to 551)

RR 1.32
(0.74 to 2.36)

122
(2 RCTs)

⊕⊕⊝⊝
low1,2

Acceptability of treatment (measured by participants leaving the study early)

follow‐up: 8 weeks

214 per 1000

234 per 1000
(105 to 514)

RR 1.09
(0.49 to 2.40)

85
(1 RCT)

⊕⊝⊝⊝
very low1,2,3

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Downgraded one step for risk of bias: unclear methods of randomisation, blinding not assessed, and potential introduction of detection bias due to subjective nature of outcome assessments.
2 Downgraded one step for imprecision: the two included studies included only 132 participants and the 95% CI around the effect estimate indicated both appreciable benefit for ceruletide and no effect.

3 Downgraded one step for indirectness: leaving the study early can give an indication, but is not a direct measurement, of treatment acceptability.

Figuras y tablas -
Summary of findings 8. POLYPEPTIDE ‐ CERULETIDE versus PLACEBO for antipsychotic‐induced tardive dyskinesia
Summary of findings 9. HYPNOSIS or RELAXATION versus TAU for antipsychotic‐induced tardive dyskinesia

HYPNOSIS OR RELAXATION versus TAU for antipsychotic‐induced tardive dyskinesia

Patients or population: female and male 35 (mean) years old patients with schizophrenia and tardive dyskinesia, acute extrapyramidal symptoms, and/or pseudoparkinsonism
Setting: outpatients in the USA
Interventions: hypnosis or relaxation (8 sessions) versus TAU

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with TAU

Risk with hypnosis or relaxation

Tardive dyskinesia: No clinically important improvement
follow‐up: 8 weeks

1,000 per 1,000

450 per 1,000
(210 to 940)

RR 0.45
(0.21 to 0.94)

15
(1 RCT)

⊕⊝⊝⊝
very low1,2

Tardive dyskinesia: Deterioration of symptoms
follow‐up: 8 weeks

200 per 1,000

36 per 1,000
(2 to 762)

RR 0.18
(0.01 to 3.81)

15
(1 RCT)

⊕⊝⊝⊝
very low1,3

Adverse effects ‐ not reported

This outcome was not reported.

Acceptability of treatment (measured by participants leaving the study early)
follow‐up: 8 weeks

0 per 1,000

0 per 1,000
(0 to 0)

not estimable

15
(1 RCT)

⊕⊝⊝⊝
very low1,4

No events were reported.

Social confidence, social inclusion, social networks, or personalised quality of life ‐ not reported

This outcome was not reported.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: Risk ratio; TAU: treatment as usual

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Downgraded two steps for risk of bias: fully randomised sequence generation and blinding was not achieved.
2 Downgraded one step for imprecision: very small sample size.
3 Downgraded two steps for imprecision: 95% CI includes benefit for both intervention arms; very small sample size with few events reported.
4 Downgraded two steps for imprecision: effect could not be estimated due to very small sample size with no events reported.

Figuras y tablas -
Summary of findings 9. HYPNOSIS or RELAXATION versus TAU for antipsychotic‐induced tardive dyskinesia
Table 1. Other relevant reviews

Review

Citation

Anticholinergics

Bergman 2018a

Benzodiazepines

Bergman 2018

Calcium‐channel blockers

Essali 2011

Cholinergics

Tammenmaa 2002

GABAergic compounds

Alabed 2011

Neuroleptic medications (including dose reduction and cessation)

Soares‐Weiser 2006

Non‐neuroleptic compounds that impact on the dopamine and noradrenaline systems (catecholaminergics)

El‐Sayeh 2006

Vitamin E

Soares‐Weiser 2011

This review, Miscellaneous treatments

Figuras y tablas -
Table 1. Other relevant reviews
Table 2. Overview of study characteristics

