Page 1 of 76
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`JAZZ EXHIBIT 2017
`Ranbaxy Inc. (Petitioner) v. Jazz Pharms. Ireland Ltd. (Patent Owner)
`Case IPR2016-00024
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`T A B L E O F C O N T E N T S
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`HEADER .
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`ABSTRACT .
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`PLAIN LANGUAGE SUMMARY
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`BACKGROUND .
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`OBJECTIVES
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`METHODS
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`RESULTS .
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`Figure 1.
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`Figure 2.
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`Figure 3.
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`Figure 4.
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`Figure 5.
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`Figure 6.
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`AUTHORS’ CONCLUSIONS
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`ACKNOWLEDGEMENTS
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`REFERENCES .
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`CHARACTERISTICS OF STUDIES
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`DATA AND ANALYSES .
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`Analysis 1.1. Comparison 1 Valproate versus placebo, Outcome 1 Study withdrawal due to episode of mood disorder.
`Analysis 1.2. Comparison 1 Valproate versus placebo, Outcome 2 Participant withdrawal from treatment-any cause. .
`Analysis 1.3. Comparison 1 Valproate versus placebo, Outcome 3 Participant withdrawal from treatment due to intolerance
`or non-compliance.
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`Analysis 1.4. Comparison 1 Valproate versus placebo, Outcome 4 Adverse events.
`Analysis 2.1. Comparison 2 Valproate versus lithium, Outcome 1 Study withdrawal due to episode of mood disorder.
`Analysis 2.2. Comparison 2 Valproate versus lithium, Outcome 2 Number of hospital admissions.
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`Analysis 2.3. Comparison 2 Valproate versus lithium, Outcome 3 New drug treatment for mood episode.
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`Analysis 2.4. Comparison 2 Valproate versus lithium, Outcome 4 Time to relapse (days).
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`Analysis 2.5. Comparison 2 Valproate versus lithium, Outcome 5 Participant withdrawal from treatment-any cause. .
`Analysis 2.6. Comparison 2 Valproate versus lithium, Outcome 6 Participant withdrawal from treatment due to intolerance
`or non-compliance.
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`Analysis 2.7. Comparison 2 Valproate versus lithium, Outcome 7 Adverse events.
`Analysis 2.8. Comparison 2 Valproate versus lithium, Outcome 8 GAF-number of participants not responding at 24
`months.
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`Analysis 2.9. Comparison 2 Valproate versus lithium, Outcome 9 Quality of life-number of participants not responding at
`24 months. .
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`Analysis 2.10. Comparison 2 Valproate versus lithium, Outcome 10 DSH-number of participants with at least one episode
`of deliberate self-harm. .
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`Analysis 2.11. Comparison 2 Valproate versus lithium, Outcome 11 Death.
`Analysis 3.1. Comparison 3 Valproate versus olanzapine, Outcome 1 Study withdrawal due to episode of mood disorder.
`Analysis 3.2. Comparison 3 Valproate versus olanzapine, Outcome 2 Participant withdrawal from treatment-any cause.
`Analysis 3.3. Comparison 3 Valproate versus olanzapine, Outcome 3 Participant withdrawal from treatment due to
`intolerance or non-compliance.
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`Analysis 4.1. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 1 Study withdrawal due to episode of
`mood disorder.
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`Analysis 4.2. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 2 Number of hospital admissions.
`Analysis 4.3. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 3 New drug treatment for mood
`episode.
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`Analysis 4.4. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 4 Participant withdrawal from treatment-
`any cause.
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`Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder (Review)
`Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`Analysis 4.5. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 5 Participant withdrawal from treatment
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`Analysis 4.6. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 6 Serious adverse events.
`Analysis 4.7. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 7 GAF-number of participants not
`responding at 24 months. .
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`Analysis 4.8. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 8 Quality of life-number of participants
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`Analysis 4.9. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 9 DSH-number of participants with at
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`Analysis 4.10. Comparison 4 Valproate plus lithium versus lithium alone, Outcome 10 Death.
`Analysis 5.1. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 1 Study withdrawal due to episode of
`mood disorder.
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`Analysis 5.2. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 2 Number of hospital admissions.
`Analysis 5.3. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 3 New drug treatment for mood
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`Analysis 5.4. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 4 Participant withdrawal from
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`Analysis 5.5. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 5 Participant withdrawal from
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`Analysis 5.6. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 6 Serious adverse events.
