Antidepressants for people with epilepsy and depression

Melissa J Maguire; Anthony G Marson; Sarah J Nevitt

doi:10.1002/14651858.CD010682.pub3

Antidepresivos para personas con epilepsia y depresión

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Referencias

Referencias de los estudios incluidos en esta revisión

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Gilliam FG, Black KJ, Carter J, Freedland KE, Sheline YI, Tsai W-Y, et al. A trial of sertraline or cognitive behavior therapy for depression in epilepsy. Annals of Neurology 2019;86(4):552-60. [DOI: https://dx.doi.org/10.1002/ana.25561] [ISSN: 1531-8249] [PMID: 31359460]

Hovorka J, Herman E, Nemcova I. Treatment of interictal depression with citalopram in patients with epilepsy. Epilepsy and Behavior 2000;1:444-7.

Kanner A, Kozak A, Frey M. The use of sertraline in patients with epilepsy: is it safe? Epilepsy and Behavior 2000;1:100-5.

Kuhn K, Quednow B, Thiel M, Falkai P, Maier W, Elger C. Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants. Epilepsy and Behavior 2003;4:674-9.

Li W, Ma D. A randomized controlled trial to evaluate the efficacy of paroxetine and doxepin in treating epileptic patients with depression. Chinese Journal of Clinical Rehabilitation 2005;9(12):20-1.

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Orjuela-Rojas JM, Martinez-Juarez IE, Ruiz-Chow A, Crail-Melendez D. Treatment of depression in patients with temporal lobe epilepsy: a pilot study of cognitive behavioral therapy vs. selective serotonin reuptake inhibitors. Epilepsy & Behavior 2015;51:176-81. [DOI: 10.1016/j.yebeh.2015.07.033] [PMID: 26284748]

Robertson M, Trimble M. The treatment of depression in patients with epilepsy: a double blind trial. Journal of Affective Disorders 1985;9:127-36.

Specchio L, Iudice A, Specchio N, La Neve A, Spinelli A, Galli R, et al. Citalopram as treatment of depression in patients with epilepsy. Clinical Neuropharmacology 2004;27(3):133-6.

Thome-Souza M, Kuczynski E, Valente K. Sertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression. Epilepsy & Behavior 2007;10:417-25.

Zhu S, Luo L, Gui Y. Short-term efficacy of venlafaxine treating the depression in epilepsy patients. Chinese Journal of Rehabilitation 2004;19(2):101.

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Referencias de los estudios excluidos de esta revisión

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Blumer D. Antidepressant and double antidepressant treatment for the affective disorder of epilepsy. Journal of Clinical Psychiatry 1997;58(1):3-11. [DOI: 10.4088/JCP.v58n0101]

Harmant J, Van Rijckevorsel-Harmant K, De Barsy T, Hendrickx B. Fluvoxamine: an antidepressant with low (or no) epileptogenic effect. Lancet 1990;336(8711):386.

Machado R, Espinosa A, Montoto A. Cholesterol concentrations and clinical response to sertraline in patients with epilepsy: preliminary results. Epilepsy & Behavior 2010;19:509-12.

NCT00595699. Escitalopram treatment of major depression in patients with temporal lobe epilepsy. clinicaltrials.gov/ct/show/NCT00595699 (first posted 16 January 2008).

NCT01244724. Lexapro for major depression in patients with epilepsy. clinicaltrials.gov/show/NCT01244724 (first posted 19 November 2010).

NCT03464383. Anxiety and depression in epilepsy: a treatment study [Anxiety and depression in epilepsy: a pilot epileptologist-driven treatment study]. clinicaltrials.gov/ct2/show/record/NCT03464383 (first received 7 March 2018).

Referencias de los estudios en curso

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EUCTR2017-000990-35-IT. Effects of the antidepressive therapy with agomelatin and escitalopram in people with depression and epilepsy [Effects of antidepressant treatment with agomelatine on patients affected by depression and epilepsy. A double blind randomized study with active control (escitalopram) with parallel groups]. www.clinicaltrialsregister.eu/ctr-search/search?query=2017-000990-35 (first posted 6 February 2019).

EUCTR2018-003464-32-HU. Effect of mirtazapine on seizure frequency in epileptic patients with vagal nerve stimulation device. www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003464-32 (first posted 5 November 2019).

Referencias adicionales

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Adams SJ, O'Brien TJ, Lloyd J, Kilpatrick CJ, Salzberg MR, Velakoulis D. Neuropsychiatric morbidity in focal epilepsy. British Journal of Psychiatry 2008;192(6):464-9. [PMID: 18515901]

Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biological Psychiatry 2007;62(4):345-54. [PMID: 17223086]

American Psychiatric Association. Diagnostic and Statistical Manual. 4th edition. Washington DC: American Psychiatric Association, 2000.

Bagdy G, Kecskemeti V, Riba P, Jakus R. Serotonin and epilepsy. Journal of Neurochemistry 2007;100(4):857-73. [PMID: 17212700]

Baker G, Jacoby A, Chadwick D. The associations of psychopathology in epilepsy: a community study. Epilepsy Research 1996;25:29-39.

Boylan LS, Flint LA, Labovitz DL, Jackson SC, Starner K, Devinsky O. Depression but not seizure frequency predicts quality of life in treatment-resistant epilepsy. Neurology 2004;62(2):258-61.

Cotterman-Hart S. Depression in epilepsy: why aren't we treating? Epilepsy & Behavior 2010;19(3):419-21. [PMID: 20851689]

Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011;343:d4551. [PMID: 21810886]

Dell'osso MC, Caserta A, Baroni S, Nisita C, Marazziti D. The relationship between epilepsy and depression: an update. Current Medicinal Chemistry 2013 Mar 15 [Epub ahead of print]. [PMID: 23521673]

Gilliam FG. Diagnosis and treatment of mood disorders in persons with epilepsy. Current Opinion in Neurology 2005;18(2):129-33. [PMID: 15791142]

Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al, for the GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6.

Hamid H, Kanner AM. Should antidepressant drugs of the selective serotonin reuptake inhibitor family be tested as antiepileptic drugs? Epilepsy & Behavior 2013;26(3):261-5. [PMID: 23395350]

Hermann BP, Seidenberg M, Bell B. Psychiatric comorbidity in chronic epilepsy: identification, consequences, and treatment of major depression. Epilepsia 2000;41(Suppl 2):S31-41. [PMID: 10885738]

Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk factor for seizures in older adults. Annals of Neurology 2000;47(2):246-9.