Study

N and setting

Condition

Sex and age

Intervention and duration

Comparison

Outcomes

Bucci 1971

20 outpatients in the USA

schizophrenia + TD

F+M
45‐62 years

Isocarboxazid + AP
40 weeks

Procyclidine + AP

TD symptoms, AEs

Cai 1988

57 participants, setting not reported

TD

F+M
28‐59 years

L‐stepholidine + AP
8 weeks

Placebo + AP

TD symptoms, AEs, mental state

Castro 2011

13 in‐ and outpatients in Venezuela

various psychiatric conditions + TD

F+M
46‐75 years

Melatonin + AP
12 weeks

Placebo + AP

TD symptoms, AEs, mental state

Emsley 2006

84 in‐ and outpatients in South Africa

schizophrenia or schizoaffective disorder + TD

F+M
m = 42 years

Omega‐3 fatty acid + AP
12 weeks

Placebo + AP

TD symptoms, AEs, mental state

Gardos 1979

22 inpatients in the USA

schizophrenia, dementia + TD

F+M
32‐84 years

Papaverine + AP
6 weeks

TAU + AP

TD symptoms

Glazer 1985

12 outpatients in the USA

various psychiatric conditions + TD

F
50‐65 years

Oestrogen + AP
3 weeks

Placebo + AP

TD symptoms, AEs

Glover 1982

15 outpatients in the USA

schizophrenia + TD or EPS

F+M
m = 34.9 years

Hypnosis or relaxation + AP
8 sessions

TAU + AP

TD symptoms

Goff 1993

33 outpatients in the USA

TD

F+M
m = 49 years

Selengiline + AP
6 weeks

Placebo + AP

TD symptoms

Hajioff 1983

20 inpatients in the UK

various psychiatric conditions + TD

F+M
60‐92 years

Ergoloid mesylates + AP
6 weeks

Placebo + AP

TD symptoms

Kojima 1992

85 in‐ and outpatients in Japan

schizophrenia + TD

F+M
31‐75 years

Ceruletide + AP
6 weeks

Placebo + AP

TD symptoms, AEs

Koshino 1979

42 inpatients in Japan

various psychiatric conditions + TD

F+M
m = 56 years

Cyproheptadine + AP
4 weeks

Placebo + AP

TD symptoms, AEs

Koshino 1983

28 inpatients in Japan

schizophrenia + TD

F+M
m = 59 years

Ergoloid mesylates + AP
6 weeks

Placebo + AP

TD symptoms, AEs, mental state

Libov 2007

40 inpatients in Israel

schizophrenia or schizoaffective disorder + TD

F+M
26‐69 years

Piracetam + AP
4 weeks

Placebo + AP

TD symptoms, AEs, global state

Mackay 1980

11 inpatients in the UK

various psychiatric conditions + TD

NR
56‐70 years

Lithium + AP
5 weeks

Placebo + AP

TD symptoms, AEs

Matsunaga 1988

37 inpatients in Japan

various psychiatric conditions + TD

F+M
m = 59 years

Ceruletide + AP
4 weeks

Placebo + AP

TD symptoms, AEs

Meco 1989

10 inpatients in Italy

schizophrenia + TD

F+M
33‐72 years

Ritanserin + AP
4 weeks

Placebo + AP

TD symptoms, AEs, mental state

Mosnik 1997

18 in‐ and outpatients in the USA

schizophrenia + TD

M
28‐65 years

Phenylalanine + AP
1 day

Placebo + AP

Leaving the study early

Mouret 1991

20 inpatients in Morocco

schizophrenia + TD

F+M
20‐67 years

Insulin + AP
12 weeks

Placebo + AP

TD symptoms

O'Brien 2014

88 in‐ and outpatients in the USA

various psychiatric conditions + TD

NR
18‐85 years

NBI‐98854 (VMAT2 inhibitor valbenazine) + AP
6 weeks

Placebo + AP

TD symptoms, AEs

Rastogi 1982

40 inpatients in the UK

various psychiatric conditions + TD

F+M
m = 70 years

Ergoloid mesylates + AP
6 weeks

Placebo + AP

TD symptoms

Richardson 2003

52 in‐ and outpatients in the USA

various psychiatric conditions + TD

M
m = 45 years

Branched‐chain amino acids + AP
3 weeks

Placebo + AP

TD symptoms

Shamir 2000

19 inpatients in Israel

schizophrenia + TD

F+M
62‐91 years

Melatonin + AP
4 weeks

Placebo + AP

TD symptoms, AEs

Shamir 2001

22 inpatients in Israel

schizophrenia + TD

F+M
28‐82 years

Melatonin + AP
6 weeks

Placebo + AP

AEs

Shi 2009

76 inpatients in China

TD

F+M
m = 56 years

Melatonin + AP
12 weeks

TAU + AP

Cognitive function

UCB Pharma 2005

69 inpatients in Belgium and Bulgaria

TD

F+M
18‐80 years

Levetiracetam + AP
8 weeks

Placebo + AP

TD symptoms, AEs

Wolkin 1986

16 in‐ and outpatients in the USA