`Analysis 5.7. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 7 GAF-number of participants not
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`Analysis 5.8. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 8 Quality of life-number of participants
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`Analysis 5.9. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 9 DSH-number of participants with at
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`Analysis 5.10. Comparison 5 Valproate plus lithium versus valproate alone, Outcome 10 Death.
`ADDITIONAL TABLES .
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`WHAT’S NEW .
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`HISTORY .
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`CONTRIBUTIONS OF AUTHORS
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`DECLARATIONS OF INTEREST .
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`SOURCES OF SUPPORT .
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`DIFFERENCES BETWEEN PROTOCOL AND REVIEW .
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`INDEX TERMS
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`Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder (Review)
`Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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`Page 3 of 76
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`

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`[Intervention Review]
`
`Valproic acid, valproate and divalproex in the maintenance
`treatment of bipolar disorder
`
`Andrea Cipriani1, Keith Reid2, Allan H Young3, Karine Macritchie4, John Geddes5
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`1Department of Psychiatry, University of Oxford, Oxford, UK. 2Bamburgh Clinic, Northumberland Tyne and Wear NHS Foundation
`Trust, Newcastle, UK. 3Division of Brain Sciences, Centre for Mental Health, Imperial College London, London, UK. 4Division of
`Psychiatry, University of Edinburgh, Edinburgh, UK. 5Department of Psychiatry, University of Oxford/Warneford Hospital, Oxford,
`UK
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`Contact address: John Geddes, Department of Psychiatry, University of Oxford/Warneford Hospital, Oxford, OX3 7JX, UK.
`john.geddes@psych.ox.ac.uk.
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`Editorial group: Cochrane Depression, Anxiety and Neurosis Group.
`Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 10, 2013.
`Review content assessed as up-to-date: 11 January 2013.
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`Citation: Cipriani A, Reid K, Young AH, Macritchie K, Geddes J. Valproic acid, valproate and divalproex in the main-
`tenance treatment of bipolar disorder. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD003196. DOI:
`10.1002/14651858.CD003196.pub2.
`
`Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`Background
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`A B S T R A C T
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`Bipolar disorder is a recurrent illness that is amongst the top 30 causes of disability worldwide and is associated with significant
`healthcare costs. In the past, emphasis was placed solely on the treatment of acute episodes of bipolar disorder; recently, the importance
`of episode prevention and of minimisation of iatrogenicity has been recognised. For many years, lithium was the only mood stabiliser
`in common use, and it remains an agent of first choice in the preventative treatment of bipolar disorder. However, an estimated 20%
`to 40% of patients may not respond adequately to lithium. Valproate is an anticonvulsant drug that has been shown to be effective
`in acute mania and is frequently used in maintenance treatment of bipolar disorder. When the acceptability of long-term treatment is
`considered, together with efficacy, the adverse event profile of a medication is also important. This is an update of a Cochrane review
`first published in 2001 and last updated in 2009.
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`Objectives
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`1. To determine the efficacy of valproate continuation and maintenance treatment:
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`a) in preventing or attenuating manic, depressive and mixed episodes of bipolar disorder;
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`b) in preventing or attenuating episodes of bipolar disorder in patients with rapid cycling disorder; and
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`c) in improving patients’ general health and social functioning, as measured by global clinical impression, employment and marital
`stability.
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`2. To review the acceptability to patients of long-term valproate treatment, as measured by numbers of dropouts and reasons for
`dropping out, by compliance and by reference to patients’ expressed views regarding treatment.
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`3. To investigate the adverse effects of valproate treatment (including general prevalence of side effects) and overall mortality rates.
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`Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder (Review)
`Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
`
`1
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`Page 4 of 76
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`

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`Search methods
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`Search of the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CC-
`DANCTR) (to January 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The
`Cochrane Library (all years), EMBASE, (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). No language restric-
`tions were applied. Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies
`marketing valproate and experts in this field were contacted for supplemental data.
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`Selection criteria
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`Randomised controlled trials allocating participants with bipolar disorder to long-term treatment with valproate or any other mood
`stabiliser, or antipsychotic drugs, or placebo. Maintenance treatment was defined as treatment instituted specifically or mainly to prevent
`further episodes of illness.