Hesdorffer DC, Hauser WA, Olafsson E, Ludvigsson P, Kjartansson O. Depression and suicide attempt as risk factors for incident unprovoked seizures. Annals of Neurology 2006;59(1):35-41. [PMID: 16217743]

Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 2009;50(5):978-86. [PMID: 19496806]

Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Annals of Neurology 2012;72(2):184-91. [PMID: 22887468]

Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from training.cochrane.org/handbook/archive/v5.1/.

Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from www.training.cochrane.org/handbook.

Indaco A, Carrieri B, Naapi C, Gentile S, Striano S. Interictal depression in epilepsy. Epilepsy Research 1992;12:45-50.

Jacoby A, Baker G, Steen N, Potts P, Chadwick D. The clinical course of epilepsy and its psychological correlates: finding from a U.K. community study. Epilepsia 1996;37:148-61.

Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, Smyth R, et al. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 2010;340:c365. [PMID: 20156912]

Klerman G. Treatment of recurrent unipolar major depressive disorder. Commentary on the Pittsburgh study. Archives of General Psychiatry 1990;47(12):1158-61.

Kondziella D, Asztely F. Don't be afraid to treat depression in patients with epilepsy! Acta Neurologica Scandinavica 2009;119(2):75-80. [PMID: 18759799]

Lambert M, Robertson M. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia 1999;40(Suppl 10):s21-47.

Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012;380(9848):1180-92. [PMID: 23021287]

Mendez M, Cummings J, Benson D. Depression in epilepsy: significance and phenomenology. Archives of Neurology 1986;43:766-70.

Mula M, Schmitz B. Depression in epilepsy: mechanisms and therapeutic approach. Therapeutic Advances in Neurological Disorders 2009;2(5):337-44. [PMID: 21180624]

Mula M, Kanner AM, Schmitz B, Schachter S. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic Strategies of the ILAE Commission on Neuropsychobiology. Epilepsia 2013;54(1):199-203. [PMID: 22994856]

Preskorn SH, Fast GA. Tricyclic antidepressant-induced seizures and plasma drug concentration. Journal of Clinical Psychiatry 1992;53(5):160-2. [PMID: 1592842]

Sackeim HA, Roose SP, Lavori PW. Determining the duration of antidepressant treatment: application of signal detection methodology and the need for duration adaptive designs (DAD). Biological Psychiatry 2006;59(6):483-92. [PMID: 16517241]

Stahl SM. Blue genes and the mechanism of action of antidepressants. Journal of Clinical Psychiatry 2000;61(3):164-5. [PMID: 10817098]

Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. Journal of Clinical Epidemiology 2000;53(11):1119-29. [PMID: 11106885]

Tellez-Zenteno JF, Patten SB, Jette N, Williams J, Wiebe S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 2007;48(12):2336-44. [PMID: 17662062]

Trimble MR. New antiepileptic drugs and psychopathology. Neuropsychobiology 1998;38(3):149-51. [PMID: 9778603]

Wroblewski BA, McColgan K, Smith K, Whyte J, Singer WD. The incidence of seizures during tricyclic antidepressant drug treatment in a brain-injured population. Journal of Clinical Psychopharmacology 1990;10(2):124-8. [PMID: 2341586]

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry 2006;63(8):856-64. [PMID: 16894061]

Referencias de otras versiones publicadas de esta revisión

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Maguire MJ, Pulman J, Singh J, Marson AG. Antidepressants for people with epilepsy and depression. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No: CD010682. [DOI: 10.1002/14651858.CD010682]

Maguire MJ, Weston J, Singh J, Marson AG. Antidepressants for people with epilepsy and depression. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No: CD010682. [DOI: 10.1002/14651858.CD010682.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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Gilliam 2019

*Study characteristics*
Methods	Multi‐centre, randomised controlled trial conducted in the USA Baseline period: 3 month retrospective baseline (seizures) Treatment period:16 weeks
Participants	140 participants; 77 female 21 to 75 years old 58% focal epilepsy CES‐D score >14
Interventions	Sertraline 50 mg/day to 200 mg/day versus CBT
Outcomes	BDI, CES‐D, seizure recurrence and monthly frequency, AEP, adverse events
Notes	ITT analysis, 49/72 in sertraline group completed assigned treatment, 49/68 in CBT group completed assigned treatment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Simple non‐stratified computerised randomisation code generated by an investigator not otherwise involved in the study
Allocation concealment (selection bias)	Low risk	Treatment assignment obtained by telephone communication (centralised randomisation)
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding of participants and personnel not possible by design (sertraline or CBT)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Site investigators blinded to outcome assessment but research assistants implementing study procedures not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	23/72 participants (32%) in the sertraline group and 19/68 participants (28%) in the CBT group did not complete treatment. Intention‐to‐treat analysis imputed missing data by multiple imputation
Selective reporting (reporting bias)	Low risk	Outcomes stated in methods section of report are present in the results. No protocol available
Other bias	High risk	High risk of recall bias as seizure rates were collected retrospectively at baseline

Hovorka 2000

*Study characteristics*
Methods	A single‐centre, non‐randomised, uncontrolled, prospective before and after study (Prague) Baseline period: 2 months Treatment period: 8 weeks
Participants	43 people with focal epilepsy exceeding 15 points on the Hamilton Rating Scale for Depression (HAMD) 21 scale for depression 35 females and 8 males Aged 21 to 49 years: mean 33.2 years
Interventions	Citalopram at a flexible dose; the average dose was 19.3 mg ± 2.6 mg at the end of the first month, 22.62 mg ± 8.3 mg at the end of the second month
Outcomes	1) Seizure frequency 2) Depressive symptoms measured by the HAMD‐21 3) Adverse effects
Notes	No dropouts and no exclusions from the analysis

Kanner 2000

*Study characteristics*
Methods	A single‐centre, non‐randomised, uncontrolled, prospective before and after study (USA) Baseline period: not reported Treatment period: mean 10.3 months (0.2 to 38 months)
Participants	100 people with focal epilepsy, with depressive or obsessive compulsive disorder 51 males and 49 females Aged 6 to 62 years: mean 29.9 years
Interventions	Sertraline, mean dose of 108 mg ± 56.9 mg per day
Outcomes	1) Improvement in depressive symptoms 2) Seizure frequency 3) Adverse effects
Notes	18 people withdrew due to adverse effects; all included in analysis

