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Tratamientos misceláneos para la discinesia tardía inducida por antipsicóticos

Appendices

Appendix 1. Earlier searches

1.1 The 2002 update search

The Cochrane Schizophrenia Group's Register (January 2002) was searched with the following phrase

*dyskinesia* AND (*botulin* or *endorphin* or *estrogen* or *fatty acid* or *EX ?11?582A* or *ganglioside* or *insulin* or *lithium* or *naloxone* or *periactin* or *phenylalanine* or *piracetam* or *stepholidine* or *tryptophan* or *neurosurg* or * ect*)

1.2 The search for the previous versions of this review

1.2.1 Biological Abstracts (January 1982 to May 1995) was searched using the Cochrane Schizophrenia Group's phrase for randomised controlled trials (see Group search strategy) combined with the phrase:

[and ((tardive near (dyskine* or diskine*) or (abnormal near movement* near disorder*) or (involuntar* near movement*))]

The resulting set of reports was handsearched for possible trials and researched, within the bibliographic package, ProCite, with the phrase [botulin or endorphin or estrogen or (fatty and acid) or EX ?11?582A or ganglioside or lithium or naloxone or periactin or phenylalanine or piracetam or stepholidine or tryptophan or neurosurg* or ect]

1.2.2 Cochrane Schizophrenia Group's Register (January 1996) was searched using the phrase:

[(dyskinesia or (#30=60) or (#30=2)) and botulin or endorphin or estrogen or (#42=297) or (fatty and acid) or EX ?11?582A or ganglioside or lithium or (#42=16) or naloxone or (#42=8) or periactin or phenylalanine or piracetam or (#42=119) or stepholidine or tryptophan or (#42=181) or neurosurg* or ect or (#42=48))]

1.2.3 EMBASE (January 1980 to May 1995) was searched using the Cochrane Schizophrenia Group's phrase for randomised controlled trials (see Group search strategy) combined with the phrase:

[and ((tardive dyskinesia in thesaurus ‐subheadings, prevention, drug therapy, side effect and therapy) or (neuroleptic dyskinesia in thesaurus ‐all subheadings) or (tardive or dyskines*) or (movement* or disorder*) or (abnormal or movement* or disorder*))]

The resulting set of reports was handsearched for possible trials and researched, within the bibliographic package, ProCite, with the phrase [botulin or endorphin or estrogen or (fatty and acid) or EX ?11?582A or ganglioside or lithium or naloxone or periactin or phenylalanine or piracetam or stepholidine or tryptophan or neurosurg* or ect]

1.2.4 LILACS (January 1982 to September 1996) was searched using the Cochrane Schizophrenia Group's phrase for randomised controlled trials (see Group search strategy) combined with the phrase:

[and ((tardive or (dyskinesia* or diskinesia*)) or (drug induced movement disorders in thesaurus))]

The resulting set of reports was handsearched for possible trials and researched, within the bibliographic package, ProCite, with the phrase [botulin or endorphin or estrogen or (fatty and acid) or EX ?11?582A or ganglioside or lithium or naloxone or periactin or phenylalanine or piracetam or stepholidine or tryptophan or neurosurg* or ect]

1.2.5 MEDLINE (January 1966 to May 1995) was searched using the Cochrane Schizophrenia Group's phrase for randomised controlled trials (see Group search strategy) combined with the phrase:

[and ((movement‐disorders in MeSH / explode all subheadings) or (anti‐dyskinesia‐agents in MeSH / explode all subheadings) or (dyskinesia‐drug‐induced in MeSH / explode all subheadings) and
(psychosis in MeSH / explode all subheadings) or (schizophrenic disorders in MeSH / explode all subheadings) or (tardive near (dyskine* or diskine*)) or (abnormal* near movement* near disorder*) or (involuntar* near movement*))]

The resulting set of reports was handsearched for possible trials and researched, within the bibliographic package, ProCite, with the phrase [botulin or endorphin or estrogen or (fatty and acid) or EX ?11?582A or ganglioside or lithium or naloxone or periactin or phenylalanine or piracetam or stepholidine or tryptophan or neurosurg* or ect]

1.2.6 PsycLIT (January 1974 to May 1995) was searched using the Cochrane Schizophrenia Group's phrase for randomised controlled trials (see Group search strategy) combined with the phrase:

[and ((explode movement‐disorders in DE) or (explode tardive‐dyskinesia in DE) or (tardive near (dyskine* or diskine*)]

The resulting set of reports was handsearched for possible trials and researched, within the bibliographic package, ProCite, with the phrase [botulin or endorphin or estrogen or (fatty and acid) or EX ?11?582A or ganglioside or lithium or naloxone or periactin or phenylalanine or piracetam or stepholidine or tryptophan or neurosurg* or ect]

1.2.7 SCISEARCH ‐ Science Citation Index
Each of the included studies was sought as a citation on the SCISEARCH database. Reports of articles that had cited these studies were inspected in order to identify further trials.