schizophrenia + TD

M
m = 54 years

Evening primrose oil + AP
6 weeks

Placebo + AP

TD symptoms, mental state

Woods 2008

50 outpatients in the USA

various psychiatric conditions + TD

F+M
m = 47 years

Levetiracetam + AP
12 weeks

Placebo + AP

TD symptoms, mental state

Yang 1999

34 inpatients in China

schizophrenia + TD

F+M
m = 50 years

Promethazine + AP
12 weeks

Placebo + AP

TD symptoms, AEs, mental state, global state

Zeng 1995

42 inpatients in China

schizophrenia + TD

F+M
m = 32.5 years

Buspirone + AP
6 weeks

Placebo + AP

TD symptoms

Zeng 1996

46 inpatients in China

schizophrenia + TD

F+M
m = 33 years

Pemoline + AP
6 weeks

Placebo + AP

TD symptoms

Zhang 2011

157 inpatients in China

schizophrenia + TD

M
m = 45 years

Ginkgo biloba + AP
12 weeks

Placebo + AP

TD symptoms, mental state, cognitive function

AE = adverse effects, AP = antipsychotics, EPS = extrapyramidal symptoms, F = female, M = male, m = mean, N = number, TAU = treatment as usual, TD = tardive dyskinesia

Figuras y tablas -
Table 2. Overview of study characteristics
Comparison 1. ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.97]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.5 [0.23, 1.09]

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.55]

4 Tardive dyskinesia: 3. Average endpoint scale score (Simpson scale, high=poor) ‐ medium term Show forest plot

1

28

Mean Difference (IV, Fixed, 95% CI)

‐2.80 [‐12.25, 6.65]

5 Tardive dyskinesia: Average scale change scores (various scales, high=poor) ‐ medium term Show forest plot

2

59

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.31 [‐0.83, 0.20]

5.1 AIMS+RTDS

1

40

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.31 [‐0.93, 0.32]

5.2 ADS

1

19

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.33 [‐1.24, 0.57]

6 Mental state: Deterioration ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

0.5 [0.05, 4.90]

7 Adverse events ‐ medium term Show forest plot

1

28

Risk Ratio (M‐H, Fixed, 95% CI)

2.33 [0.75, 7.23]

8 Leaving the study early ‐ medium term Show forest plot

2

48

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.02, 7.32]

Figuras y tablas -
Comparison 1. ALKALOID ‐ DIHYDROGENATED ERGOT ALKALOIDS versus PLACEBO
Comparison 2. ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.35, 0.82]

2 Mental state: 1. Average endpoint scale score (BPRS, high=poor) ‐ medium term Show forest plot

1

20

Mean Difference (IV, Fixed, 95% CI)

‐4.5 [‐7.60, ‐1.40]

3 Adverse events: any adverse events ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Leaving the study early ‐ medium term Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 2. ALKALOID ‐ L‐STEPHOLIDINE (SPD) versus PLACEBO
Comparison 3. ALKALOID ‐ PAPAVERINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

22

Mean Difference (IV, Fixed, 95% CI)

0.51 [‐1.18, 2.20]

Figuras y tablas -
Comparison 3. ALKALOID ‐ PAPAVERINE versus PLACEBO
Comparison 4. AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.79 [0.63, 1.00]

2 Tardive dyskinesia: 1. Not any improvement ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.36, 1.11]

3 Tardive dyskinesia: 2. Deterioration ‐ short term Show forest plot

1

36

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.07, 1.19]

4 Tardive dyskinesia: Average endpoint score (Simpson scale, high=poor) ‐ short term Show forest plot

1

41

Mean Difference (IV, Fixed, 95% CI)

‐92.9 [‐167.57, ‐18.23]

5 Leaving the study early ‐ short term Show forest plot

1

52

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.37, 1.92]

Figuras y tablas -
Comparison 4. AMINO ACID ‐ BRANCHED‐CHAIN AMINO ACID (BCAA) versus PLACEBO
Comparison 5. AMINO ACID ‐ PHENYLALANINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Leaving the study early ‐ short term Show forest plot