Kuhn 2003

*Study characteristics*
Methods	A single‐centre, non‐randomised, prospective study (Germany) Baseline period: 4 days Observation period: 20 to 30 weeks
Participants	75 people with temporal lobe epilepsy exceeding 15 points on the HAMD‐21 scale for depression 45 females and 30 males Aged 19 to 68 years: mean 40.1 years
Interventions	Citalopram (N = 33), dose at endpoint: 24.2 mg Mirtazapine (N = 27), dose at endpoint: 32.2 mg Reboxetine (N = 15), dose at endpoint: 6.9 mg
Outcomes	1) Improvement in depressive symptoms 2) Seizure frequency and severity 3) Adverse effects
Notes	Large amount of withdrawals from week 4 to weeks 20 to 30. Last observation carried forward approach used

Li 2005

*Study characteristics*
Methods	A single‐centre, randomised controlled trial (China) Baseline period: unclear Treatment phase: 8 weeks
Participants	67 participants with epilepsy and depression (meeting CCMD‐3 criteria for depression and HAMD‐21 score > 18)
Interventions	Paroxetine (N = 33): 17 males, 16 females aged 14 to 62 years, dose 10 mg/day to 40 mg/day Doxepin (N = 34): 15 males, 19 females, aged 16 to 59 years, dose 25 mg/day titrated up according to response (mean dose 100 mg)
Outcomes	1) Change in depression scores (HAMD‐21) from baseline 2) Adverse events
Notes	3 participants discontinued study in doxepin arm because of adverse events, with 31 participants analysed for this treatment arm
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation carried out by flipping of a coin
Allocation concealment (selection bias)	Unclear risk	No details available regarding methods of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Missing data reported, ITT not used
Selective reporting (reporting bias)	Low risk	Outcomes stated in methods section of report were present in the results. No protocol available
Other bias	Unclear risk	Insufficient details in report to judge the influence of other bias

Orjuela‐Rojas 2015

*Study characteristics*
Methods	Single centre, prospective cohort study in Mexico Baseline period; not reported Treatment period; 12 weeks
Participants	15 participants, 11 female, > 18 years old, all with temporal lobe epilepsy
Interventions	SSRI (sertraline or citalopram) vs CBT
Outcomes	BDI HADS‐D HADS‐A QOLIE‐31 MINI Seizures per month
Notes	2 dropouts reported in CBTgroup, 1 lost to follow‐up

Robertson 1985

*Study characteristics*
Methods	A single‐centre, randomised, double‐blind, controlled trial (UK) Baseline period: unclear Treatment period: 12 weeks (6 weeks for all 3 arms of trial, then 6 weeks for the 2 antidepressants only)
Participants	42 people with epilepsy exceeding 15 points on the HAMD‐21 scale for depression 26 females and 13 males Aged 18 to 60 years
Interventions	Amitriptyline (N = 14) 25 mg TDS Nomifensine (N = 14) 25mg TDS Placebo (N = 14)
Outcomes	1) Improvement in depressive symptoms 2) Seizure frequency 3) Adverse effects
Notes	39 people included in the analysis. At 6 weeks, non‐responders in the active drug arms had dose doubled, and those in the placebo arm were withdrawn from the study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number codes used, however generation of this randomisation sequence is unclear
Allocation concealment (selection bias)	Low risk	Pharmacy‐controlled allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study personnel and participants blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Missing data detected and attrition reported
Selective reporting (reporting bias)	Low risk	Outcomes stated in methods section of report are present in the results. No protocol available
Other bias	Unclear risk	After 6 weeks, placebo group removed from trial; only active antidepressant treatment groups continued in the trial

Specchio 2004

*Study characteristics*
Methods	A multi‐centre, non‐randomised, uncontrolled, prospective before‐after study (Italy) Baseline period: not reported Treatment period: 4 months
Participants	45 people with focal epilepsy, and exceeding or equal to 20 on the MADRS 31 females and 14 males Mean age of 42.7 years
Interventions	Citalopram 20 mg per day
Outcomes	1) Seizure frequency 2) Improvement in depression measured by MADRS and Zung‐SDS 3) Adverse effects
Notes	39 participants received intended treatment and analysed

Thome‐Souza 2007

*Study characteristics*
Methods	A single‐centre, non‐randomised, uncontrolled, prospective before‐after study (Brazil) Baseline period: not reported Treatment period: mean 25.8 months (range 12 months to 78 months)
Participants	36 children and adolescents with focal epilepsy and diagnosis of depression 19 females and 17 males Aged 5 to 18 years, mean: 12.7 years
Interventions	Sertraline up to 200 mg/day, mean dose 111.5 mg/day (50 mg/day to 200 mg/day) Fluoxetine up to 80 mg/day, mean dose 45.7 mg/day (20 mg/day to 80 mg/day)
Outcomes	1) Seizure severity 2) Improvement in depressive symptoms 3) Adverse effects
Notes	No dropouts

Zhu 2004

*Study characteristics*
Methods	Single‐centre, randomised trial of venlafaxine versus no treatment (China) Baseline period: not reported Treatment period: 8 weeks
Participants	64 people with epilepsy (presumed genetic or cause unknown) and depression 39 males and 25 females Aged 7 to 60 years (mean 27 years)
Interventions	Venlafaxine 25 mg to 75 mg/day (N = 32) No treatment (N = 32)
Outcomes	1) Change in HAMD‐21 scores 2) Adverse events
Notes	No dropouts
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Methods for generation of random sequence were not detailed in the report
Allocation concealment (selection bias)	Unclear risk	Methods for allocation were not detailed in the report
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details of blinding methods in the report
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Unclear whether outcome assessor blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data
Selective reporting (reporting bias)	Low risk	Outcomes stated in methods section of report were present in the results. No protocol available
Other bias	Unclear risk	Insufficient details in report to judge the influence of other bias