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`Data collection and analysis
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`Three review authors independently extracted data. A double-entry procedure was employed by two review authors. Information
`extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy,
`acceptability and tolerability. For dichotomous data, risk ratios were calculated with 95% confidence intervals (CIs). For statistically
`significant results, we calculated the number needed to treat for an additional beneficial outcome (NNTB) and the number needed
`to treat for an additional harmful outcome (NNTH). For continuous data, mean differences (MDs) or standardised mean differences
`(SMDs) were calculated along with 95% CIs. MDs were used when the same scale was used to measure an outcome; SMDs were
`employed when different scales were used to measure the same outcome. The primary analysis used a fixed-effect model. Binary
`outcomes were calculated on a strict intention-to-treat (ITT) basis; dropouts were included in this analysis. When data were missing
`and the method of “last observation carried forward” (LOCF) had been used to do an ITT analysis, then the LOCF data were used.
`
`Main results
`
`Six randomised controlled trials (overall 876 participants) lasting 6 to 24 months were included. Two studies (overall 312 participants)
`compared valproate with placebo, four studies (overall 618 participants) valproate with lithium, one study (overall 23 participants)
`valproate with olanzapine and one study (overall 220 participants) valproate with the combination of valproate plus lithium. In terms
`of study quality, most studies reported the methods used to generate random sequence; however, only one study reported enough
`details on allocation concealment. Four of six included studies described their design as “double blind”, but only two trials reported
`full details about blinding. Valproate was more effective than placebo in preventing study withdrawal due to any mood episode (RR
`0.68, 95% CI 0.49 to 0.93; NNTB 8), but no difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87
`to 1.20). Valproate was associated with fewer participants dropping out of treatment for any cause when compared with placebo or
`lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination therapy with lithium
`plus valproate was more likely to prevent relapse than was monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant
`differences in adverse event frequencies were found, and lithium was associated with more frequent diarrhoea, polyuria, increased thirst
`and enuresis, whereas valproate was associated with increased sedation and infection.
`
`Authors’ conclusions
`
`Limited evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. Clinicians and patients should
`consider acceptability and tolerability profile when choosing between lithium and valproate-their combination or other agents-as long-
`term treatment for bipolar disorder.
`
`P L A I N L A N G U A G E S U M M A R Y
`
`Valproate for keeping people with bipolar disorder well, after mood episodes
`
`Bipolar disorder is a common and important disorder that includes episodes of depression, mixed states or mania. Depression includes
`low mood and energy, as well as lack of enjoyment, often combined with other problems such as sleep disturbance. Mania includes
`the opposite, with ’too much’ energy and problems with high mood or irritation. In mixed states, the symptoms of depression and
`mania are combined. These mood episodes usually happen several times in an individual’s life, so long-term treatment (maintenance
`treatment) can be very important in preventing relapse and recurrence. As valproate is a drug that may be useful in treating the acute
`
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`phase of bipolar disorder, in this review we wanted to answer the following question: Is valproate useful as maintenance treatment for
`bipolar disorder?
`
`We searched, in a wide-ranging way, for all the useful studies (randomised controlled trials, or RCTs) we could find on long-term
`treatment of people with bipolar disorder using valproate or any other mood stabiliser, or antipsychotic drugs, or placebo. Three of
`us looked at RCTs to make sure they were fair experiments. We extracted data from the studies, put all of the evidence together and
`carried out a statistical analysis to look for significant results.
`
`We conducted these searches to 11 January 2013 and found six studies, including a total of 876 participants. The quality of the studies
`in terms of design was not good, which means that the effects of some drugs might have been overestimated. All of the trials taken
`together suggest that valproate might help to prevent relapse in bipolar disorder, especially depressive episodes. However, because of
`limited available evidence, conclusions on valproate compared with placebo and lithium (or other active drugs) cannot be made with
`any reliable degree of confidence. Lithium is an important drug to compare with valproate because lithium is already known to be
`effective in preventing relapses of bipolar disorder. When we combined the findings of all studies comparing valproate with lithium,
`the evidence did not favour valproate or lithium in terms of efficacy. People taking valproate over a long time were more likely than
`patients given lithium to keep taking their allocated medication. Clinicians and patients should consider the side effects of valproate,
`including alopecia, tremor and weight gain.
