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Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder

  1. Andrea Cipriani1,
  2. Keith Reid2,
  3. Allan H Young3,
  4. Karine Macritchie4,
  5. John Geddes5,*

Editorial Group: Cochrane Common Mental Disorders Group

Published Online: 17 OCT 2013

Assessed as up-to-date: 11 JAN 2013

DOI: 10.1002/14651858.CD003196.pub2


How to Cite

Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003196. DOI: 10.1002/14651858.CD003196.pub2.

Author Information

  1. 1

    University of Oxford, Department of Psychiatry, Oxford, UK

  2. 2

    Northumberland Tyne and Wear NHS Foundation Trust, Bamburgh Clinic, Newcastle, UK

  3. 3

    Imperial College London, Division of Brain Sciences, Centre for Mental Health, London, UK

  4. 4

    University of Edinburgh, Division of Psychiatry, Edinburgh, UK

  5. 5

    University of Oxford/Warneford Hospital, Department of Psychiatry, Oxford, UK

*John Geddes, Department of Psychiatry, University of Oxford/Warneford Hospital, Oxford, OX3 7JX, UK. john.geddes@psych.ox.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 17 OCT 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Altamura 2004

Methods6-Month, open-label, randomised, controlled study


Participants23 participants

Drug formulation: valproate

Age: at baseline, mean age of 40.2 (±13.5) years for olanzapine group and 51.0 (±13.9) years for valproate group

Diagnosis (Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I): 6 participants with a diagnosis of bipolar disorder I (5 in olanzapine group and 1 in valproate group), 11 of bipolar disorder II (2 in olanzapine group and 9 in valproate group) and 3 of schizoaffective disorder bipolar type (olanzapine group)

Exclusion criteria: patients taking concomitant psychotropic compounds except for benzodiazepines or with medical or physiological conditions (pregnant women, fertile women not on adequate contraceptive methods, and breast-feeding women) contraindicating the administration of olanzapine or valproate


InterventionsOlanzapine and valproate doses adjusted according to clinical needs

Olanzapine final mean dosage: 9 (±3.2) mg

Valproate final mean dosage: 415 (±16.39) mg. At the end of the study, mean valproate plasma level of 62.7 (±19.5) microg/mL; therapeutic level of 50 microg/mL required

Duration of trial: 6 months


OutcomesPercentage of participants who relapsed during follow-up (relapse defined as a participant fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for a major mood episode: depressive, manic or mixed

Brief Psychiatric Rating Scale (administered by blind raters)

Clinical Global Impression (administered by blind raters)


NotesIn this study, authors compared percentage of participants who relapsed during follow-up with that of the 6-month period before the beginning of the study, during which participants did not take any mood stabiliser


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomly assigned". Probably done

Allocation concealment (selection bias)Unclear riskNo information reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "open-label fashion"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote: "Twenty outpatients (9 males and 11 females) completed the study. Three patients assigned to OLZ group prematurely discontinued the study because of the occurrence of side effects (weight gain, sedation)." No information about analysis reported at all

Selective reporting (reporting bias)High riskStudy report (journal letter) fails to include results for some outcomes that would be expected to have been reported for such a study

Other biasUnclear riskSponsorship bias cannot be ruled out

BALANCE 2010

MethodsRandomised, open-label, controlled, parallel-group trial


Participants330 men and women

Drug formulation: valproate semisodium

Age: 16 years and older

Diagnosis: clinical diagnosis of bipolar I disorder (on the basis of a previous episode of mania meeting Diagnostic and Statistical Manual-IV criteria)

Eligibility for entry into the run-in phase

  • Written informed consent was given
  • Individual was not having an acute episode, and long-term drug therapy was clinically indicated to prevent relapse
  • Combination therapy with lithium plus valproate was considered clinically reasonable for the individual by the clinician
  • No medical disorder or condition contraindicated either of the investigational drugs (e.g. pregnancy)
  • Individual was normally resident in one country and had a residential address


