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

Andrea Cipriani; Keith Reid; Allan H Young; Karine Macritchie; John Geddes

doi:10.1002/14651858.CD003196.pub2

Ácido valproico, valproato y divalproex en el tratamiento de mantenimiento del trastorno bipolar

Authors' declarations of interest

Version published: 17 October 2013 Version history

https://doi.org/10.1002/14651858.CD003196.pub2

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Resumen

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Antecedentes

El trastorno bipolar es una enfermedad recurrente que se encuentra entre las 30 causas principales de discapacidad a nivel mundial y se asocia con costos significativos de asistencia sanitaria. Anteriormente se hizo énfasis exclusivamente en el tratamiento de los episodios agudos del trastorno bipolar; recientemente se ha reconocido la importancia de la prevención de los episodios y de la reducción al mínimo de la iatrogenicidad. Durante muchos años, el litio fue el único estabilizador del estado de ánimo de uso habitual y todavía es un agente de primera elección en el tratamiento preventivo del trastorno bipolar. Sin embargo, se calcula que del 20% al 40% de los pacientes puede no responder al litio de forma adecuada. El valproato es un fármaco anticonvulsivante que ha mostrado efectividad en la manía aguda y se utiliza con frecuencia en el tratamiento de mantenimiento del trastorno bipolar. Cuando se considera la aceptabilidad del tratamiento a largo plazo, junto con la eficacia, también es importante el perfil de eventos adversos de una medicación. Ésta es una actualización de una revisión Cochrane publicada por primera vez en 2001 y actualizada por última vez en 2009.

Objetivos

1. Determinar la eficacia del tratamiento de mantenimiento y continuación con valproato:

a) para la prevención o la atenuación de los episodios maníacos, depresivos y mixtos del trastorno bipolar;

b) para la prevención o la atenuación de los episodios de trastorno bipolar en pacientes con trastorno de ciclaje rápido; y

c) para mejorar la salud general y el funcionamiento social del paciente, medidos según la impresión clínica global, y la estabilidad laboral y marital.

2. Revisar la aceptabilidad para los pacientes del tratamiento con valproato a largo plazo, medida según la cantidad de abandonos y los motivos del abandono, mediante el cumplimiento y las referencias a las opiniones expresadas de los pacientes con respecto al tratamiento.

3. Investigar los efectos adversos del tratamiento con valproato (incluida la prevalencia general de efectos secundarios) y las tasas de mortalidad general.

Métodos de búsqueda

Se realizaron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) y en el Registro del Grupo Cochrane de Depresión, Ansiedad y Neurosis (Cochrane Depression, Anxiety and Neurosis Group, CCDANCTR) (hasta enero de 2013), que incluyen ensayos controlados aleatorios relevantes obtenidos a partir de las siguientes bases de datos bibliográficas: The Cochrane Library (todos los años), EMBASE (1974 hasta la fecha), MEDLINE (1950 hasta la fecha) y PsycINFO (1967 hasta la fecha). No se aplicaron restricciones en cuanto al idioma. Se realizaron búsquedas manuales en las listas de referencias de los artículos pertinentes y en revisiones sistemáticas anteriores. Se estableció contacto con compañías farmacéuticas que comercializan valproato y con expertos en la materia para solicitarles datos adicionales.

Criterios de selección

Ensayos controlados aleatorios que asignaron a los participantes con trastorno bipolar a tratamiento a largo plazo con valproato o cualquier otro estabilizador del estado de ánimo, o fármacos antipsicóticos, o placebo. El tratamiento de mantenimiento se definió como el tratamiento que se estableció específica o principalmente para prevenir episodios adicionales de la enfermedad.

Obtención y análisis de los datos

Tres revisores extrajeron los datos de forma independiente. Dos revisores introdujeron los datos por duplicado. La información extraída incluyó las características de los estudios, las características de los participantes, los detalles de la intervención y las medidas de resultado en cuanto a la eficacia, la aceptabilidad y la tolerabilidad. Para los datos dicotómicos se calcularon los cocientes de riesgos con intervalos de confianza (IC) del 95%. Para los resultados estadísticamente significativos se calculó el número necesario a tratar para lograr un resultado beneficioso adicional (NNTB) y el número necesario a tratar para lograr un resultado perjudicial adicional (NNTD). Para los datos continuos se calcularon las diferencias de medias (DM) o las diferencias de medias estandarizadas (DME) junto con los IC del 95%. Las DM se emplearon cuando se utilizó la misma escala para medir un resultado; las DME se emplearon cuando se utilizaron diferentes escalas para medir el mismo resultado. El análisis primario utilizó un modelo de efectos fijos. Los resultados binarios se calcularon sobre una base de intención de tratar (ITT) estricta; los abandonos se incluyeron en este análisis. Cuando hubo datos faltantes y se había utilizado el método de la "última observación realizada" (LOCF, por sus siglas en inglés) para realizar un análisis ITT, entonces se utilizaron los datos de la LOCF.