`
`We also found a study that compared valproate taken alone with valproate combination therapy (two drugs taken at the same time).
`This study compared people who took lithium only or valproate only with people who took valproate and lithium together. No evidence
`showed that use of valproate and lithium compared with lithium alone helped to ensure that patients kept taking their allocated
`medication.
`
`B A C K G R O U N D
`
`Description of the condition
`
`Bipolar disorder (or bipolar affective disorder, or manic depressive
`disorder) refers to a group of affective disorders that together are
`characterised by marked mood swings between mania (mood el-
`evation) and depression that cause significant personal distress or
`social dysfunction, and are not caused by drugs or known physical
`disorders (Phillips 2013). Bipolar type I disorder is diagnosed when
`episodes of depression are interspersed with mania. Bipolar type
`II disorder is diagnosed when depression is interspersed with less
`severe episodes of elevated mood (hypomania) that do not lead to
`dysfunction or disability (Müller-Oerlinghausen 2002). Lifetime
`prevalence rates of bipolar type I disorder range from 0.3% to 1.5%
`in the general population (Weissmann 1996). Men and women
`are at similar risk, and mean age at first onset ranges from 19 to
`29 years (an average of six years earlier than first onset of major
`depression). The cause of bipolar disorder is uncertain, although
`family and twin studies suggest a genetic basis (Craddock 2013).
`Bipolar disorder is a recurrent illness in which affective episodes
`of varying form may produce lasting destructive effects on suffer-
`ers’ psychological, professional and social welfare (Gonzalez-Pinto
`2010). Its chronic and recurrent nature places it amongst the top
`
`30 causes of disability worldwide, especially in the age group of 15
`to 44 years (Murray 1997). A meta-analysis undertaken to com-
`pare observed versus expected rates of suicide in an age- and sex-
`matched sample of the general population found that the lifetime
`prevalence of suicide in people with bipolar disorder was about
`2%-about 15 times greater than would be expected (Harris 1997).
`
`Description of the intervention
`
`‘Mood stabilisers’ are defined as drugs that alleviate the frequency
`and/or intensity of manic, depressive or mixed episodes in pa-
`tients with bipolar disorder and, further, do not increase the fre-
`quency or severity of any of the subtypes or course variables of
`bipolar disorder (Bowden 1996). For many years, lithium was the
`only mood stabiliser in common use, and it remains a first choice
`in the preventative treatment of bipolar disorder (APA 1994b;
`CANMAT 2009; Goodwin 2009; Geddes 2013). However, an
`estimated 20% to 40% of patients may not respond adequately
`to lithium. In particular, a high incidence of inadequate response
`has been noted in individuals with rapid cycling disorder (Post
`1989), a variant of bipolar disorder associated with greater mor-
`bidity and mortality than its classic form, including greater risk
`of suicide (Fawcett 1990). A search for adjunctive and alternative
`treatments to lithium has uncovered evidence that other medi-
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`cations, including anticonvulsant agents (e.g. valproic acid, car-
`bamazepine) and several atypical antipsychotics, have mood-sta-
`bilising properties. Valproic acid (together with sodium valproate
`or valproate sodium, either of which is a sodium salt of valproic
`acid) is an anticonvulsant that is used also in neurology for the
`treatment of patients with epilepsy and migraine; in Europe it has
`been used since 1966 as maintenance treatment for bipolar disor-
`der (Lambert 1966).
`
`How the intervention might work
`
`Valproic acid and its derivatives, hereafter given the generic term
`’valproate’, are weak blockers of sodium ion channels that produce
`a weak inhibitor of enzymes that deactivate gamma-aminobutyric
`acid (GABA) (such as GABA transaminase) (Fawcett 1989). The
`exact mechanisms that contribute to the efficacy of valproate in
`treating bipolar disorder remain unclear. However, it seems un-
`likely that GABAergic transmission is related to the psychotropic
`action of valproate, as other different molecular mechanisms might
`be involved, such as serotonergic and glutamatergic transmis-
`sion, energy metabolism and neuronal membrane lipid synthe-
`sis (Winterer 2000). Recently, amongst other potential mecha-
`nisms of action, neurotrophic and neuroplastic effects of valproate
`have been explored (Schloesser 2008). Valproate has a complex
`pharmacokinetic profile that follows a three-compartment model
`and shows protein-binding saturation. Monitoring of plasma level
`is supposedly, therefore, of more limited use than with carba-
`mazepine or lithium. A dose of at least 750 mg/d or a serum level
`of at least 50 mg/L may be associated with response (Taylor 1997).