1

18

Risk Ratio (M‐H, Fixed, 95% CI)

2.45 [0.11, 53.25]

Figuras y tablas -
Comparison 5. AMINO ACID ‐ PHENYLALANINE versus PLACEBO
Comparison 6. ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

33

Risk Ratio (M‐H, Fixed, 95% CI)

1.37 [0.96, 1.94]

2 Leaving the study early ‐ medium term Show forest plot

1

33

Risk Ratio (M‐H, Fixed, 95% CI)

10.39 [0.62, 173.97]

Figuras y tablas -
Comparison 6. ANTIDEPRESSANT (MAO‐B inhibitor) ‐ SELEGILINE versus PLACEBO
Comparison 7. ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.24 [0.08, 0.71]

2 Tardive dyskinesia: 1. Not any improvement ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.14 [0.03, 0.64]

3 Adverse effects ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 65.90]

4 Leaving the study early ‐ long term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.14, 65.90]

Figuras y tablas -
Comparison 7. ANTIDEPRESSANT (MAOI) ISOCARBOXAZID versus PROCYCLIDINE
Comparison 8. ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: No clinically important improvement (short term) Show forest plot

1

10

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.70, 1.43]

2 Tardive dyskinesia: Not any improvement (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.28 [0.02, 4.66]

3 Tardive dyskinesia: Deterioration (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.47 [0.02, 9.26]

4 Tardive dyskinesia: Average change score (AIMS, high=poor) (short term) Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐2.0 [‐5.93, 1.93]

5 General mental state: Deterioration (short term) Show forest plot

1

10

Risk Ratio (IV, Fixed, 95% CI)

0.47 [0.02, 9.26]

6 General mental state: Average change score (BPRS, high=poor) (short term) Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐0.80 [‐3.10, 1.50]

Figuras y tablas -
Comparison 8. ANTIDEPRESSANT (SSRI) ‐ RITANSERIN vs PLACEBO
Comparison 9. ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Average endpoint score (AIMS, high=poor) ‐ medium term Show forest plot

1

50

Mean Difference (IV, Fixed, 95% CI)

‐2.18 [‐3.65, ‐0.71]

2 Tardive dyskinesia: 1. Average change score (hyperkinesia subscale of the SHRS , high=poor) ‐ medium term Show forest plot

1

69

Mean Difference (IV, Fixed, 95% CI)

0.13 [‐0.73, 0.99]

3 Leaving the study early ‐ medium term Show forest plot

2

119

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.46, 2.22]

4 Adverse effects ‐ medium term Show forest plot

1

69

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.25, 1.04]

5 Mental state: deterioration ‐ medium term Show forest plot

1

50

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.12, 3.65]

Figuras y tablas -
Comparison 9. ANTIEPILEPTIC ‐ LEVETIRACETAM versus PLACEBO
Comparison 10. ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.54 [0.27, 1.08]

2 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.74]

3 Adverse events ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.04, 2.95]

4 Leaving the study early ‐ short term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.74]

Figuras y tablas -
Comparison 10. ANTIHISTAMINE ‐ CYPROHEPTADINE versus PLACEBO
Comparison 11. ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: No clinically important improvement (medium term) Show forest plot

1

34

Risk Ratio (M‐H, Fixed, 95% CI)

0.24 [0.11, 0.55]

2 Tardive dyskinesia: Not any improvement (medium term) Show forest plot

1

34

Risk Ratio (IV, Fixed, 95% CI)

0.06 [0.01, 0.43]

3 Tardive dyskinesia: Average endpoint score (AIMS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐7.10 [‐9.53, ‐4.67]

4 General mental state: Average endpoint score (BPRS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

0.70 [‐3.77, 5.17]

5 Adverse effects: Any adverse effects (TESS, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐0.53, 0.33]

6 Adverse effects: Parkinsonism ‐ Average endpoint score (RSESE) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐0.5 [‐1.36, 0.36]

7 Global state: Average endpoint score (CGI, high=poor) (medium term) Show forest plot

1

34

Mean Difference (IV, Fixed, 95% CI)

‐1.00 [‐3.78, ‐2.22]

Figuras y tablas -
Comparison 11. ANTIPSYCHOTIC ‐ PROMETHAZINE vs PLACEBO
Comparison 12. ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.33, 0.84]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.15, 0.75]