Eligibility for randomisation

  • No clear treatment preference for either investigational drug was apparent
  • Lithium plasma concentration was between 0.4 and 1.0 mmol/L
  • Valproate dose was at least 750 mg, or valproic acid serum concentration was at least 50 μg/mL
  • Combination of lithium and valproate was tolerated at trial doses
  • Adherence during the run-in phase was judged by the investigator to be at least 70%


InterventionsDuring the run-in, participants received 4 to 8 weeks of treatment with both lithium carbonate, at doses producing a serum concentration of 0.4 to 1.0 mmol/L, and valproate semisodium, at least 750 mg per day, with a target daily dose of 1250 mg or the highest dose tolerated. Low doses of valproate were allowed if needed for tolerability, and if the serum concentration was at least 50 μg/mL before randomisation

After run-in, participants were randomly allocated to one of three groups

  • Combination therapy with lithium and valproate
  • Lithium monotherapy (valproate withdrawn and lithium continued)
  • Valproate monotherapy (lithium withdrawn, valproate continued)


Allocated drugs were continued at the dose established during the run-in. In monotherapy groups, the discontinued drug was withdrawn over 4 weeks to reduce risk of relapse associated with abrupt discontinuation. Doses of investigational drugs could be increased if the serum concentration fell below the minimum threshold (measurement of serum concentrations after randomisation was performed at the discretion of the investigator) and decreased (within the trial ranges) if side effects became troublesome

Duration of trial: 2 years


OutcomesTime to new intervention for an emerging mood episode, including drug treatment (commencement of a new drug, increase in dose of concurrent drug, restarting of a discontinued drug, or increase in the investigational drug dose in response to an emergent mood episode) or admission to hospital

Time to new intervention for an emerging depressive or manic episode (including mixed and cycling)

Global assessment of functioning

Episodes of deliberate self-harm

Quality of life according to the EuroQol (EQ-5D) questionnaire

Adverse events including both emergent serious adverse events and participant-reported adverse effects

Withdrawal from study treatment

Adherence to study treatment as estimated by investigator


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The computerised randomisation program included a minimisation algorithm to ensure balanced allocation of participants across the intervention groups for six prognostic factors: (1) nature of most recent episode (mania or non-mania); (2) number of previous psychiatric admissions (<two or ≥two); (3) previous maintenance treatment (yes or no); (4) age (<35 years or ≥35 years); (5) sex; and (6) region"

Allocation concealment (selection bias)Low riskQuote: "Treatment allocation was via the 24-h telephone service at the Clinical Trial Service Unit, University of Oxford, UK. Investigators telephoned the service and logged the patient as eligible for randomisation. The investigator was then informed of the treatment allocation"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "Investigators and participants were aware of treatment allocation because of the complexities of masking of lithium therapy and the concern that concealment would restrict participation and generalisability. The consequent risk of performance and ascertainment biases was managed by restriction of randomisation to patients for whom there was no strong treatment preference on the part of the patient or clinician and by careful verification of outcomes. All outcome events were considered by the trial management team, who were masked to treatment assignment. In the case of any doubt, a description of the event was sent to an independent adjudicator"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Investigators and participants were aware of treatment allocation because of the complexities of masking of lithium therapy and the concern that concealment would restrict participation and generalisability. The consequent risk of performance and ascertainment biases was managed by restriction of randomisation to patients for whom there was no strong treatment preference on the part of the patient or clinician and by careful verification of outcomes. All outcome events were considered by the trial management team, who were masked to treatment assignment. In the case of any doubt, a description of the event was sent to an independent adjudicator"

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Analysis was by intention to treat, and followed a detailed, prespecified plan. Time to first event during the scheduled follow-up was compared between the three groups. Follow-up was censored at the last available assessment in patients who were lost to follow-up without having an event. Time from randomisation to event was summarised by Kaplan-Meier curves, and compared with the log rank test. Hazard ratios (HRs) with 95% CIs were calculated with Cox’s regression to estimate size of the treatment effect. The proportional hazards assumption was tested formally with analysis of Schoenfeld residuals. An analysis adjusting for minimisation factors was also done. Because BALANCE had very specific hypotheses and only one outcome of primary importance, we made no formal adjustment for multiple significance testing. We used Stata (version 10) for all power calculations and analyses"