AEP: Adverse Events Profile
BDI: Beck Depression Inventory
CCMD‐3: Chinese Classification of Mental Disorders
CBT: Cognitive Behavioral Therapy
CES‐D: Center for Epidemiologic Studies Depression
HADS‐D: Hospital Anxiety and Depression Scale‐Depression
HADS‐A: Hospital Anxiety and Depression Scale‐Anxiety
HAMD: Hamilton Rating Scale for Depression
ITT: Intention‐To‐Treat
MADRS: Montgomery–Åsberg Depression Rating Scale
MINI: Mini International Neuropsychiatric Interview
NA: Not Applicable
SSRI: Selective serotonin Reuptake Inhibitor
TDS: Three times a day
QOLIE‐31: Quality of Life in Epilepsy Inventory ‐31
Zung‐SDS: Zung Self‐Rating Depression Scale

Characteristics of excluded studies [ordered by study ID]

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estudios en curso

Study	Reason for exclusion
Blumer 1997	Case series; study not meeting the inclusion criteria
Harmant 1990	Did not report any results for any of the primary and secondary outcomes. We attempted to contact trial author of the study but received no response.
Machado 2010	Did not report any results for any of the primary and secondary outcomes. We attempted to contact trial author of the study but received no response.
NCT00595699	Did not report any results for any of the primary and secondary outcomes. We attempted to contact trial author of the study but received no response.
NCT01244724	Trial listed on ClinicalTrials.gov and recorded as terminated
NCT03464383	Very small pilot study with only 3 participants recruited to antidepressant (escitalopram 10 mg) and referral to psychiatry treatment arms

Characteristics of ongoing studies [ordered by study ID]

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EUCTR2017‐000990‐35‐IT

Study name	Effects of the antidepressive therapy with agomelatin and escitalopram in people with depression and epilepsy
Methods	A double‐blind randomised study with active control (escitalopram) with parallel groups
Participants	222
Interventions	escitalopram 10 mg daily vs agomelatine 25 mg daily for 6 months
Outcomes	Primary outcome: efficacy (depression BDI‐II) Secondary outcomes: depression (HDRS), quality of life (QOLIE‐31P, quality of life in epilepsy II version), sleep quality (PSQI), daytime sleepiness (ESS), and cognition (MDB)
Starting date	2019
Contact information	Prof. Fabio Placidi
Notes

EUCTR2018‐003464‐32‐HU

Study name	Effect of mirtazapine on seizure frequency in epileptic patients with vagal nerve stimulation device
Methods	Double‐blind, randomised, placebo controlled trial
Participants	Target sample size 30 participants Adults (18 to 65 years ) with drug resistant epilepsy with focal seizures, with or without loss of consciousness, and a vagal nerve stimulation device implanted and activated > 6 months prior to enrolment
Interventions	Mirtazapine (30 mg) compared to placebo
Outcomes	Change in seizure frequency at weeks 12 and 27 Quality of Life: using the self‐administered Quality of Life in Epilepsy 89 (QOLIE‐89) at weeks 12, 15, and 27 Depression: using Beck Depression Inventory (BDI), and Hamilton Depression Rating Scale (HAM‐D) at weeks 12, 15, and 27
Starting date	08 /11/2019
Contact information	None provided
Notes

Data and analyses

Open in table viewer

Comparison 1. RCT: paroxetine versus doxepin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 > 50% reduction in depressive symptoms Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.88, 1.52]
Open in figure viewer Analysis 1.1 Comparison 1: RCT: paroxetine versus doxepin, Outcome 1: > 50% reduction in depressive symptoms
1.2 Mean depression scores Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.2 Comparison 1: RCT: paroxetine versus doxepin, Outcome 2: Mean depression scores
1.2.1 HAMD scores	1	67	Mean Difference (IV, Fixed, 95% CI)	0.65 [‐2.15, 3.45]
1.3 Withdrawals (any reason) Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]
Open in figure viewer Analysis 1.3 Comparison 1: RCT: paroxetine versus doxepin, Outcome 3: Withdrawals (any reason)
1.4 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 1.4 Comparison 1: RCT: paroxetine versus doxepin, Outcome 4: Adverse effects
1.4.1 Blurred vision	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.09, 1.32]
1.4.2 Dizziness	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.21 [0.03, 1.37]
1.4.3 Dry mouth	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.26 [0.06, 1.20]
1.4.4 Sleep disorders	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.32 [0.08, 1.20]
1.4.5 Urinary retention	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.01, 21.99]

Open in table viewer

Comparison 2. RCT: amitriptyline versus nomifensine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 > 50% reduction in depressive symptoms Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.28, 1.06]
Open in figure viewer Analysis 2.1 Comparison 2: RCT: amitriptyline versus nomifensine, Outcome 1: > 50% reduction in depressive symptoms

Open in table viewer

Comparison 3. RCT: venlafaxine versus no treatment controls

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 > 50% reduction in depressive symptoms Show forest plot	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [1.19, 8.90]
Open in figure viewer Analysis 3.1 Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 1: > 50% reduction in depressive symptoms
3.2 Mean depression scores ‐ HAMD Show forest plot	1	64	Mean Difference (IV, Fixed, 95% CI)	‐7.59 [‐11.52, ‐3.66]
Open in figure viewer Analysis 3.2 Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 2: Mean depression scores ‐ HAMD