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

42

Mean Difference (IV, Fixed, 95% CI)

0.0 [‐1.45, 1.45]

4 Leaving the study early ‐ medium term Show forest plot

1

42

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 12. ANXIOLYTIC ‐ BUSPIRONE versus PLACEBO
Comparison 13. COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Average endpoint score (ESRS, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

‐0.70 [‐4.30, 2.90]

2 Parkinsonism: 1. Average endpoint score (ESRS, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

2.5 [‐4.73, 9.73]

3 Leaving the study early ‐ short term Show forest plot

1

40

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.03, 1.85]

4 Global state: Average endpoint score (CGI, high=poor) ‐ short term Show forest plot

1

35

Mean Difference (IV, Fixed, 95% CI)

0.20 [‐0.35, 0.75]

Figuras y tablas -
Comparison 13. COGNITIVE ENHANCER ‐ PIRACETAM versus PLACEBO
Comparison 14. COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.48 [0.29, 0.77]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.13, 0.66]

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

46

Mean Difference (IV, Fixed, 95% CI)

‐3.90 [‐5.47, ‐2.33]

4 Leaving the study early ‐ medium term Show forest plot

1

46

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 14. COGNITIVE ENHANCER/STIMULANT ‐ PEMOLINE versus PLACEBO
Comparison 15. ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

92

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.46, 0.86]

2 Tardive dyskinesia: 3. Average change score (AIMS, high=poor) ‐ medium term Show forest plot

1

89

Mean Difference (IV, Fixed, 95% CI)

‐2.5 [‐2.00, ‐1.00]

3 Adverse events ‐ medium term Show forest plot

1

100

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [0.92, 2.45]

4 Leaving the study early ‐ medium term Show forest plot

1

102

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.31, 3.25]

Figuras y tablas -
Comparison 15. ENZYME INHIBITOR ‐ VMAT2 INHIBITORS versus PLACEBO
Comparison 16. FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 2. No clinically important improvement ‐ medium term Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.57, 1.18]

2 Mental state: deterioration ‐ medium term Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.49 [0.05, 5.14]

3 Adverse events: Parkinsonism ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

0.30 [‐1.17, 1.77]

4 Adverse events: Dystonia ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

‐0.35 [‐0.58, ‐0.12]

5 Adverse events: Akathisia ‐ Average change in scale score (ESRS, low=better) ‐ medium term Show forest plot

1

75

Mean Difference (IV, Fixed, 95% CI)

‐0.04 [‐0.30, 0.22]

6 Leaving the study early ‐ medium term Show forest plot

1

84

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.27, 1.22]

Figuras y tablas -
Comparison 16. FATTY ACID ‐ ETHYL EICOSAPENTAENOIC ACID versus PLACEBO
Comparison 17. FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.69, 1.45]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.24, 2.33]

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

1.5 [0.34, 6.70]

4 Tardive dyskinesia: 1. Average change in scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

16

Mean Difference (IV, Fixed, 95% CI)

‐0.20 [‐3.10, 2.70]

5 Mental state: 2. Average change in scale score (BPRS, high=poor) ‐ medium term Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐6.0 [‐15.99, 3.99]

6 Leaving the study early ‐ medium term Show forest plot

1

16

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 17. FATTY ACID ‐ GAMMA‐LINOLENIC ACID versus PLACEBO
Comparison 18. HERB ‐ GINKGO BILOBA versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.81, 0.96]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.41, 0.65]

3 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

157

Mean Difference (IV, Fixed, 95% CI)

‐2.06 [‐2.94, ‐1.18]

4 Leaving the study early ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.25 [0.03, 2.22]

5 Mental state: deterioration ‐ medium term Show forest plot

1

157

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.16]

6 Mental state: 1. Average endpoint scale score (PANSS total, high=poor) ‐ medium term Show forest plot

1

157

Mean Difference (IV, Fixed, 95% CI)

‐3.30 [‐6.51, ‐0.09]

7 Cognitive function: CPT‐37 ‐ proportion correct responses (high=better) ‐ medium term Show forest plot

1

119

Mean Difference (IV, Fixed, 95% CI)

‐0.02 [‐0.10, 0.06]

Figuras y tablas -
Comparison 18. HERB ‐ GINKGO BILOBA versus PLACEBO
Comparison 19. HORMONE ‐ OESTROGEN versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.76, 1.83]