Selective reporting (reporting bias)Low riskQuote: "The primary outcome was time to new intervention for an emerging mood episode, including drug treatment (commencement of a new drug, increase in dose of concurrent drug, restarting of a discontinued drug, or increase in the investigational drug dose in response to an emergent mood episode) or admission to hospital. Secondary outcomes were time to new intervention for an emerging depressive episode, time to new intervention for an emerging manic episode (including mixed and cycling), global assessment of functioning, 25 episodes of deliberate self-harm, quality of life according to the EuroQol (EQ-5D) questionnaire, adverse events including both emergent serious adverse events and participant-reported adverse effects, withdrawal from study treatment, and adherence to study treatment estimated by investigator"

Other biasUnclear riskNone.

Bowden 2000

MethodsRandomised double-blind placebo-controlled parallel-group trial


Participants372 participants

Drug formulation: divalproex

Age: 18 to 75 years

Diagnosis: DSM-III-R criteria for bipolar affective disorder with at least one manic episode in the past 3 years

Exclusion criteria

  • History of intolerance to lithium or valproate


  • Alcohol abuse within the previous 6 months, current substance dependence or positive results on urine toxicology tests


  • Potentially confounding concomitant drug treatment


  • Disorders of the nervous system or uncontrolled systemic disorders


  • Serious suicidal risk


  • Ongoing psychotherapy


  • Poor compliance with open-phase treatment


  • Pregnancy


InterventionsOpen phase: up to 3 months
Index episode treated according to clinical judgement. No depot neuroleptic or E.C.T. All drugs other than lithium and valproate discontinued before randomisation
Discontinuation of first-phase mood stabilisers could occur in protocol

Randomly assigned to valproate, lithium or placebo

Doses adjusted to reach serum trough levels: valproate 71 to 125 micrograms/mL and lithium 0.8 to 1.2 mEq/L

Rescue medication:

  • Lorazepam up to 6 mg/d for maximum of 14 days in first month and for up to 7 days for remainder of study
  • Haloperidol up to 10 mg/d allowed in second week of first month after 1 week of lorazepam


Participants with DSS scores greater than or equal to 25 treated with sertraline or paroxetine: data censored from analyses of time to mania relapse on the day antidepressant treatment began

Duration of trial: 52 weeks


Outcomes
  • Time to affective episode
  • Time to manic or depressive episode
  • Average change in baseline scores on Mania Rating Scale, Depression Syndrome Scale and Global Assessment Scale during maintenance treatment


NotesFor the purposes of this review, we used withdrawal from the study because of the occurrence of an episode of mood disorder as the main outcome measure. This was not the primary outcome measure used in the original study, which is now discussed in detail. In the original study, the primary outcome measure was time to next mood episode. Secondary outcome measures were time to manic episode, time to depressive episode and average change from baseline in scores on the Mania Rating Scale, the Depression Syndrome Scale and the Global Assessment Scale during maintenance treatment. As the trial progressed, the initial outcome measures were revised at the suggestion of reviewers. A manic episode was defined as being represented by a Mania Rating Scale of 16 or greater, or requiring hospital admission. A depressive episode was defined as one requiring antidepressant use or premature discontinuation of the study because of symptoms. Patients with Depression Syndrome Scale scores of 25 or higher were treated with sertraline or paroxetine, and their data were censored from the analyses of time to mania relapse on the day that antidepressant treatment began. The Schedule of Affective Disorders and the Schizophrenia-Change version, augmented by the addition of eleven items to the Mania Rating Scale, were used to measure symptom severity


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomised". Probably done

Allocation concealment (selection bias)Unclear riskNo information reported

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo clear information reported

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "All randomised patients were evaluated for safety and reasons for premature discontinuation. Comparability of groups at baseline was assessed by one-way analysis of variance and Kruskal-Wallis tests. Differences between treatment groups in categorical measures were examined with Cochran-Mantel-Haenszel and Fisher exact tests. Survival analyses of time to occurrence of a manic or depressive episode were performed for the intent-to-treat sample (all patients receiving at least one dose of study drug)"