Open in table viewer

Comparison 4. RCT: sertraline versus cognitive behavioural therapy (CBT)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.1 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 1: Mean depression scores (BDI)
4.1.1 BDI‐II scores at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	‐2.50 [‐6.28, 1.28]
4.1.2 BDI‐II scores at 16 weeks	1	117	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐4.47, 3.47]
4.2 Remission in depressive symptoms Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.65, 1.17]
Open in figure viewer Analysis 4.2 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 2: Remission in depressive symptoms
4.3 Seizure frequency Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.3 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 3: Seizure frequency
4.3.1 Generalised tonic‐clonic seizures per month at 8 weeks	1	86	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.26, 0.06]
4.3.2 Generalised tonic‐clonic seizures per month at 16 weeks	1	96	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.10, 0.10]
4.3.3 Focal seizures with impaired awareness per month at 8 weeks	1	75	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐6.52, 1.32]
4.3.4 Focal seizures with impaired awareness per month at 16 weeks	1	73	Mean Difference (IV, Fixed, 95% CI)	‐3.00 [‐7.81, 1.81]
4.4 Seizure recurrence Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.27, 3.94]
Open in figure viewer Analysis 4.4 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 4: Seizure recurrence
4.5 Withdrawals (any reason) Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.64, 2.46]
Open in figure viewer Analysis 4.5 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 5: Withdrawals (any reason)
4.6 Quality of life (QOLIE‐89) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.6 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 6: Quality of life (QOLIE‐89)
4.6.1 QOLIE‐89 score at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	6.10 [‐0.28, 12.48]
4.6.2 QOLIE‐89 score at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	3.10 [‐3.41, 9.61]
4.7 Adverse events profile Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 4.7 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 7: Adverse events profile
4.7.1 Adverse event profile at 8 weeks	1	106	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐6.62, 1.22]
4.7.2 Adverse event profile at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	‐2.10 [‐6.21, 2.01]
4.8 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only
Open in figure viewer Analysis 4.8 Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 8: Adverse events
4.8.1 Anxiety	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.2 Chest pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.47 [0.05, 4.21]
4.8.3 Cold	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.13, 3.13]
4.8.4 Diarrhoea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	19.85 [0.49, 805.53]
4.8.5 Dizziness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.51 [0.37, 6.14]
4.8.6 Dry mouth	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.78 [0.22, 65.10]
4.8.7 Headache	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.48 [0.69, 3.19]
4.8.8 Insomnia	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.16 [0.73, 6.38]
4.8.9 Memory difficulty	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.71 [0.10, 4.82]
4.8.10 Muscle strain or pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.21 [0.36, 4.12]
4.8.11 Nausea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.60 [0.62, 10.96]
4.8.12 Rash	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	4.72 [0.29, 76.72]
4.8.13 Sexual dysfunction	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.14 Shakiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	12.28 [0.88, 171.59]
4.8.15 Tiredness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.54 [1.40, 8.96]
4.8.16 Unsteadiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.57 [0.25, 9.81]
4.8.17 Worsening depression	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.13 [0.25, 5.07]

Open in table viewer

Comparison 5. NRSI: citalopram (before and after)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mean depression scores HAMD‐21 Show forest plot	2	176	Std. Mean Difference (IV, Fixed, 95% CI)	1.17 [0.96, 1.38]
Open in figure viewer Analysis 5.1 Comparison 5: NRSI: citalopram (before and after), Outcome 1: Mean depression scores HAMD‐21
5.2 Mean monthly seizure frequency Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.2 Comparison 5: NRSI: citalopram (before and after), Outcome 2: Mean monthly seizure frequency

Open in table viewer

Comparison 6. NRSI: SSRIs (sertraline or citalopram) versus CBT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 6.1 Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 1: Mean depression scores (BDI)
6.1.1 BDI at 6 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐11.58, 6.38]
6.1.2 BDI at 12 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.90 [‐14.60, 4.80]
6.2 Remission in depressive symptoms Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.77, 3.06]
Open in figure viewer Analysis 6.2 Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 2: Remission in depressive symptoms
6.3 Seizure frequency per month at 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐5.63, 2.43]
Open in figure viewer Analysis 6.3 Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 3: Seizure frequency per month at 12 weeks
6.4 Withdrawals (any reason) Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.05, 3.85]
Open in figure viewer Analysis 6.4 Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 4: Withdrawals (any reason)
6.5 Quality of life (QOLIE‐31 overall score) Show forest plot	1	15	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐19.67, 18.67]
Open in figure viewer Analysis 6.5 Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 5: Quality of life (QOLIE‐31 overall score)

Figure 1

Study flow diagram

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Analysis 1.1

Comparison 1: RCT: paroxetine versus doxepin, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 1.2

Comparison 1: RCT: paroxetine versus doxepin, Outcome 2: Mean depression scores

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Analysis 1.3

Comparison 1: RCT: paroxetine versus doxepin, Outcome 3: Withdrawals (any reason)

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Analysis 1.4

Comparison 1: RCT: paroxetine versus doxepin, Outcome 4: Adverse effects

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Analysis 2.1

Comparison 2: RCT: amitriptyline versus nomifensine, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 3.1

Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 3.2

Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 2: Mean depression scores ‐ HAMD

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Analysis 4.1

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 1: Mean depression scores (BDI)

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Analysis 4.2

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 2: Remission in depressive symptoms

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Analysis 4.3

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 3: Seizure frequency

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Analysis 4.4

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 4: Seizure recurrence

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Analysis 4.5

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 5: Withdrawals (any reason)

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Analysis 4.6

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 6: Quality of life (QOLIE‐89)

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Analysis 4.7

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 7: Adverse events profile

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Analysis 4.8

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 8: Adverse events

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Analysis 5.1

Comparison 5: NRSI: citalopram (before and after), Outcome 1: Mean depression scores HAMD‐21

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Analysis 5.2

Comparison 5: NRSI: citalopram (before and after), Outcome 2: Mean monthly seizure frequency

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Analysis 6.1

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 1: Mean depression scores (BDI)

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Analysis 6.2

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 2: Remission in depressive symptoms

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Analysis 6.3

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 3: Seizure frequency per month at 12 weeks

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Analysis 6.4

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 4: Withdrawals (any reason)

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Analysis 6.5

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 5: Quality of life (QOLIE‐31 overall score)

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Summary of findings 1. Paroxetine compared to doxepin for people with epilepsy and depression

Paroxetine compared to doxepin for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: paroxetine Comparison: doxepin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	doxepin	paroxetine
> 50% reduction in depressive symptoms Follow‐up: 8 weeks	706 per 1000	819 per 1000 (621 to 1000)	RR 1.16 (0.88 to 1.52)	67 (1 RCT)	⊕⊕⊕⊝ moderate^a
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks	NA	The mean HAMD depression score in the intervention groups was 0.65 higher (2.15 lower to 3.45 higher)	NA	67 (1 RCT)	⊕⊕⊕⊝ moderate^a
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: 8 weeks	88 per 1000	13 per 1000 (1 to 242)	RR 0.15 (0.01 to 2.74)	67 (1 RCT)	⊕⊕⊕⊝ moderate^a	doxepin: 3 withdrew paroxetine: 0 withdrew
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: 8 weeks	Reported adverse events: blurred vision, dizziness, dry mouth, sleep disorders, and urinary retention	Reported adverse events: blurred vision, dizziness, dry mouth, and sleep disorders	NA	67 (1 RCT)	⊕⊕⊕⊝ moderate^a	There were no significant differences between treatment groups for any reported adverse events
The basis for the assumed risk* is the event rate in the doxepin group. 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; HAMD: Hamilton Rating Scale for Depression; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded for imprecision, because only one small study contributed to the outcomes.

