Abstract
Background
There are a number of effective interventions for the treatment of depression. It is possible that the efficacy of these treatments will be improved further by the use of adjunctive therapies such as inositol.
Objectives
1. To determine the effectiveness of inositol in the treatment of depression. 2. To determine the adverse effects and acceptability of treatment with inositol.
Search methods
The Cochrane Controlled Trials Register (CCTR), The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) incorporating results of group searches of EMBASE, MEDLINE, LILACS, CINAHL, PSYNDEX and PsycLIT were searched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Experts in the field and pharmaceutical companies were contacted regarding unpublished material.
Selection criteria
All randomised controlled trials that compare treatment with inositol, whether as monotherapy or adjunctive therapy, to an alternative treatment, whether another antidepressant medication or placebo, for patients with a diagnosis of depressive disorder (diagnosed according to explicit criteria).
Data collection and analysis
Data were independently extracted from the original reports by two reviewers. Statistical analysis was conducted using Review Manager version 4.2.1.
Main results
Four trials were identified, with a total of 141 participants. These were short term trials of double‐blind design. The trials did not show clear evidence of a therapeutic benefit, nor any evidence of poor acceptability.
Authors' conclusions
It is currently unclear whether or not inositol is of benefit in the treatment of depression. Ongoing studies should reduce this uncertainty.
Plain language summary
Inositol for depression
Inositol is a nutritional supplement that has been suggested as a treatment for depressive disorders. The reviewers found the current evidence is unclear whether or not inositol is of benefit in the treatment of depression. There are ongoing studies that should reduce this uncertainty.
Background
Depression is a major cause of worldwide disability. In the United States the one month prevalence of a major depressive episode has been estimated to be 4.9% (Blazer 1994) and comparable figures have been found in the U.K. (Jenkins 1997). Depressive disorders share central features of low mood, lack of enjoyment, pessimistic thinking, and reduced energy, all of which lead to decreased functioning. The Global Burden of Disease Study found unipolar depression to be the fourth leading cause of worldwide disability even after excluding deaths due to suicide (Murray 1997a). The prevalence of major depressive disorder may be on the increase (CNCG 1992) and the Global Burden of Disease Study predicted that, by 2020, unipolar major depression will be the second leading cause of disability worldwide (Murray 1997b).
There are several effective interventions available for the acute treatment of depression including pharmacotherapy and psychotherapy (Geddes 2001). Since the introduction of antidepressants in the 1950s, the number of available pharmacological treatments has increased, but their efficacy has remained largely unchanged. A recent review reported a response rate of 50% with active drug compared to 32% with placebo (AHCPR 1999). One possible method of improving response to antidepressant medication is by using adjunctive agents such as nutritional supplements.
Inositol, or myo‐inositol, is a naturally occurring compound, an isomer of glucose. It is sometimes considered part of the vitamin B complex. Inositol is consumed in a range of foods such as whole‐grain cereals, fruits, plants, and meats, and the typical dietary intake of inositol is around 1g per day. It is not a prescription medication, but is widely available as a dietary supplement. Within the body, inositol is used for the production of inositol triphosphate (IP3) and diacylglycerol (DAG), important 'second messengers' allowing cell surface receptors for neurotransmitters, including serotonin, to affect intracellular processes.
Lower than normal levels of inositol are found in the cerebrospinal fluid of people with depression (Barkai 1978). Post mortem studies have shown that levels of inositol in particular areas of the cortex of suicide victims, and people with bipolar disorder are also lowered (Shimon 1997). It has also been reported that the anti‐manic effect of lithium treatment is associated with a reduction in inositol levels (Allison 1971; Kofman 1993). These findings raised the possibility that increasing inositol levels in depression might be therapeutic. Treatment with inositol has been effective in so‐called 'animal models' of depression (Einat 2001). Inositol taken orally has been shown to increase inositol levels within the central nervous system in humans (Levine 1993).