`The therapeutic dose usually ranges between 1000 and 1500 mg/
`d but can reach a maximum of 2000 mg/d. Valproate is highly
`protein bound (up to 94%). Other drugs that are highly protein
`bound can displace valproate from albumin and precipitate tox-
`icity (e.g. aspirin). Valproate is hepatically metabolised and can
`increase the plasma levels of some drugs, possibly by inhibiting
`their metabolism (e.g. tricyclic antidepressants, lamotrigine).
`
`Why it is important to do this review
`
`Until the recent millennium, valproate was recommended as a
`second-line prophylactic agent in bipolar disorder and a first-line
`choice in rapid cycling disorder in the United States of Amer-
`ica and in Great Britain (APA 1994b; Sachs 1996; Maudsley
`2001). Notwithstanding its sometimes troublesome side effect
`profile, valproate is still frequently used in clinical practice (Geddes
`2013). Side effects of valproate include neurological symptoms
`such as tremor, sedation and ataxia (especially with concomitant
`administration of other anticonvulsants or neuroleptics), alope-
`cia, lethargy, dizziness, haematological dysfunction, hepatic fail-
`ure and other gastrointestinal complaints. Asymptomatic eleva-
`tion in hepatic transaminases may occur. Pancreatitis and hepa-
`
`totoxicity are rare but potentially serious and fatal complications.
`Possible induction of polycystic ovaries and hyperandrogenism
`with long-term valproate treatment has been reported, especially
`in young females (Garland 1996; Geller 1998). Teratogenicity has
`been reported in the form of neural tube defects associated with
`first trimester use (Jeavons 1982), congenital heart lesions, digital
`anomalies, oral clefts and craniofacial dysmorphic features (Dukes
`1996). It has also been found that the use of valproate in preg-
`nancy was associated with a reduction in cognitive functioning in
`the children of mothers with epilepsy (Adab 2004a; Adab 2004b;
`Meador 2009). Concerns regarding teratogenicity led to the rec-
`ommendation by the United Kingdom National Institute of Clini-
`cal Excellence (NICE) that valproate should not be prescribed rou-
`tinely for women of child-bearing potential (NICE 2006). Over
`the past decade, the range of agents available for the maintenance
`treatment of bipolar disorder has expanded, and new efficacy and
`safety data on the use of valproate have become available. This is
`an update of a Cochrane review first published in 2001 and last
`updated in 2009 (Macritchie 2009). In light of recent develop-
`ments, this re-appraisal of valproate in the maintenance treatment
`of bipolar disorder is due and timely.
`
`O B J E C T I V E S
`
`1. To determine the efficacy of valproate continuation and
`maintenance treatment:
`
`i) in preventing or attenuating manic, depressive and
`mixed episodes of bipolar disorder;
`
`ii) in preventing or attenuating episodes of bipolar
`disorder in patients with rapid cycling disorder; and
`
`iii) in improving patients’ general health and social
`functioning, as measured by global clinical impression,
`employment and marital stability.
`
`2. To review the acceptability to patients of long-term
`valproate treatment, as measured by numbers of dropouts and
`reasons for dropping out, by compliance and by reference to
`patients’ expressed views regarding treatment.
`
`3. To investigate the adverse effects of valproate treatment
`(including general prevalence of side effects) and overall
`mortality rates.
`
`M E T H O D S
`
`Criteria for considering studies for this review
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`Types of studies
`
`Comparator intervention
`
`Prospective randomised controlled trials (RCTs) comparing val-
`proate maintenance treatment with placebo or alternative drug
`treatment in bipolar disorder were included in this review. Main-
`tenance treatment was defined as treatment instituted specifically
`or mainly to prevent further episodes of illness. When trials com-
`bined acute treatment and maintenance phases, these data would
`be analysed separately when possible for the purposes of this re-
`view.
`
`• Placebo
`• Alternative mood stabiliser (i.e. lithium, carbamazepine)
`• Other treatments (e.g. antipsychotics)
`
`See Data extraction and management below for a list of main
`comparisons.