Summary of findings 1. Paroxetine compared to doxepin for people with epilepsy and depression

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Summary of findings 2. Amitriptyline compared to nomifensine for people with epilepsy and depression

Amitriptyline compared to nomifensine for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: amitriptyline Comparison: nomifensine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	nomifensine	amitriptyline
> 50% reduction in depressive symptoms Follow‐up: 12 weeks	786 per 1000	432 per 1000 (220 to 833)	RR 0.55 (0.28 to 1.06)	28 (1 RCT)	⊕⊕⊝⊝ low^a
Mean depression scores Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the nomifensine group. 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; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded twice for imprecision, because only very small study contributed limited outcome data.

Summary of findings 2. Amitriptyline compared to nomifensine for people with epilepsy and depression

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Summary of findings 3. Venlafaxine compared to no treatment for people with epilepsy and depression

Venlafaxine compared to no treatment for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: venlafaxine Comparison: no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no treatment	venlafaxine
> 50% reduction in depressive symptoms Follow‐up: 8 weeks	125 per 1000	406 per 1000 (149 to 1000)	RR 3.25 (1.19 to 8.9)	64 (1 RCT)	⊕⊕⊝⊝ low^a^,b
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks	NA	The mean HAMD depression score in the intervention group was 7.59 lower (11.52 lower to 3.66 lower)	NA	64 (1 RCT)	⊕⊕⊝⊝ low^a^,b
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the no treatment group. 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; HAMD: Hamilton Rating Scale for Depression; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded for imprecision, because only one small study contributed to the outcomes. ^bCertainty of the evidence downgraded once due to risk of bias; unclear methodological information provided regarding randomisation and allocation concealment.

Summary of findings 3. Venlafaxine compared to no treatment for people with epilepsy and depression

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Summary of findings 4. Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression

Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: sertraline Comparison: cognitive behavioural therapy (CBT)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CBT	sertraline
> 50% reduction in depressive symptoms Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Mean depression scores (BDI scores; lower = better) Follow‐up: 16 weeks	NA	The mean BDI depression score in the intervention group was 0.50 lower (4.47 lower to 3.47 higher)	NA	117 (1 RCT)	⊕⊕⊕⊝ moderate^a	At 8 weeks: MD ‐2.50 (95% CI ‐6.28 to 1.28; 104 participants)
Seizure frequency Follow‐up: 16 weeks	NA	The mean frequency of GTCS per month in the intervention group was 0 lower (‐0.10 lower to 0.10 higher) The mean frequency of focal seizures with impaired awareness per month in the intervention group was 3.00 lower (7.81 lower to 1.81 higher)	NA	96 with GTCS plus 75 with focal seizures (1 RCT)	⊕⊕⊝⊝ low^b	At 8 weeks: GTCS per month: MD ‐0.10 (95% CI ‐0.26 to 0.06; 86 participants) focal seizures with impaired awareness per month: MD ‐2.60 (95% CI ‐6.52 to 1.32; 75 participants)
Withdrawals Follow‐up: 16 weeks	176 per 1000	222 per 1000 (113 to 434 per 1000)	RR 1.26 (0.64 to 2.46)	140 (1 RCT)	⊕⊕⊕⊝ moderate^a	CBT: 6 withdrew, 6 lost to follow‐up sertraline: 7 withdrew, 9 lost to follow‐up
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life (QOLIE‐89 scale; lower = better) Follow‐up: 16 weeks	NA	The mean QOLIE‐89 score in the intervention group was 3.10 higher (3.41 lower to 9.61 higher)	NA	118 (1 RCT)	⊕⊕⊕⊝ moderate^a	at 8 weeks: MD 6.10 (95% CI ‐0.28 to 12.48; 104 participants)
Adverse effects Follow‐up: 16 weeks	NA	The mean adverse event profile score in the intervention group was 2.10 lower (6.21 lower to 2.01 higher)	NA	118 (1 RCT)	⊕⊕⊕⊝ low^a^,c	Sertraline resulted in more cases of tiredness than CBT (RR 3.54, 99% CI 1.40 to 8.96; 140 participants) Sertraline did not result in more cases of any other adverse effects than CBT.
The basis for the assumed risk* is the event rate in the CBT group. 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). BDI: Beck Depression Inventory; CBT: cognitive behavioural therapy; CI: confidence interval; MD: mean difference; NA: not applicable; QOLIE: Quality of life in Epilepsy; RCT: randomised controlled trial; RR: risk ratio; GTCS: generalised tonic‐clonic seizures
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded once due to risk of bias: participants and personnel not blinded, and lack of blinding may have influenced outcome ^bCertainty of the evidence downgraded twice due to risk of bias and imprecision: risk of recall bias as seizure frequency data at baseline was collected retrospectively, and data not available for all participants ^cCertainty of the evidence downgraded once due to imprecision: adverse event data not available for all participants who received an intervention

Summary of findings 4. Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression

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Summary of findings 5. Citalopram (before and after treatment) for people with epilepsy and depression

Citalopram (before and after treatment) for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: citalopram Control: before citalopram treatment
Outcomes	*Illustrative comparative risks (95% CI)**	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Citalopram (before and after)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
> 50% reduction in depressive symptoms Follow‐up: 4 months	11 out of 45 participants (24%) showed a 50% or more improvement in depression scores after treatment compared to baseline.	45 (1 NRSI)	⊕⊕⊝⊝ low^a
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks to 4 months	Improved depression scores were shown after citalopram compared to before (see comment)	88 (2 NRSI)	⊕⊕⊝⊝ low^a^,b,c	SMD in HAMD score was 1.17 (95% CI 0.96 to 1.38), indicating improved outcomes and a large treatment effect.
Seizure frequency Follow‐up: 8 weeks to 4 months	See comment	88 (2 NRSI)	⊕⊝⊝⊝ very low^a^,c	Results were mixed between studies; due to very high heterogeneity (I² = 81%), we did not present the overall effect estimate.
Withdrawals Follow‐up: 8 weeks to 4 months	6/45 participants (13%) withdrew from one study; 0/43 from the other study	88 (2 NRSI)	⊕⊕⊝⊝ low^a
Cognitive functioning Follow‐up: NA	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	0 (0 studies)	‐
Adverse effects Follow‐up: 8 weeks to 4 months	22/45 participants (56%) experienced adverse events in one study; 5/43 (12%) in the other study	88 (2 NRSI)	⊕⊕⊝⊝ low^a	Specific adverse events reported: nausea, sexual dysfunction, headache, dizziness, drowsiness, and fatigue
CI: confidence interval; HAMD: Hamilton Rating Scale for Depression; NRSI: non‐randomised studies of interventions
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded twice as studies were judged to be at serious risk of bias due to lack of blinding, which may have influenced participant‐recorded outcomes, and lack of adjustment for confounding variables. ^bCertainty of the evidence upgraded once as large effect found. ^cCertainty of the evidence downgraded due to inconsistency: substantial statistical heterogeneity was present (I² > 50%).