This review aims to assess the available evidence that treatment with inositol, whether alone or as an adjunct to other antidepressant medication, is effective in the treatment of depression.
Objectives
1. To determine the effectiveness of inositol, whether alone or as an adjunct to other antidepressant medication, in the treatment of depression.
2. To determine the adverse effects and acceptability of inositol in the treatment of depression
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
All patients suffering from a depressive disorder diagnosed according to explicit criteria (e.g. following a specified diagnostic schema such as the American Psychiatric Association's Diagnostic and Statistical Manual), including major depressive disorder, dysthymic disorder, and bipolar affective disorder.
Types of interventions
1. Inositol compared to placebo, 2. Inositol compared to antidepressant medication, or 3. Inositol plus antidepressant compared to antidepressant alone, in the treatment of depressive disorder.
Types of outcome measures
A. Primary outcome measure Resolution of a depressive episode within defined periods of observation is the primary outcome measure. Resolution is often measured using depressive symptom rating scales, when possible we have analysed these as continuous data. These continuous data, however, are often dichotomised at an arbitrary cut point (e.g. Hamilton Depression Rating Scale score <8, or a >50% reduction on the HDRS) because this facilitates clinical interpretation, accordingly such data are analysed as dichotomous data.
B. Secondary outcome measures Where possible we have also investigated the following outcomes using continuous and dichotomous data as appropriate: The overall drop‐out rate as a proxy measure of overall acceptability of treatment The drop‐out rate due to side‐effects The number of patients reporting at least one adverse event i.e. troublesome side effects Quality of life Global clinical impression rated by the clinician Global clinical impression rated by the patient Social functioning Occupational functioning Rate of relapse or onset of manic episode Rates of admission to hospital Duration of admission to hospital Mortality due to all causes and specifically suicides and verdicts of undetermined deaths.
Search methods for identification of studies
See Collaborative Review Group search strategy. 1. Electronic databases were searched: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), incorporating results of group searches of MEDLINE (1966 ‐), EMBASE (1980 ‐), CINAHL (1982 ‐), PsycLIT (1974 ‐), PSYNDEX (1977 ‐) and LILACS (1982 ‐) using the following terms: inositol OR myo‐inositol OR meso‐inositol OR i‐inositol OR epi‐inositol OR l‐chiro‐inositol
The Cochrane Library Controlled Trials Register (CCTR), using the following terms: (inositol* OR myo?inositol* OR myoinositol* OR myo‐inositol* OR meso?inositol* OR mesoinositol* OR meso‐inositol* OR i‐inositol* OR epi?inositol* OR epi‐inositol* OR l‐chiro?inositol* OR l‐chiro‐inositol*) AND (depress* OR dysthym* OR (dysthym* NEXT disord*) OR (bipolar disorder))
To supplement the results from the CCDANCTR and the CCTR the databases MEDLINE (1966 ‐ Jan Week 3, 2004), EMBASE (1980 ‐ 2004 Week 3), PsycINFO (1872 ‐ Jan Week 3, 2004), and CINAHL (1982 ‐ Dec Week 2, 2003) were searched using the Cochrane Library RCT filter and the following terms: (exp inositol OR inositol* OR myo?inositol* OR myoinositol* OR myo‐inositol* OR meso?inositol* OR mesoinositol* OR meso‐inositol* OR i‐inositol* OR epi?inositol* OR epi‐inositol* OR l‐chiro?inositol* OR l‐chiro‐inositol*) AND (exp depressive disorder OR exp bipolar disorder OR exp major depression OR exp manic depression OR exp manic depressive psychosis OR depress* OR dysthymia OR (dysthym* NEXT disord*))
2. Reference checking The reference lists of all selected studies were inspected for more published reports and citations of unpublished research. In addition other relevant papers and major textbooks which cover affective disorder were checked.
3. Personal communications To ensure that as many randomised controlled trials as possible were identified, the authors of significant papers and other experts in the field were contacted.