Resultados principales

Se incluyeron seis ensayos controlados aleatorios (876 participantes en total) con una duración de seis a 24 meses. Dos estudios (312 participantes) compararon valproato con placebo, cuatro estudios (618 participantes) compararon valproato con litio, un estudio (23 participantes) comparó valproato con olanzapina y un estudio (220 participantes) comparó valproato con la combinación de valproato más litio. En cuanto a la calidad de los estudios, la mayoría informó los métodos utilizados para generar la secuencia aleatoria; sin embargo, solamente un estudio informó detalles suficientes sobre la ocultación de la asignación. Cuatro de seis estudios incluidos describieron su diseño como "doble ciego", aunque solo dos ensayos informaron detalles completos acerca del cegamiento. El valproato fue más efectivo que placebo para prevenir el retiro del estudio debido a cualquier episodio relacionado con el estado de ánimo (CR 0,68; IC del 95%: 0,49 a 0,93; NNTB 8), aunque no se encontraron diferencias en la eficacia entre el valproato y el litio (CR 1,02; IC del 95%: 0,87 a 1,20). El valproato se asoció con menos participantes que abandonaron el tratamiento por cualquier causa en comparación con placebo o litio (CR 0,82; IC del 95%: 0,71 a 0,95 y CR 0,87; IC del 95%: 0,77 a 0,98; respectivamente). Sin embargo, el tratamiento combinado con litio más valproato presentó mayores probabilidades de prevenir las recurrencias que la monoterapia con valproato (CR 0,78; IC del 95%: 0,63 a 0,96). Se encontraron diferencias significativas en la frecuencia de los eventos adversos y el litio se asoció con más frecuencia con diarrea, poliuria, aumento de la sed y enuresis, mientras que el valproato se asoció con un aumento en la sedación y la infección.

Conclusiones de los autores

Pruebas limitadas apoyan la eficacia del valproato en el tratamiento a largo plazo del trastorno bipolar. Los médicos y los pacientes deben considerar el perfil de aceptabilidad y tolerabilidad al elegir entre el litio y el valproato (su combinación u otros agentes) como tratamiento a largo plazo para el trastorno bipolar.

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

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Valproato para mantener controlados a los pacientes con trastorno bipolar, luego de episodios relacionados con el estado de ánimo

El trastorno bipolar es un trastorno frecuente e importante que incluye episodios de depresión, estados mixtos o manía. La depresión incluye decaimiento anímico y reducción de la energía, así como falta de placer, a menudo combinados con otros problemas como trastornos del sueño. La manía incluye lo contrario, es decir, "demasiada" energía y problemas relacionados con excitación o irritación. En los estados mixtos se combinan los síntomas de depresión y manía. Estos episodios del estado de ánimo generalmente suceden varias veces en la vida de un paciente, por lo que el tratamiento a largo plazo (tratamiento de mantenimiento) puede ser muy importante para prevenir la recaída y la recurrencia. Debido a que el valproato es un fármaco que puede ser útil en el tratamiento de la fase aguda del trastorno bipolar, en esta revisión se deseó responder a la siguiente pregunta: ¿El valproato es útil como tratamiento de mantenimiento para el trastorno bipolar?

Se realizaron búsquedas amplias de todos los estudios útiles (ensayos controlados aleatorios o ECA) que se pudieran encontrar sobre el tratamiento a largo plazo de los pacientes con trastorno bipolar con valproato o cualquier otro estabilizador del estado de ánimo, o fármacos antipsicóticos, o placebo. Tres de los revisores analizaron los ECA para asegurar que fueran experimentos adecuados. Se extrajeron los datos de los estudios, se reunieron todas las pruebas y se realizó un análisis estadístico para buscar los resultados significativos.

Estas búsquedas se realizaron el 11 de enero de 2013 y se encontraron seis estudios con 876 participantes. La calidad de los estudios en cuanto al diseño no fue buena, lo que significa que podrían haberse sobrestimado los efectos de algunos fármacos. Todos los ensayos considerados en conjunto indican que el valproato podría ayudar a prevenir la recurrencia en el trastorno bipolar, en especial los episodios depresivos. Sin embargo, debido a las pruebas limitadas disponibles, no es posible establecer conclusiones con algún grado de confianza sobre el valproato comparado con placebo y litio (u otros fármacos activos). El litio es un fármaco importante para comparar con valproato debido a que ya se conoce su efectividad para prevenir las recurrencias del trastorno bipolar. Al combinar los hallazgos de todos los estudios que compararon valproato con litio, las pruebas no favorecieron al valproato ni al litio en cuanto a la eficacia. Los pacientes que recibieron valproato durante mucho tiempo tuvieron mayores probabilidades de continuar con la medicación asignada que los pacientes que recibieron litio. Los médicos y los pacientes deben considerar los efectos secundarios del valproato, incluida la alopecía, el temblor y el aumento de peso.