Selective reporting (reporting bias)Unclear riskStudy protocol not available

Other biasUnclear riskSponsorship bias cannot be ruled out

Calabrese 2005

MethodsRandomised double-blind placebo-controlled parallel-group trial


Participants60 participants

Drug formulation: divalproex

Age: mean age of 36 years

Diagnosis: DSM-IV Bipolar I or II disorder

Inclusion criteria

  • Rapid cycling disorder in the previous 12 months
  • Hypomanic, manic or mixed episode in previous 3 months, in good physical health


Exclusion criteria from maintenance phase

  • Previous concurrent lithium and valproate treatment
  • Intolerance
  • Pregnancy or planned pregnancy
  • Exogenous steroids
  • Drug or alcohol misuse in the previous 6 months
  • Suicidality
  • Refractory affective episode in stabilisation phase afterward


InterventionsOpen-label stabilisation phase of between 12 and 24 weeks to stabilise and to establish treatment on concurrent valproate and lithium; all other psychotropic medications tapered off before randomisation

Randomly assigned to monotherapy valproate or lithium under double-blind conditions

Doses adjusted to reach serum trough levels: minimum 0.8 mEq/L for lithium and 50 microgrammes/L for valproate, down-titrated for side effects

Rescue medication: unclear

Duration of trial: 20 months


OutcomesStudy withdrawal due to episode of mood disorder

Adverse events

Withdrawal due to adverse events


NotesNone


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomly assigned". Probably done

Allocation concealment (selection bias)Unclear riskNo information reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "Double-blind, double-substitution methodology was used to transition patients from open-label combination therapy with both medications to double-blind monotherapy. Patients were started on equal numbers of capsules of double-blind active lithium 300-mg capsules and matching (in colour, taste, and size) lithium placebo capsules, and equal numbers of double-blind active valproate in 250-mg capsules and matching valproate placebo capsules.... Patients randomly assigned to monotherapy had one blinded active capsule replaced with a matching placebo capsule once every 2 weeks for as long as necessary. The process of tapering to monotherapy took place over an average of 6 weeks if patients were taking 1200 mg of lithium or 1500 mg of valproate—longer if the doses of either were higher and more quickly if the doses of either were lower. After the taper was completed, matching placebo for the drug that was discontinued was discontinued for the rest of the maintenance phase. This slow, gradual process of transitioning patients to monotherapy obscured the progress of the taper until completed. The maintenance phase began at the beginning of the taper, and the survival analysis began at that time as well. After the taper was completed, the number of capsules of active compound and placebo was unchanged for the rest of the maintenance phase, except for adjustments made to both by the unblinded medical monitor when blood levels decreased to less than 0.8 meq/liter for lithium and 50 μg/mL for valproate"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "The intent-to-treat population included all patients who were randomly assigned to a study treatment condition. Kaplan-Meier methodology was used to plot the survival data, and median survival times were calculated. A log-rank test at an alpha = 0.05 level of significance was employed to evaluate differences between survival curves. A Cox regression was performed evaluating the following predictors of outcome: treatment arm assignment, type of bipolar diagnosis (bipolar I or bipolar II), and index episode at study entry"

Selective reporting (reporting bias)Unclear riskStudy protocol not available

Other biasLow riskNone

Findling 2005

MethodsRandomised double-blind placebo-controlled parallel-group trial


Participants60 youths

Drug formulation: divalproex

Age: 5 to 17 years

Diagnosis: Bipolar I or II disorder by DSM-IV semi-structured interview

Inclusion criteria for maintenance phase:

  • Medically healthy
  • Manic or hypomanic episode in past 3 months


Exclusion criteria for maintenance phase:

  • Requirement for treatment outside protocol in stabilisation phase
  • Intolerance of therapeutic serum concentrations in stabilisation phase (trough 0.6 mmol/L Li, 0.5 microgramme/L valproate)
  • Previous lithium-resistant mania confirmed while trough serum Li > 0.6 mmol/L
  • Pregnancy, breast-feeding, risk of pregnancy
  • Pervasive developmental disorder or learning disability


InterventionsStabilisation phase prescribed open-label concurrent valproate and lithium for up to 20 weeks, including tapering of other psychotropic medication, except ADHD medications. Need for antidepressants or antipsychotic medications led to dropout before phase 2. Serum trough lithium maintained between 0.6 and 1.2 mmol/L lithium, and 50 to 100 microgramme/L valproate.