4. Pharmaceutical Companies Pharmaceutical companies manufacturing inositol were contacted to find out if they knew of any published or unpublished randomised controlled trials relevant to this review.
Data collection and analysis
1. Selection of trials Studies generated by the search strategies were checked independently by two reviewers to ensure that they met the previously defined inclusion criteria.
2. Quality assessment Two reviewers independently assessed the methodological quality of the included studies. The reviewers were not blind to the authorship and source of the papers (Berlin 1997). Quality was assessed according to the Cochrane criteria for quality assessment (Sackett 1997). This pays particular attention to the quality of the randomisation procedure including allocation concealment. On this basis studies were given a quality rating of A (adequate), B (unclear), and C (inadequate). If the raters disagreed, the final rating was made by consensus with the involvement, if necessary, of another of the review group. In addition, aspects of quality such as whether the trial was of a double blind design and reporting of withdrawals and dropouts were described. Where adequate details of randomisation and other characteristics of trials are not provided the authors have been contacted in order to obtain further information.
3. Data extraction Data were extracted from the included studies about participant characteristics, intervention details, study design, and outcome measures. This included numbers of patients randomised to each treatment group, and the numbers of patients failing to reach the end of the study. For continuous outcome measures, the mean score and standard deviation, and the number of participants evaluated, were extracted for each time point. Any disagreements were resolved by consensus discussions with a third member of the review team.
4. Data analysis Data were entered into Review Manager 4.1.1 software. For binary efficacy outcomes, a relative risk (with 95% confidence intervals) was calculated using a fixed effects model. Heterogeneity between studies was assessed using the chi‐squared test. Random effects models were used routinely to investigate the sensitivity of results to the choice of statistical method. For continuously distributed outcomes the weighted mean difference (WMD) was calculated when the same scale was used in a similar manner across studies, otherwise, the standardised weighted mean difference (SMD) was used. We used intention‐to‐treat data when available, using last observation carried forward where available, and where this was not possible, endpoint data for trial completers was used. Non‐quantitative data are presented descriptively. Subgroup analyses were planned to assess the extent to which the results differed between diagnostic groups, e.g. between bipolar affective disorder and major depressive disorder, to explore the possibility of clinical heterogeneity of response. Sensitivity analyses were planned to assess the robustness of the results to the exclusion of studies of lower methodological quality.
Results
Description of studies
Four trials met the inclusion criteria for this review, in which a total of 141 participants were randomised. They were all of a parallel group design.
Participants All participants were aged over 18 years. The trials recruited both male and female participants. One trial (Levine 1995) included people with a diagnosis of unipolar or bipolar depression who had failed to respond to, or had not tolerated, conventional antidepressants. Another trial (Chengappa 2000) included patients with bipolar depression despite adequate doses of a mood stabiliser, almost half (10/22) of whom who had already failed to respond to conventional antidepressant. The two remaining trials were both concerned with unipolar depression. In one participants simply had major depression (Levine 1999), in the other they had also failed to improve with conventional antidepressant treatment (Nemets 1999).
Setting The trials were all performed in outpatient populations. Three trials (Levine 1995; Levine 1999; Nemets 1999) were performed by a group working in Israel. The other trial (Chengappa 2000) was performed in the United States of America.
Interventions All trials compared the use of oral inositol, at a daily dosage of 12 g, with the use of a glucose placebo. In one trial (Levine 1995) inositol was used as the only antidepressant treatment. In the other studies it was used in addition to conventional antidepressant agents.
Duration The trials were of short duration with three trials lasting four weeks (Levine 1995; Levine 1999; Nemets 1999), and the remaining trial lasting six weeks (Chengappa 2000).
Primary outcome measures Three trials used the 24‐item Hamilton Depression Rating Scale (HDRS‐24), and provided data on scores at trial endpoint. The remaining trial used the 17‐item Hamilton Depression Rating Scale (HDRS‐17), the Montgomery‐Asberg Depression Rating Scale (MADRS), and an additional eight items for the HDRS, and provided data for change in scores over the duration of the trial.