También se encontró un estudio que comparó valproato solo con el tratamiento combinado con valproato (dos fármacos administrados al mismo tiempo). Este estudio comparó a pacientes que recibieron litio solamente o valproato solamente con pacientes que recibieron valproato y litio juntos. No hubo pruebas que mostraran que la administración de valproato y litio en comparación con litio solo ayudara a asegurar que los pacientes continuaran con la medicación asignada.

Authors' conclusions

Implications for practice

A key clinical question is whether valproate or lithium should be favoured as the first‐line therapy in the prevention of recurrence in bipolar disorder. Given the lack of clear findings of this review and the limited amount of evidence obtained, conclusions on the efficacy and acceptability of valproate compared with placebo and lithium cannot be made with any degree of confidence. The evidence of efficacy for valproate versus placebo (in terms of both total participants randomised and independently replicated results) is less robust when compared with the more substantial evidence for the efficacy of lithium versus placebo (Burgess 2001). Clinicians should always individualise the best maintenance drug treatment for each patient, in accordance with the efficacy and tolerability of long‐term treatments of documented efficacy. However, in making such clinical decisions, clinicians and patients may wish to consider evidence from a related review that highlights other important factors. These may include differences in the efficacy of drugs in acute treatment of mania (Cipriani 2011) and the relative acceptability and tolerability of valproate and lithium. In terms of safety, lithium and valproate had different side effect profiles. Our analysis suggests that valproate may be better tolerated than lithium, but comparatively high lithium levels were used in the trial, and it has been shown that informed management of lithium plasma levels may ensure both improved utility and improved outcomes (Mahli 2012). Moreover, a combination therapy with lithium plus valproate may be an option if the patient can tolerate the combination; however, this suggestion is based on evidence from a single study.

Implications for research

Longer‐term and larger sample size RCTs, with clinically appropriate designs, are needed, preferentially conducted independent of the manufacturer, to examine the relative efficacy and acceptability of valproate in the maintenance treatment of bipolar disorder. The review of lithium in maintenance therapy concluded that, although the total number of participants randomly assigned was rather small, reasonable evidence for the efficacy of lithium was found (Burgess 2001). We would therefore argue that it is unnecessary for future studies to include a placebo arm: The ethical and practical costs of doing so outweigh the possible benefits. Future trials need to compare valproate with other mood‐stabilising agents that have not been compared with valproate so far (e.g. carbamazepine, atypical antipsychotics) and must be of sufficient duration to inform real‐life clinical decision making. Good‐quality trials of valproate are needed: Analysis should be conducted on an intention‐to‐treat basis, and power calculations should be undertaken by using realistic estimates of recurrence rates. Trial outcomes should include measures that are meaningful to patients and clinicians, and recorded side effects should reflect the concerns of patients. Finally, although it is unclear whether valproate exhibits discontinuation effects similar to those exhibited by lithium, trial design should avoid rapid discontinuation of any mood stabiliser.

Even though two of the included studies focused on rapid cycling disorder, they were very small, and there remains a need for additional evidence on the use of valproate in such populations of patients.

Background

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 elevation) 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 sufferers' 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 compare 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 patients with bipolar disorder and, further, do not increase the frequency 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 morbidity 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 medications, including anticonvulsant agents (e.g. valproic acid, carbamazepine) and several atypical antipsychotics, have mood‐stabilising 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 disorder (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 unlikely that GABAergic transmission is related to the psychotropic action of valproate, as other different molecular mechanisms might be involved, such as serotonergic and glutamatergic transmission, energy metabolism and neuronal membrane lipid synthesis (Winterer 2000). Recently, amongst other potential mechanisms 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 carbamazepine 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 toxicity (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 America 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), alopecia, lethargy, dizziness, haematological dysfunction, hepatic failure and other gastrointestinal complaints. Asymptomatic elevation in hepatic transaminases may occur. Pancreatitis and hepatotoxicity 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 pregnancy 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 recommendation by the United Kingdom National Institute of Clinical Excellence (NICE) that valproate should not be prescribed routinely 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 developments, this re‐appraisal of valproate in the maintenance treatment of bipolar disorder is due and timely.

Objectives

To determine the efficacy of valproate continuation and maintenance treatment:
1. in preventing or attenuating manic, depressive and mixed episodes of bipolar disorder;
2. in preventing or attenuating episodes of bipolar disorder in patients with rapid cycling disorder; and
3. in improving patients' general health and social functioning, as measured by global clinical impression, employment and marital stability.
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.
To investigate the adverse effects of valproate treatment (including general prevalence of side effects) and overall mortality rates.