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.05, 2.37]

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

10

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.01, 3.35]

4 Tardive dyskinesia: 4. Average scale score (AIMS, high=poor) ‐ short term Show forest plot

1

10

Mean Difference (IV, Fixed, 95% CI)

‐1.2 [‐4.18, 1.78]

5 Adverse effects ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.02, 6.86]

6 Leaving the study early ‐ short term Show forest plot

1

12

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.08, 12.56]

Figuras y tablas -
Comparison 19. HORMONE ‐ OESTROGEN versus PLACEBO
Comparison 20. HORMONE ‐ INSULIN versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.29, 0.96]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.06 [0.00, 0.90]

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.45]

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

20

Mean Difference (IV, Fixed, 95% CI)

‐6.20 [‐10.53, ‐1.87]

5 Leaving the study early ‐ medium term Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 20. HORMONE ‐ INSULIN versus PLACEBO
Comparison 21. HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement Show forest plot

2

32

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.71, 1.12]

1.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.83, 1.21]

1.2 Medium term

1

13

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.44, 1.23]

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.47, 2.60]

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.22 [0.01, 4.05]

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ medium term Show forest plot

1

13

Mean Difference (IV, Fixed, 95% CI)

‐2.38 [‐6.58, 1.82]

5 Adverse effects Show forest plot

3

54

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Medium term

2

35

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Leaving the study early Show forest plot

3

54

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.1 Short term

1

19

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.2 Medium term

2

35

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Cognitive function: Average scale score ‐ medium term Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

7.1 WAIS

1

76

Mean Difference (IV, Fixed, 95% CI)

15.83 [4.61, 27.05]

7.2 WMS

1

76

Mean Difference (IV, Fixed, 95% CI)

3.77 [‐8.21, 15.75]

8 Mental state: deterioration ‐ medium term Show forest plot

1

13

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 21. HORMONE ‐ MELATONIN versus PLACEBO OR NO TREATMENT
Comparison 22. MOOD STABILISER ‐ LITHIUM versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

1.59 [0.79, 3.23]

2 Tardive dyskinesia: 2. Not any improvement ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

4.29 [0.25, 72.90]

3 Tardive dyskinesia: 3. Deterioration ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

4.29 [0.25, 72.90]

4 Tardive dyskinesia: 3. Average scale score (AIMS, high=poor) ‐ short term Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

0.63 [‐5.23, 6.49]

5 Adverse events ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

6.0 [0.38, 94.35]

6 Leaving the study early ‐ short term Show forest plot

1

11

Risk Ratio (M‐H, Fixed, 95% CI)

2.57 [0.13, 52.12]

Figuras y tablas -
Comparison 22. MOOD STABILISER ‐ LITHIUM versus PLACEBO
Comparison 23. POLYPEPTIDE ‐ CERULETIDE versus PLACEBO

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. Not any improvement Show forest plot

2

132

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.65, 1.07]

1.1 Short term

1

47

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.50, 1.06]

1.2 Medium term

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.64, 1.27]

2 Tardive dyskinesia: 2. Deterioration Show forest plot

2

103

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.14, 6.80]

2.1 Short term

1

37

Risk Ratio (M‐H, Fixed, 95% CI)

2.85 [0.12, 65.74]

2.2 Medium term

1

66

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.90]

3 Adverse effects Show forest plot

2

122

Risk Ratio (M‐H, Fixed, 95% CI)

1.32 [0.74, 2.36]

3.1 Short term

1

37

Risk Ratio (M‐H, Fixed, 95% CI)

3.79 [0.47, 30.77]

3.2 Medium term

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

1.13 [0.61, 2.07]

4 Leaving the study early ‐ medium term Show forest plot

1

85

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.49, 2.40]

Figuras y tablas -
Comparison 23. POLYPEPTIDE ‐ CERULETIDE versus PLACEBO
Comparison 24. HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Tardive dyskinesia: 1. No clinically important improvement ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.45 [0.21, 0.94]

2 Tardive dyskinesia: 2. Not any improvement ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 3.81]

3 Tardive dyskinesia: 3. Deterioration ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.18 [0.01, 3.81]

4 Leaving the study early ‐ medium term Show forest plot

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.1 Short term

1

15

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 24. HYPNOSIS OR RELAXATION versus TREATMENT AS USUAL