Secondary outcome measures Ascertainment of side effects of treatment was performed using a modified Treatment Emergent Symptom Scale in one trial (Levine 1995), and using both the UKU Side Effects Rating Scale and spontaneous reports in another (Chengappa 2000). The other studies did not specify the method employed.
Risk of bias in included studies
Allocation The trials gave few details of the randomisation procedures followed. The methods used to maintain concealment of allocation were unclear, therefore all the trials received a 'B' rating according to Cochrane criteria (Sackett 1997).
Blinding All the trials described the use of 'double‐blind' methods, with blinding of subjects achieved using a glucose placebo in the same powdered form as the inositol. One trial (Nemets 1999) explicitly states that the outcome assessor was blind to treatment allocation, but it is unclear in the other trials whether the blinding was of clinician and/or outcome assessor.
Reporting of withdrawals and dropouts All the trials reported numbers of withdrawals and dropouts, but none included all of these participants in analyses. Chengappa 2000 reports data from all those who had at least one post‐randomisation assessment; the other studies analysed those who had completed at least one week (Levine 1995), three weeks (Nemets 1999) or four weeks (Levine 1999) of treatment.
Effects of interventions
Resolution of a depressive episode Continuous rating scales were used by all four trials allowing comparison of scores between the groups at trial end points. The trial (Levine 1995) comparing treatment with inositol alone to the use of placebo reported a difference in Hamilton Depression Rating Scale (HDRS‐24) score of ‐7.30, favouring inositol, although the 95% confidence intervals (95% CI) are wide (‐14.73 to 0.13) and do not exclude an absence of effect. The trials comparing the use of inositol or placebo in addition to an SSRI did not find any statistically significant difference in HDRS‐24 score between the groups, and again confidence intervals around the main effect were wide (Levine 1999 WMD 1.80, 95% CI ‐7.32 to 10.92, Nemets 1999 WMD 1.90, 95% CI ‐4.55 to 8.35). The remaining trial used a different form of the Hamilton Depression Rating Scale (HDRS‐17), and found the change in this score by the trial end point did not differ between inositol and placebo (WMD ‐0.20, 95% CI ‐5.90 to 5.50). Combining these continuous measures using Standardised Weighted Mean Difference (SMD), no statistically significant overall heterogeneity of effect between trials is observed (Chi‐square 3.57, df 3, p 0.31). The pooled estimate of effect (SMD ‐0.08, 95% CI ‐0.45 to 0.30) is consistent with both a presence or absence of therapeutic benefit . Repetition of these analyses using a random effects model did not qualitatively change the results found. Analysing changes in HDRS score in a dichotomous fashion, e.g. achievement of a 50% reduction in score, also fails to exclude a lack of effect from inositol.
Acceptability of treatment None of the trials found any statistically significant difference in drop out rates between the groups receiving inositol and those receiving placebo. A pooled estimate for the four trials taken together was calculated, since it was judged that tolerability of treatment with inositol would not be substantially affected by the differences between the study designs. This analysis also found no significant difference (RR 1.49, 95% CI 0.77 to 2.90). Similarly no significant difference was found in numbers of dropouts attributed to side effects (RR 0.81, 95% CI 0.32 to 2.09), nor in the numbers of subjects experiencing at least one adverse event (RR 0.89, 95% CI 0.48 to 1.64).
Other outcomes Levine 1995 reportsone person receiving placebo dropping out from the study because of hypomania, and Chengappa 2000 reports one person from the placebo arm developing mania after switching to inositol in an open‐label period of follow‐up. No trial reported any admissions to hospital during double‐blind treatment, but Chengappa 2000 reports one person from each arm being admitted during open‐label follow‐up, and Levine 1999 reports one person from the inositol arm being admitted shortly after the end of the trial. No deaths were reported during the trials. Chengappa 2000 assessed Clinical Global Impression rated by the clinician, but does not report the results separately. None of the trials described assessing quality of life, clinical global impression rated by the patient, social functioning or occupational functioning.