Appendix 2. Previous methods

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials. Where a trial was described as 'double‐blind', but it was only implied that the study was randomised, we included these trials in a sensitivity analysis. If there was no substantive difference within primary outcomes (seeTypes of outcome measures) when these 'implied randomisation' studies were added, then we included these in the final analysis. If there was a substantive difference, we only used clearly randomised trials and described the results of the sensitivity analysis in the text. We excluded quasi‐randomised studies, such as those allocating by using alternate days of the week.

Types of participants

We included people with schizophrenia and other types of schizophrenia‐like psychosis (e.g. schizophreniform and schizoaffective disorders), irrespective of the diagnostic criteria used, who: i. required the use of neuroleptics for more than three months; ii. developed tardive dyskinesia (diagnosed by any criteria) during neuroleptic treatment; and iii. for whom the dose of neuroleptic medication had been stable for one month or more before the trial. There is no clear evidence that the schizophrenia‐like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994).

Types of interventions

1. Drugs
Botulin toxin, dimethylaminoethanol, endorphin, oestrogen, essential fatty acid, EX 11‐582A, ganglioside GM1, lithium, methylphenidate, naloxone, naltrexone, periactin, phenylalanine, piracetam, stepholidine, tryptophan. Any doses, frequencies or means of administration were acceptable.

2. Surgical intervention of any sort.

3. Electroconvulsive therapy (ECT).

Compared with:

1. Standard care; or

2. Placebo or no treatment.

Types of outcome measures

Where possible, outcomes were grouped into time periods ‐ short term (less than 6 weeks), medium term (between 6 weeks and 6 months) and long term (over 6 months).

Primary outcomes

1. Tardive dyskinesia
1.1 No clinically important change in tardive dyskinesia

2. Mental state
2.1 No clinically important change in general mental state

3. Adverse effects
3.1 Clinically important general adverse effects

4. Leaving the study early
4.1 For general reasons

Secondary outcomes

1. Tardive dyskinesia
1.2 Not any change in tardive dyskinesia
1.3 Average endpoint tardive dyskinesia score
1.4 Average change in tardive dyskinesia score

2. Mental state
2.1 Not any change in general mental state
2.2 Average endpoint general mental state score
2.3 Average change in general mental state score
2.4 No clinically important change in specific symptoms
2.5 Not any change in specific symptoms
2.6 Average endpoint specific symptom score
2.7 Average change in specific symptom score

3. Adverse effects
3.1 Any general adverse effects
3.2 Average endpoint general adverse effect score
3.3 Average change in general adverse effect score
3.4 Clinically important change in specific adverse effects
3.5 Any change in specific adverse effects
3.6 Average endpoint specific adverse effects
3.7 Average change in specific adverse effects

4. Leaving the study early
4.1 For specific reasons

Search methods for identification of studies

Electronic searches

1. Update of 2009
We searched the Cochrane Schizophrenia Group Trials Register (September 2009) using the phrase:

[*dyskinesia* in title, abstract and index fields or REFERENCE]

This register is compiled by systematic searches of major databases, hand searches and conference proceedings (see Group Module).

2. Previous searches for earlier versions of this review
Please see (Appendix 1).

Searching other resources

1. Reference searching
We also inspected the references of all studies identified in this way for more studies.

2. Personal contact
We contacted the first author of each included study for information regarding unpublished trials.

Data collection and analysis

Selection of studies

Two reviewers independently inspected all study citations identified by the searches, and full reports of the studies of agreed relevance were obtained. Where disputes arose, we acquired the full report for more detailed scrutiny. These articles were then inspected, independently, by two reviewers to assess their relevance to this review. Again, where disagreement occurred attempts were made to resolve this through discussion; if doubt still remained we added these trials to the list of those awaiting assessment pending acquisition of further information.

Data extraction and management

1. Extraction
We independently extracted data. Where disagreement occurred attempts were made to resolve this by discussion, where doubt still remained we sought further information from the study authors to resolve the dilemma, and added the trial to the list of those awaiting assessment.

2. Management
2.1 Data storage
We extracted the data onto standard, simple forms. Where possible, data were entered into RevMan in such a way that the area to the left of the 'line of no effect' indicates a 'favourable' outcome for the treatment group. Where this was not possible, (e.g. scales that calculate higher scores=improvement) the graphs in RevMan analyses were labelled accordingly so that the direction of effects were clear.