Duration of trial: up to 76 weeks, which included a gradual weaning off of other medication over 8 weeks


OutcomesTotal study withdrawal by end of trial

Adverse events

Withdrawal due to adverse events

Withdrawal due to lack of treatment response

Withdrawal due to mania/hypomania/mixed state

Time to discontinuation for any reason

Time to relapse


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomised". Probably done

Allocation concealment (selection bias)Unclear riskNo information reported

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "double-blind". Probably done (double-dummy pills were used)

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo clear information about analysis and dealing with missing data was reported

Selective reporting (reporting bias)Unclear riskStudy protocol not available

Other biasUnclear riskA single-site study

Kemp 2009

MethodsRandomised double-blind placebo-controlled parallel-group trial


Participants31 participants

Drug formulation: divalproex

Age: average age approx 40 years

Diagnosis: Bipolar I or II disorder by structured DSM-IV interview

Inclusion criteria

  • Alcohol, cannabis or cocaine abuse within the past 3 months or dependence in the past 6 months by DSM-IV structured interview
  • Rapid cycling in the previous 12 months by structured DSM-IV interview
  • At least one hypomanic, mixed or manic episode in the 3 months preceding study entry by structured DSM-IV interview
  • A persistent bimodal response to combined treatment with lithium and divalproex. Lithium minimum trough level 0.8 mmol/L, valproate minimum serum level of 0.5 microgramme/L. Participants weaned off other psychotropic medications gradually; this was complete by at least four weeks before the comparison phase
  • Good physical health


Exclusion from maintenance phase

  • Pregnant or planning pregnancy
  • Taking exogenous steroids or anticoagulants
  • Suicidality
  • Previous intolerance to lithium or valproate


Discontinuation from valproate would therefore occur in the protocol


InterventionsParticipants randomly assigned either to continuing combined lithium and valproate or to lithium monotherapy and valproate placebo under double-blind conditions. During this phase, lorazepam up to 2 mg per day was permitted as needed for agitation, and zolpidem up to 10 mg per night was permitted for insomnia

Duration of trial: 6 months


OutcomesTotal study withdrawal

Study withdrawal due to mood disorder (any/manic/depressive)

Adverse effects


NotesNone


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomised". Probably done

Allocation concealment (selection bias)Unclear riskNo information reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo clear information about analysis and dealing with missing data reported

Selective reporting (reporting bias)Unclear riskStudy protocol not available

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bristol-Myers Squibb 2006Wrong design (not relapse prevention study—participants acutely manic)

Oquendo 2011Not randomised at the point of maintenance

Pfizer 2006Wrong design (not relapse prevention study—participants acutely manic)

Revicki 2005Randomised controlled double-blind trial; not randomised at the point of maintenance

Tohen 2003Not randomised at the point of maintenance therapy

 
Characteristics of studies awaiting assessment [ordered by study ID]
Bowden 2012

MethodsRandomised double-blind placebo-controlled parallel-group trial

Participants86 participants randomized in the maintenance phase

Age: 40.7 ± 12.4 years.

Diagnosis: Bipolar I or II disorder with major depressive epsiode (DSM-IV interview)

To be eligible for randomization in the maintenance phase, participants had to achieve control of both depressive and manic symptoms during an open phase that included both lamotrigine and divalproex (up to 8 weeks)

InterventionsMaintenance phase: Lamotrigine + placebo (45 participants); lamotrigine + divalproex (41 participants)

Mean final maintenance phase dosage for lamotrigine alone was 207 mg ⁄day (range, 50–400) and 92 mg ⁄day (range, 12.5–200 mg) for lamotrigine in combination with divalproex. The mean final dosage for divalproex was 1382 mg ⁄day (range, 250–2500 mg).