Subgroup Analysis The planned subgroup analysis by type of depressive disorder was not performed because of the small amount of data available and use of differing outcome measures between trials.
Sensitivity Analysis The planned sensitivity analysis excluding trials of low methodological quality was not performed given the small number of trials identified and their similar methodological quality.
Discussion
It is unclear on the basis of the current evidence whether or not inositol is effective in the treatment of depression. The limited evidence limits the precision of the results, and also means that a single unidentified trial could have a substantial effect on the results. As there are few studies, indirect methods of identifying publication bias such as funnel plots are of very limited value.
The included trials did not find evidence that inositol was any less well tolerated than a glucose placebo. However, the small number of people randomised means that infrequent but serious adverse events cannot be excluded.
Authors' conclusions
Implications for practice.
The currently available evidence does not indicate a clear benefit from the use of inositol in depression. People with depression and their clinicians may wish to await further evidence before using inositol in a widespread fashion.
Implications for research.
Further randomised evidence is required to reduce the uncertainty surrounding the estimates of effect of inositol. There are at least two ongoing randomised trials (Sachs; STEP‐BD) using inositol in bipolar disorder that should reduce this uncertainty when completed.
What's new
| Date | Event | Description |
|---|---|---|
| 1 November 2008 | Amended | Converted to new review format. |
History
Protocol first published: Issue 1, 2003 Review first published: Issue 2, 2004
| Date | Event | Description |
|---|---|---|
| 22 October 2003 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
We would like to thank the CCDAN Editorial Team for their support, information and advice.
Data and analyses
Comparison 1. inositol versus glucose (placebo).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Hamilton Rating Scale for Depression, trial end point | 4 | 113 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.45, 0.30] |
| 1.1 inositol monotherapy | 1 | 28 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.71 [‐1.48, 0.06] |
| 1.2 inositol augmentation of other treatments | 3 | 85 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.12 [‐0.31, 0.55] |
| 2 change in Hamilton depression rating scale (dichotomous) | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 failure to decrease HDRS score by 15 points | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 failure to decrease HDRS score by 15 points and by at least 50% | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 failure to reduce HDRS(17) by 50% and have CGI of 2 or less (completers) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 measures of tolerability | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 overall drop‐outs | 4 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.77, 2.90] |
| 3.2 drop‐outs attributed to side effects | 4 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.32, 2.09] |
| 3.3 subjects with at least one adverse event | 4 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.48, 1.64] |
1.1. Analysis.
Comparison 1 inositol versus glucose (placebo), Outcome 1 Hamilton Rating Scale for Depression, trial end point.
1.2. Analysis.
Comparison 1 inositol versus glucose (placebo), Outcome 2 change in Hamilton depression rating scale (dichotomous).
1.3. Analysis.
Comparison 1 inositol versus glucose (placebo), Outcome 3 measures of tolerability.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Chengappa 2000.
| Methods | parallel group double blind design, randomised allocation | |
| Participants | 24 adults, bipolar affective disorder, current episode depressed (DSM‐IV criteria), Hamilton Depression Rating Scale (17 item) >14 at entry, taking lithium valproate or carbamazepine in therapeutic dosage | |
| Interventions | (1) 2g of inositol in water three times daily increased to 4g three times daily after one week in addition to usual medication OR (2) 2g of grape sugar (glucose) in water three times daily increased to 4g three times daily after one week in addition to usual medication | |
| Outcomes | Hamilton Depression Rating Scale (17 and 25 item), Montgomery Asberg Depression Rating Scale, Clinical Global Impression, Young Mania Rating Scale, UKU Side Effects Scale | |
| Notes | Six week duration | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Levine 1995.