2.2 Categorical or continuous into binary
Where possible, efforts were made to convert outcome measures to binary data. This can be done by identifying cut off points on rating scales and dividing participants accordingly into "clinically improved" or "not clinically improved". It is generally assumed that if there is a 50% reduction in a scale‐derived score such as the Brief Psychiatric Rating Scale (BPRS Overall 1962) or the Positive and Negative Syndrome Scale (PANSS, Kay 1986, this could be considered a clinically significant response (Leucht 2005a, Leucht 2005). It is recognised that for many people, especially those with chronic or severe illness, a less rigorous definition of important improvement (e.g. 25% on the BPRS) would be equally valid. If individual patient data are available, we used the 50% cut‐off point for non‐chronically ill people and a 25% cut‐off point for those with chronic illness. If data based on these thresholds were not available, we used the primary cut‐off presented by the original authors.

2.3 Continuous data and their distribution
Continuous data on outcomes in mental health trials are often not normally distributed. To avoid the pitfall of applying parametric tests to non‐parametric data we applied the following standards to all endpoint data derived from continuous measures. The criteria were used before inclusion: (a) standard deviations and means had to be obtainable; and, for finite scores, such as endpoint measures on rating scales, (b) the standard deviation (SD), when multiplied by 2 had to be less than the mean (as otherwise the mean was unlikely to be an appropriate measure of the centre of the distribution) (Altman 1996). If a scale starts from a positive value (such as PANSS, which can have values from 30 to 210) the calculation described above in (b) should be modified to take the scale starting point into account. In these cases skewness is present if 2SD>(S‐Smin), where S is the mean score and Smin is the minimum score.

Skewed endpoint data from studies with less the 200 participants were not shown graphically, but were added to 'Other data' tables and briefly commented on in the text. However, skewed endpoint data from larger studies (=/>200 participants) pose less of a problem and we entered the data for analysis (Higgins 2009).

For continuous mean change data (endpoint minus baseline) the situation is even more problematic. In the absence of individual patient data it is impossible to know if change data are skewed. The RevMan meta‐analyses of continuous data are based on the assumption that the data are, at least to a reasonable degree, normally distributed. We included such data, unless endpoint data were also reported from the same scale.

2.4 Final endpoint value versus change data
Where both final endpoint data and change data were available for the same outcome category, only final endpoint data were presented. We acknowledge that by doing this much of the published change data may be excluded, but argue that endpoint data is more clinically relevant and that if change data were to be presented along with endpoint data, it would be given undeserved equal prominence.

3. Scale‐derived data
A wide range of instruments are available to measure outcomes in mental health studies. These instruments vary in quality and many are not validated, or are even ad hoc. It is accepted generally that measuring instruments should have the properties of reliability (the extent to which a test effectively measures anything at all) and validity (the extent to which a test measures that which it is supposed to measure) (Rust 1989). Unpublished scales are known to be subject to bias in trials of treatments for schizophrenia (Marshall 2000). Therefore continuous data from rating scales were included only if the measuring instrument had been described in a peer‐reviewed journal. In addition, the following minimum standards for instruments were set: the instrument should either be (a) a self‐report or (b) completed by an independent rater or relative (not the therapist) and (c) the instrument should be a global assessment of an area of functioning.

Assessment of risk of bias in included studies

We assessed risk of bias using the tool described in the Cochrane Collaboration Handbook (Higgins 2009). This tool encourages consideration of how the sequence was generated, how allocation was concealed, the integrity of blinding at outcome, the completeness of outcome data, selective reporting and other biases. We would not have included studies where sequence generation was at high risk of bias or where allocation was clearly not concealed.

The categories are defined below:

YES ‐ low risk of bias
NO ‐ high risk of bias
UNCLEAR ‐ uncertain risk of bias

If disputes arose as to which category a trial has to be allocated, again, resolution was made by discussion, after working with a third reviewer.

Earlier versions of this review used a different means of categorising risk of bias (see Appendix 3).

Measures of treatment effect

1. Binary data
For binary outcomes we calculated the relative risk (RR) and its 95% confidence interval (CI) based on the fixed effects model. Relative Risk is more intuitive (Boissel 1999) than odds ratios and odds ratios tend to be interpreted as RR by clinicians (Deeks 2000). This misinterpretation then leads to an overestimate of the impression of the effect. When the overall results were significant we calculated the number needed to treat (NNT) and the number‐ needed‐ to‐ harm (NNH). Where people were lost to follow up at the end of the study, we assumed that they had had a poor outcome and once they were randomised they were included in the analysis (intention‐to‐treat /ITT analysis).

2. Continuous data
For continuous outcomes we estimated a weighted mean difference (WMD) between groups based on a fixed effects model.