Summary of findings 5. Citalopram (before and after treatment) for people with epilepsy and depression

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Summary of findings 6. Selective serotonin reuptake inhibitors compared to cognitive behavioural therapy for people with epilepsy and depression

Selective serotonin reuptake inhibitorscompared to cognitive behavioural therapy for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: selective serotonin reuptake inhibitors (SSRIs; sertraline or citalopram) Comparison: cognitive behavioural therapy (CBT)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CBT	SSRIs
> 50% reduction in depressive symptoms Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Mean depression scores (BDI scores; lower = better) Follow‐up: 12 weeks	NA	The mean BDI depression score in the intervention group was 4.90 lower (14.90 lower to 4.80 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b	at 6 weeks: MD ‐2.60 (95% CI ‐11.58 to 6.38; 15 participants)
Seizure frequency Follow‐up: 12 weeks	NA	The mean frequency of seizures per month in the intervention group was 1.60 lower (5.63 lower to 2.43 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b
Withdrawals Follow‐up: 12 weeks	286 per 1000	126 per 1000 (14 to 1000 per 1000)	RR 0.44 (0.05 to 3.85)	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b	CBT: 2 lost to follow‐up SSRI: 1 lost to follow‐up in the
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life ‐ QOLIE‐31 scale Follow‐up: 12 weeks	NA	The mean QOLIE‐31 score in the intervention group was 0.50 lower (19.67 lower to 18.67 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝^1,2 very low
Adverse effects ‐ adverse event profile Follow‐up: 16 weeks	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the CBT group. 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). BDI: Beck Depression Inventory; CBT: cognitive behavioural therapy; CI: confidence interval; MD: mean difference; NA: not applicable; QOLIE: Quality of life in Epilepsy; RCT: randomised controlled trial; RR: risk ratio; SSRI: selective serotonin reuptake inhibitors
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. 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 certainty. We are very uncertain about the estimate.
1. Certainty of the evidence downgraded twice as the study was judged to be at serious risk of bias with regards to lack of blinding which may have influenced participant recorded outcomes and lack of adjustment for confounding variables. 2. Certainty of the evidence downgraded once due to imprecision: very small study of 15 participants, confidence intervals around effect estimates wide

Summary of findings 6. Selective serotonin reuptake inhibitors compared to cognitive behavioural therapy for people with epilepsy and depression

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Table 1. Criteria for overall risk of bias judgements from ROBINS‐I

Risk of bias judgement	Criteria based on seven risk of bias domains
Low risk of bias: the study is comparable to a well‐performed randomised trial	The study is judged to be at low risk of bias for all domains
Moderate risk of bias: the study appears to provide sound evidence for a non‐randomised study but cannot be considered comparable to a well‐performed randomised trial	The study is judged to be at low or moderate risk of bias for all domains
Serious risk of bias: the study has some important problems	The study is judged to be at serious risk of bias in at least 1 domain, but not at critical risk of bias in any domain
Critical risk of bias: the study is too problematic to provide any useful evidence on the effects of intervention	The study is judged to be at critical risk of bias in at least 1 domain
No information on which to base a judgement about risk of bias	There is no clear indication that the study is at serious or critical risk of bias, and there is a lack of information in 1 or more key domains of bias (a judgement is required for this)

Table 1. Criteria for overall risk of bias judgements from ROBINS‐I

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Table 2. Risk of bias judgements for non‐randomised studies (ROBINS‐I)

Domain and risk of bias judgement	Study
Domain and risk of bias judgement	Hovorka 2000	Kanner 2000	Kuhn 2003	Orjuela‐Rojas 2015	Specchio 2004	Thome‐Souza 2007
Bias due to confounding	Serious	Moderate	Serious	Moderate	Serious	Serious
Bias in selection of participants into the study	Moderate	Low	Moderate	Low	Serious	Moderate
Bias in classification of interventions	Low	Low	Moderate	Low	Low	Low
Bias due to deviations from intended interventions	Low	Low	Moderate	Moderate	Moderate	Low
Bias due to missing data	Low	Low	Serious	Serious	Serious	Low
Bias in measurement of outcomes	Moderate	Serious	Moderate	Moderate	Moderate	Moderate
Bias in selection of the reported result	Low	Moderate	Low	Moderate	Low	Low
Overall judgement	Serious	Serious	Serious	Serious	Serious	Serious
Support for judgement	No adjustment for confounding; unclear if participants were recruited consecutively; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes	Some analyses to investigate prognostic variables, but not a complete analysis of confounders; unclear which variables were of interest in advance, and if other characteristics were tested and analysed; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes. The measure of depression was not an accurate or reliable measure	No adjustment for confounding; many discontinuations due to adverse events and non‐compliance, with outcome data analysed by last observation carried forward; unclear if participants were already receiving the intervention on entry into the study, and exactly how groups were assigned. Lack of blinding may have influenced some participant‐reported outcomes.	Some analyses to investigate prognostic variables, but not a complete analysis of confounders; unclear which variables were of interest in advance, and if other characteristics were tested and analysed; small groups and dropouts, with outcome data analysed by last observation carried forward, Lack of blinding may have influenced some participant‐reported outcomes.	No adjustment for confounding; outcome data included only for those who completed analysis (6 participants excluded); and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes	No adjustment for confounding; unclear if participants were recruited consecutively; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes.