`
`Types of outcome measures
`
`Types of participants
`
`Primary outcomes
`
`The review included participants of both sexes with a primary diag-
`nosis of bipolar disorder corresponding to the International Classi-
`fication of Diseases (ICD), Tenth Revision (ICD-10), code F31, and
`the Diagnostic and Statistical Manual of Mental Disorders (DSM),
`Fourth Edition (DSM-IV) code 296 (trials with ICD, Ninth Re-
`vision (ICD-9) and DSM, Third Edition (DSM-III)/DSM, Third
`Edition, Revised (DSM-III-R) diagnoses approximating these codes
`were included). All subtypes of bipolar disorder (rapid cycling [suf-
`fering from four or more affective episodes per year] and types I,
`II and not otherwise specified) were included.
`No age restrictions were applied.
`When trials involved heterogenous groups of participants, in par-
`ticular, those with schizoaffective disorder and recurrent unipo-
`lar depression (diagnoses approximating ICD-10 code F25 and
`DSM-IV code 295.70; and ICD-10 code F33 and DSM-IV 296.3,
`respectively), data were separated into diagnostic groups if ran-
`domisation had been stratified.
`No restrictions on setting were applied.
`Excluded were studies with participants who had a concurrent
`primary diagnosis of an Axis I or II disorder and participants with a
`serious concomitant medical illness. Participants with cyclothymia
`were excluded as well.
`
`Types of interventions
`
`Experimental intervention
`
`This intervention consisted of valproate given as monotherapy
`or in combination with other mood stabilisers. Several formula-
`tions of valproate and valproic acid are available, including sodium
`valproate, valpromide and divalproex. In this review, we refer to
`these generically as valproate, as this is the term in common usage.
`However, the precise preparation used in each study was specified
`(see Characteristics of included studies), and if heterogeneity was
`observed, difference in preparation was considered as a potential
`explanation.
`
`1. Efficacy of valproate in preventing/attenuating further
`episodes of affective disorder
`1.1 Recurrence of any mood episodes, as measured by:
`• study withdrawal due to recurrence of any mood episode;
`• admission to hospital: (i) time to next admission; (ii)
`number of admissions during trial period;
`• institution of additional treatment for affective episode and
`time to institution; and
`• number of episodes during the trial period.
`
`We also performed the same analysis for recurrence of manic,
`mixed or depressive episodes only, if possible.
`
`Secondary outcomes
`
`2. Acceptability of treatments
`2.1 Participants dropping out of treatment during the study pe-
`riod.
`2.2 Measures of compliance: Completion of the trial was taken as
`a specific surrogate marker of acceptability.
`2.3 Participant reports of satisfaction or otherwise with treatment.
`3. Adverse effects
`3.1 Numbers of participants experiencing the following.
`• Troublesome side effects.
`• Gastrointestinal side effects: anorexia, nausea, vomiting,
`dyspepsia, diarrhoea.
`• Neurological complaints: tremor, sedation, ataxia, cognitive
`impairment.
`• Dizziness.
`• Alopecia.
`• Lethargy.
`• Haematological dysfunction.
`• Pancreatitis.
`• Evidence of hepatic dysfunction and hepatotoxicity.
`• Weight gain.
`• Menstrual irregularity, polycystic ovaries and
`hyperandrogenism.
`
`3.2 Cases of teratogenicity.
`4. General Health and Social Functioning
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`4.1 Clinical global impression of the clinician (Global Assessment
`of Functioning-GAF) (APA 2000).
`4.2 Quality of life according to the EuroQol (EQ-5D) question-
`naire (Kind 1996).
`4.3 Employment during study period.
`4.4 Separation/divorce during study period.
`5. Mortality rates and deliberate self-harm
`5.1 Overall mortality rates during study period.
`5.2 Mortality excluding suicide and verdicts of undetermined
`death.
`5.3 Mortality due to hepatic failure.
`5.4 Mortality due to pancreatitis.
`5.5 Suicide and verdicts of undetermined death.
`5.6 Rates of deliberate self-harm.
`
`Search methods for identification of studies
`
`Electronic searches
`
`CCDAN’s specialised register (CCDANCTR)
`
`The Cochrane Depression, Anxiety and Neurosis Group (CC-
`DAN) mainta