Unit of analysis issues

1. Cluster trials
Studies increasingly employ cluster randomisation (such as randomisation by clinician or practice) but analysis and pooling of clustered data poses problems. Firstly, authors often fail to account for intra class correlation in clustered studies, leading to a unit‐of‐analysis error (Divine 1992) whereby p values are spuriously low, confidence intervals unduly narrow and statistical significance overestimated. This causes Type I errors (Bland 1997, Gulliford 1999).

Where clustering had not been accounted for in primary studies, we presented the data in a table, with a (*) symbol to indicate the presence of a probable unit of analysis error. In subsequent versions of this review we will seek to contact first authors of studies to obtain intra‐class correlation co‐efficients of their clustered data and to adjust for this using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will also present these data as if from a non‐cluster randomised study, but adjusted for the clustering effect.

We have sought statistical advice and have been advised that the binary data as presented in a report should be divided by a design effect. This is calculated using the mean number of participants per cluster (m) and the intraclass correlation co‐efficient (ICC) [Design effect=1+(m‐1)*ICC] (Donner 2002). If the ICC is not reported we assumed it to be 0.1 (Ukoumunne 1999). If cluster studies had been appropriately analysed taking into account intra‐class correlation coefficients and relevant data documented in the report, we synthesised these with other studies using the generic inverse variance technique.

2. Cross‐over design
A major concern of cross‐over trials is the carry‐over effect. It occurs if an effect (e.g. pharmacological, physiological or psychological) of the treatment in the first phase is carried over to the second phase. As a consequence on entry to the second phase the participants can differ systematically from their initial state despite a wash‐out phase. For the same reason cross‐over trials are not appropriate if the condition of interest is unstable (Elbourne 2002). As both effects are very likely in schizophrenia,¬we will only use¬data¬of the first phase of cross‐over studies.

3. Studies with multiple treatment groups
Where a study involved more than two treatment arms, if relevant, the additional treatment arms were presented in comparisons. Where the additional treatment arms were not relevant, these data were not reproduced.

Dealing with missing data

1. Overall loss of credibility
At some degree of loss to follow‐up data must lose credibility (Xia 2007). We are forced to make a judgment where this is for the trials likely to be included in this review. Should more than 50% of data be unaccounted for by 8 weeks we did not reproduce these data or use them within analyses.

2 Intention to treat analysis
We excluded data from studies where more than 50% of participants in any group were lost to follow up (this did not include the outcome of 'leaving the study early'), as such data were felt to be too prone to bias. In studies with less than 50% dropout rate, people leaving early were considered to have had the negative outcome, except for the event of death. We analysed the impact of including studies with high attrition rates (25‐50%) in a sensitivity analysis. If inclusion of data from this latter group resulted in a substantive change in the estimate of effect, we did not add their data to trials with less attrition, but presented them separately.

Assessment of heterogeneity

1. Clinical heterogeneity
We preempted heterogeneity by keeping different treatment groups separate but also tried to think if there were such obvious clinical differences in studies that synthesis be inadvisable.

2. Statistical
2.1 Visual inspection
We visually inspected graphs to investigate the possibility of statistical heterogeneity.

2.2 Employing the I‐squared statistic
This provided an estimate of the percentage of inconsistency thought to be due to chance. I‐squared estimate greater than or equal to 50% was interpreted as evidence of high levels of heterogeneity (Higgins 2003).

Assessment of reporting biases

Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. These are described in section 10.1 of the Cochrane Handbook (Higgins 2009). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small‐study effects (Egger 1997). We did not use funnel plots for outcomes where there were ten or fewer studies, or where all studies were of similar sizes. Should funnel plots have been possible, we would have sought statistical advice in their interpretation.

Data synthesis

Where possible we used a fixed effects model for analyses. We understand that there is no closed argument for preference for use of fixed or random effects models. The random effects method incorporates an assumption that the different studies are estimating different, yet related, intervention effects. This does seem true to us, however, random effects does put added weight onto the smaller studies ‐ those trials that are most vulnerable to bias.

Subgroup analysis and investigation of heterogeneity

When heterogeneous results were found, we investigated the reasons for this. Where heterogeneous data substantially altered the results and the reasons for the heterogeneity were identified, these studies were not summated in the meta‐analysis, but presented separately and discussed in the text.

Sensitivity analysis

Apart from the investigation of heterogeneity, the effect of including studies with high attrition rates were analysed in sensitivity analyses.

Appendix 3. Assessment of quality

Trials were allocated to three quality categories, as described in the Cochrane Collaboration Handbook (Clarke 2000) by each reviewer working independently. When disputes arose as to which category a trial was allocated to, again, resolution was attempted by discussion. When this was not possible, and further information was necessary, data were not entered into the analyses and the study was allocated to the list of those awaiting assessment. Only trials in Category A or B were included in the review.

Message from one of the participants of the Public and patient involvement consultation of service user perspectives on tardive dyskinesia research.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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