Dosage did not differ significantly by site. The final mean plasma concentration for valproate was 500 IU (range, 182–917)

Duration of trial: 8 months

OutcomesTime to relapse - depressive episode

NotesStudy included an open phase (164 patients) and a maintenance phase (86 patients); the study was conducted at two sites – the lead San Antonio site and Raleigh, North Carolina

This study was identified after the search date, so has not been formally considered for inclusion. If it meets all the inclusion criteria it will be included in a subsequent update of this review.

NCT00071253

MethodsRandomised double-blind placebo-controlled parallel-group trial

ParticipantsEstimated Enrollment: 180

Age: 18 - 65 years

Inclusion Criteria:

  • DSM-IV-TR primary diagnosis of Bipolar I Disorder as confirmed by the SCID
  • Outpatient receiving treatment with a combination of Depakote plus olanzapine for their bipolar illness and considered clinically stable (e.g., no more than minimal symptoms, no psychiatric hospitalizations, no increase in intensity of clinical interventions) for the preceding 4 months
  • Identified at Screening a most bothersome side effect listed in the UKU which makes switching to monotherapy desirable
  • MRS total score < 12 on two consecutive ratings, separated by at least 5 days (Screening and Day 1)
  • DSS score < 13 on two consecutive ratings, separated by at least five days (Screening and Day 1)
  • CGI-S score < 3 on two consecutive ratings, separated by at least five days (Screening and Day 1)
  • Serum valproate level > 45 mcg/mL, and a maximum allowable dose of Depakote of 3000 mg/day at Screening
  • Olanzapine dose between 5 and 20 mg/day at screening

InterventionsDepakote (divalproex sodium) plus olanzapine, vs. Depakote monotherapy and olanzapine monotherapy in stable subjects during the maintenance phase of bipolar illness

OutcomesPrimary Outcome Measures: CGI-s, CGI-i, MRS, DSS, SADS-C

NotesStatus of trial on ClinicalTrials.gov = terminated

We are seeking more information regarding this trial.

 
Comparison 1. Valproate versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Study withdrawal due to episode of mood disorder2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Any mood episode
2312Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.49, 0.93]

    1.2 Manic episode
2312Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.48, 1.25]

    1.3 Depressive episode
2312Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.24, 0.89]

 2 Participant withdrawal from treatment—any cause2312Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.71, 0.95]

 3 Participant withdrawal from treatment due to intolerance or non-compliance1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 4 Adverse events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Alopecia
2312Risk Ratio (M-H, Fixed, 95% CI)2.51 [1.15, 5.51]

    4.2 Tremor
2312Risk Ratio (M-H, Fixed, 95% CI)2.41 [1.58, 3.67]

    4.3 Weight gain
2312Risk Ratio (M-H, Fixed, 95% CI)2.04 [1.07, 3.86]

 
Comparison 2. Valproate versus lithium

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Study withdrawal due to episode of mood disorder4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Any mood episode
4618Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.20]

    1.2 Manic episode
4618Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.90, 1.44]

    1.3 Depressive episode
4618Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.84, 1.49]

    1.4 Hypomanic episode
160Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.18, 2.61]

    1.5 Mixed state
160Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 8.95]

 2 Number of hospital admissions1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 New drug treatment for mood episode1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Any mood episode
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Mania
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Depression
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Time to relapse (days)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Participant withdrawal from treatment—any cause4618Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.77, 0.98]

 6 Participant withdrawal from treatment due to intolerance or non-compliance4618Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.49, 0.93]

 7 Adverse events3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Diarrhoea
2338Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.55, 0.99]