Table 2. Risk of bias judgements for non‐randomised studies (ROBINS‐I)

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Comparison 1. RCT: paroxetine versus doxepin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 > 50% reduction in depressive symptoms Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.88, 1.52]

1.2 Mean depression scores Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.2.1 HAMD scores	1	67	Mean Difference (IV, Fixed, 95% CI)	0.65 [‐2.15, 3.45]
1.3 Withdrawals (any reason) Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]

1.4 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

1.4.1 Blurred vision	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.09, 1.32]
1.4.2 Dizziness	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.21 [0.03, 1.37]
1.4.3 Dry mouth	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.26 [0.06, 1.20]
1.4.4 Sleep disorders	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.32 [0.08, 1.20]
1.4.5 Urinary retention	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.01, 21.99]

Comparison 1. RCT: paroxetine versus doxepin

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Comparison 2. RCT: amitriptyline versus nomifensine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 > 50% reduction in depressive symptoms Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.28, 1.06]

Comparison 2. RCT: amitriptyline versus nomifensine

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Comparison 3. RCT: venlafaxine versus no treatment controls

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 > 50% reduction in depressive symptoms Show forest plot	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [1.19, 8.90]

3.2 Mean depression scores ‐ HAMD Show forest plot	1	64	Mean Difference (IV, Fixed, 95% CI)	‐7.59 [‐11.52, ‐3.66]

Comparison 3. RCT: venlafaxine versus no treatment controls

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Comparison 4. RCT: sertraline versus cognitive behavioural therapy (CBT)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1.1 BDI‐II scores at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	‐2.50 [‐6.28, 1.28]
4.1.2 BDI‐II scores at 16 weeks	1	117	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐4.47, 3.47]
4.2 Remission in depressive symptoms Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.65, 1.17]

4.3 Seizure frequency Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.3.1 Generalised tonic‐clonic seizures per month at 8 weeks	1	86	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.26, 0.06]
4.3.2 Generalised tonic‐clonic seizures per month at 16 weeks	1	96	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.10, 0.10]
4.3.3 Focal seizures with impaired awareness per month at 8 weeks	1	75	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐6.52, 1.32]
4.3.4 Focal seizures with impaired awareness per month at 16 weeks	1	73	Mean Difference (IV, Fixed, 95% CI)	‐3.00 [‐7.81, 1.81]
4.4 Seizure recurrence Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.27, 3.94]

4.5 Withdrawals (any reason) Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.64, 2.46]

4.6 Quality of life (QOLIE‐89) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.6.1 QOLIE‐89 score at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	6.10 [‐0.28, 12.48]
4.6.2 QOLIE‐89 score at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	3.10 [‐3.41, 9.61]
4.7 Adverse events profile Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.7.1 Adverse event profile at 8 weeks	1	106	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐6.62, 1.22]
4.7.2 Adverse event profile at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	‐2.10 [‐6.21, 2.01]
4.8 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

4.8.1 Anxiety	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.2 Chest pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.47 [0.05, 4.21]
4.8.3 Cold	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.13, 3.13]
4.8.4 Diarrhoea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	19.85 [0.49, 805.53]
4.8.5 Dizziness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.51 [0.37, 6.14]
4.8.6 Dry mouth	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.78 [0.22, 65.10]
4.8.7 Headache	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.48 [0.69, 3.19]
4.8.8 Insomnia	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.16 [0.73, 6.38]
4.8.9 Memory difficulty	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.71 [0.10, 4.82]
4.8.10 Muscle strain or pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.21 [0.36, 4.12]
4.8.11 Nausea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.60 [0.62, 10.96]
4.8.12 Rash	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	4.72 [0.29, 76.72]
4.8.13 Sexual dysfunction	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.14 Shakiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	12.28 [0.88, 171.59]
4.8.15 Tiredness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.54 [1.40, 8.96]
4.8.16 Unsteadiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.57 [0.25, 9.81]
4.8.17 Worsening depression	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.13 [0.25, 5.07]

Comparison 4. RCT: sertraline versus cognitive behavioural therapy (CBT)

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Comparison 5. NRSI: citalopram (before and after)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mean depression scores HAMD‐21 Show forest plot	2	176	Std. Mean Difference (IV, Fixed, 95% CI)	1.17 [0.96, 1.38]

5.2 Mean monthly seizure frequency Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

Comparison 5. NRSI: citalopram (before and after)

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Comparison 6. NRSI: SSRIs (sertraline or citalopram) versus CBT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1.1 BDI at 6 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐11.58, 6.38]
6.1.2 BDI at 12 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.90 [‐14.60, 4.80]
6.2 Remission in depressive symptoms Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.77, 3.06]

6.3 Seizure frequency per month at 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐5.63, 2.43]

6.4 Withdrawals (any reason) Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.05, 3.85]

6.5 Quality of life (QOLIE‐31 overall score) Show forest plot	1	15	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐19.67, 18.67]

Comparison 6. NRSI: SSRIs (sertraline or citalopram) versus CBT

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Referencias

Referencias de los estudios incluidos en esta revisión

Gilliam 2019 {published data only}NCT00026637

Hovorka 2000 {published data only}

Kanner 2000 {published data only}

Kuhn 2003 {published data only}

Li 2005 {published data only}

Orjuela‐Rojas 2015 {published data only}NCT02262156

Robertson 1985 {published data only}

Specchio 2004 {published data only}

Thome‐Souza 2007 {published data only}

Zhu 2004 {published data only}

Referencias de los estudios excluidos de esta revisión

Blumer 1997 {published data only}

Harmant 1990 {published data only}

Machado 2010 {published data only}

NCT00595699 {unpublished data only}

NCT01244724 {published data only}

NCT03464383 {published data only}

Referencias de los estudios en curso

EUCTR2017‐000990‐35‐IT {published data only}

EUCTR2018‐003464‐32‐HU {published data only}

Referencias adicionales

Adams 2008

Alper 2007

APA 2000

Bagdy 2007

Baker 1996

Boylan 2004

Cotterman‐Hart 2010

Coupland 2011

Dell'osso 2013

Gilliam 2005b

Guyatt 2008

Hamid 2013

Hermann 2000

Hesdorffer 2000

Hesdorffer 2006

Hesdorffer 2009

Hesdorffer 2012

Higgins 2011

Higgins 2020

Indaco 1992

Jacoby 1996

Kirkham 2010

Klerman 1990

Kondziella 2009

Lambert 1999

Lin 2012

Mendez 1986

Mula 2009

Mula 2013

Preskorn 1992

Sackeim 2006

Stahl 2000

Sterne 2000

Tellez‐Zenteno 2007

Trimble 1998

Wroblewski 1990

Zarate 2006

Referencias de otras versiones publicadas de esta revisión

Maguire 2013

Maguire 2014

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

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