| Methods | parallel group double blind design, randomised allocation | |
| Participants | 39 adults (12 male, 16 female; ages 20‐80) with major depressive episode or bipolar disorder, current episode depressed (DSM‐III‐R criteria), not responded to or not tolerated antidepressant treatment or intolerable continuation of depression despite use of lithium | |
| Interventions | 3‐7 day washout period (medications except benzodiazepines stopped) then (1) 6g inositol (in juice) twice daily OR (2) 6g glucose (in juice) twice daily | |
| Outcomes | Hamilton Depression Rating Scale (24 item), modified Treatment Emergent Symptom Scale | |
| Notes | Four week duration | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Levine 1999.
| Methods | parallel group double blind design, randomised allocation | |
| Participants | 36 adults (8 male, 19 female completed), major depression (DSM‐IV criteria) | |
| Interventions | 3‐7 day drug free period then (1) 3g inositol in juice or tea four times daily plus SSRI OR (2) 3g grape sugar (glucose) in juice or tea four times daily plus SSRI | |
| Outcomes | Hamilton Depression Rating Scale (24 item) | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Nemets 1999.
| Methods | parallel group double blind design, randomised allocation | |
| Participants | 42 adults (14 male, 22 female completed), major depression without psychotic features (DSM‐IV criteria), no more than mild improvement in symptoms after at least 3 weeks treatment with SSRI, Hamilton Depression Rating Scale (24 item) score >17 | |
| Interventions | (1) 3g inositol in juice or tea four times daily in addition to SSRI OR (2) 3g grape sugar (glucose) in juice or tea four times daily in addition to SSRI | |
| Outcomes | Hamilton Depression Rating Scale (24 item) | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
DSM‐IV ‐ Diagnostic and Statistical Manual 4th edition; DSM‐III‐R ‐ Diagnostic and Statistical Manual, 3rd edition, revised; SSRI ‐ Selective serotonin reuptake inhibitor.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Levine 1995b | not a trial of treatment for depression, not explicitly randomised |
| Levine 1997 | not a trial of treatment for depression |
Characteristics of ongoing studies [ordered by study ID]
Sachs.
| Trial name or title | 98‐325A |
| Methods | |
| Participants | treatment refractory bipolar depression (n=20) |
| Interventions | inositol or placebo added to stable mood stabiliser |
| Outcomes | |
| Starting date | enrolling |
| Contact information | Gary Sachs, MD, Massachusetts General Hospital Boston, Massachusetts |
| Notes |
STEP‐BD.
| Trial name or title | STEP‐BD (Systematic treatment enhancement program for bipolar disorder) |
| Methods | |
| Participants | 5000 patients with bipolar disorder or cyclothymic disorder (DSM‐IV criteria) in 20 centers |
| Interventions | Lithium, valproate, bupropion, paroxetine, lamotrigine, risperidone, inositol, tranylcypramine, Cognitive Behaviour Therapy. Family‐Focused Therapy, Interpersonal and Social Rhythms Therapy |
| Outcomes | |
| Starting date | enrolling |
| Contact information | For more information, call toll‐free: 1‐866‐240‐3250 stepbd@mailcity.com www.stepbd.org |
| Notes |
Contributions of authors
MT, HW, and JG conceived the review. MT, HW, ZB, and JG designed the review. MT and HW selected trials. ZB and JG assessed methodological quality. MT and HW extracted data. MT performed data analysis. MT, HW, ZB, and JG contributed to data interpretation and the writing of the review. MT coordinated the review and will act as guarantor.
Sources of support
Internal sources
Department of Psychiatry, University of Oxford, UK.
Oxfordshire Mental Healthcare NHS Trust, UK.
External sources
No sources of support supplied
Declarations of interest
JG has received research funding and support from Sanofi‐Aventis and GlaxoSmithKline and is currently in discussion with several other companies that manufacture SSRIs about collaboration on planned independent trials and systematic reviews.
Edited (no change to conclusions)
References
References to studies included in this review
Chengappa 2000 {published data only}
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STEP‐BD {published data only}
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