    7.2 Sedation
2338Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.00, 2.10]

    7.3 Polyuria
2338Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.16, 0.58]

    7.4 Increased thirst
2338Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.15, 0.65]

    7.5 Infection
1278Risk Ratio (M-H, Fixed, 95% CI)2.07 [1.16, 3.68]

    7.6 Enuresis
160Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.05, 0.94]

 8 GAF—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 Quality of life—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 DSH—number of participants with at least one episode of deliberate self-harm1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 11 Death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 3. Valproate versus olanzapine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Study withdrawal due to episode of mood disorder1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Any mood episode
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Manic only
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Depressive only
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 2 Participant withdrawal from treatment—any cause1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Participant withdrawal from treatment due to intolerance or non-compliance1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 4. Valproate plus lithium versus lithium alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Study withdrawal due to episode of mood disorder1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Number of hospital admissions1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 New drug treatment for mood episode1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Any mood episode
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Mania
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Depression
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Participant withdrawal from treatment—any cause1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Participant withdrawal from treatment due to intolerance or non-compliance1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 GAF—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 8 Quality of life—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 DSH—number of participants with at least one episode of deliberate self-harm1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 5. Valproate plus lithium versus valproate alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Study withdrawal due to episode of mood disorder1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Number of hospital admissions1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 New drug treatment for mood episode1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    3.1 Any mood episode
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.2 Mania
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    3.3 Depression
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Participant withdrawal from treatment—any cause1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Participant withdrawal from treatment due to intolerance or non-compliance1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 6 Serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 7 GAF—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 8 Quality of life—number of participants not responding at 24 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 9 DSH—number of participants with at least one episode of deliberate self-harm1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 10 Death1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Table 1. Adverse events

Adverse eventStudyValproateComparatorRisk Ratio, Fixed [95% CI]


EventsTotalEventsTotal

Valproate vs placebo

AcneKemp 20090152160.21 [0.01, 4.10]

AkathisiaBowden 200011871940.50 [0.03, 7.95]

Blurred visionKemp 20092151162.13 [0.22, 21.17]

Cognitive dysfunctionKemp 20092152161.07 [0.17, 6.64]

DiarrhoeaBowden 2000; Kemp 200969202341101.11 [0.78, 1.56]

Dry mouthKemp 20093150167.44 [0.42, 132.95]

FatigueKemp 20095151165.33 [0.70, 40.54]

Increased appetiteKemp 20090152160.21 [0.01, 4.10]

InfectionBowden 20005118718941.42 [0.88, 2.29]

NauseaBowden 2000; Kemp 200981202321101.32 [0.94, 1.86]

PolydipsiaKemp 20096155161.28 [0.49, 3.33]

PolyuriaBowden 2000151879940.84 [0.38, 1.84]

SedationBowden 20007818733941.19 [0.86, 1.64]

Sexual dysfunctionKemp 20092152161.07 [0.17, 6.64]

TachycardiaBowden 200011871940.50 [0.03, 7.95]

ThirstBowden 2000111877940.79 [0.32, 1.97]

TinnitusBowden 2000121871946.03 [0.80, 45.69]

Valproate vs lithium

AkathisiaBowden 200011874910.12 [0.01, 1.07]

AlopeciaBowden 2000; Calabrese 2005; Findling 20053024591531.74 [0.85, 3.56]

Balance problemsCalabrese 20052281322.29 [0.22, 23.88]

Cognitive difficultiesCalabrese 20050281320.38 [0.02, 8.95]

Decreased appetiteFindling 20053303301.00 [0.22, 4.56]

Dry eyesBowden 200001873910.07 [0.00, 1.34]

FeverFindling 20051304300.25 [0.03, 2.11]

Gastrointestinal discomfortCalabrese 20052285320.46 [0.10, 2.17]

Haematological dyscrasiaFindling 20051300303.00 [0.13, 70.83]

HeadacheCalabrese 2005; Findling 200511584622.64 [0.96, 7.24]

NauseaBowden 2000; Findling 200581217461210.89 [0.68, 1.18]

Serious adverse eventsBALANCE 2010711051101.40 [0.46, 4.28]

Sore throatFindling 20053301303.00 [0.33, 27.23]

SpeechCalabrese 20050281320.38 [0.02, 8.95]

Stomach painFindling 20057303302.33 [0.67, 8.18]

TachycardiaBowden 200011874910.12 [0.01, 1.07]

TremorBowden 2000; Calabrese 2005; Findling 200583245531530.86 [0.65, 1.14]

Upper respiratory congestionFindling 20053302301.50 [0.27, 8.34]

Visual impairmentCalabrese 20050283320.16 [0.01, 3.02]

VomitingFindling 20053309300.33 [0.10, 1.11]

Weight gainBowden 2000; Calabrese 200541215131231.60 [0.89, 2.85]