Methods

Criteria for considering studies for this review

Types of studies

Prospective randomised controlled trials (RCTs) comparing valproate maintenance treatment with placebo or alternative drug treatment in bipolar disorder were included in this review. Maintenance treatment was defined as treatment instituted specifically or mainly to prevent further episodes of illness. When trials combined acute treatment and maintenance phases, these data would be analysed separately when possible for the purposes of this review.

Types of participants

The review included participants of both sexes with a primary diagnosis of bipolar disorder corresponding to the International Classification 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 Revision (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 [suffering 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 particular, those with schizoaffective disorder and recurrent unipolar 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 randomisation 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 formulations 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.

Comparator intervention

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

Primary outcomes

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 period.

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

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) questionnaire (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 (CCDAN) maintains two clinical trials registers at its editorial base in Bristol, UK: a references register and a studies‐based register. The CCDANCTR‐References Register contains more than 31,500 reports of randomised controlled trials in depression, anxiety and neurosis. Approximately 65% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR‐Studies Register, and records are linked between the two registers through the use of unique study ID tags. Coding of trials is based on the EU‐Psi coding manual. Please contact the CCDAN Trials Search Co‐ordinator for further details.

Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review‐specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization’s trials portal (ICTRP), drug companies, and handsearching of key journals, conference proceedings and other (non‐Cochrane) systematic reviews and meta‐analyses. Details of CCDAN's generic search strategies can be found at the Group's website.

The CCDANCTR‐Studies Register was searched using the following terms:
Condition=(bipolar or mani* or schizoaffective) and Intervention=(divalproex or valpro*)

The CCDANCTR‐References Register was searched using a more sensitive set of free‐text terms to find additional untagged/uncoded references:
(valpro* or divalpro*) and (bipolar or mania or manic or hypomani* or psychos* or psychotic or postpsycho* or post‐psycho* or "rapid cycling" or schizoaffective)

The CCDANCTR was searched (all years to 11 January 2013).

Review authors conducted their own searches on EMBASE, MEDLINE, PsycLit and Psyndex to May 2012.

International trial registries

The WHO Clinical trials Portal (ICTRP) and ClinicalTrials.gov were searched (January 2013) to identify additional ongoing or unpublished studies. Clinicalstudyresults.org was also searched (to May 2011). This database no longer exists.

Regulatory agencies

Trial databases of the following drug‐approving agencies were searched for published, unpublished and ongoing controlled trials: the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the European Medicines Agency (EMA) in the EU. We also searched ongoing trial registers such as International Standard Randomised Controlled Trial Number Register (ISRCTN) and the National Research Register in the UK, Nederland's Trial Register in the Netherlands and European Union Drug Regulating Authorities Clinical Trials (EudraCT) in the EU. These searches were undertaken in February 2012.

Searching other resources

Personal communication

The contact authors of all review papers or trials over the relevant search period were identified from authorship lists. They and other experts in the field were contacted and asked about their knowledge of other studies, published or unpublished, relevant to the review. Pharmaceutical companies marketing valproate products were requested to provide relevant published and unpublished data.

Reference checking

The reference lists of all reviews, identified RCTs, other relevant papers and major English textbooks on mood disorder were checked for published reports and citations of unpublished research.

Data collection and analysis

Selection of studies

Two independent review authors checked to ensure that studies related to valproate generated by the search strategies of the CCDANCTR References and other complementary searches met the inclusion criteria, first based on the title and abstracts. All studies that were rated as possible candidates by either of the two review authors were added to the preliminary list, and their full texts were retrieved. AC and KM then assessed all of the full text articles in this preliminary list to see whether they met the strict inclusion criteria. If the raters disagreed, the final rating was made by consensus, with the involvement, if necessary, of another member of the review group (JG or AHY).

Data extraction and management

AC and KM extracted data from the included studies. Any disagreement was discussed, and decisions were documented. If necessary, we contacted authors of studies for clarification. We extracted the following data: (i) participant characteristics (age, sex, diagnosis, comorbidity, severity of illness, study setting); (ii) intervention details (intended dosage range, mean daily dosage actually prescribed, co‐intervention if any, sponsorship); and (iii) outcome measures of interest from the included studies.

Main comparisons

Valproate versus placebo.
Valproate versus alternative mood stabiliser.
Valproate versus other treatments (e.g. antipsychotics).
Valproate plus mood stabiliser versus mood stabiliser alone.
Valproate plus mood stabiliser versus valproate alone.

Assessment of risk of bias in included studies

Two review authors independently assessed trial quality in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This set of criteria is based on evidence of associations between effect overestimation and high risk of bias in an article, such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. Categories are defined as low risk of bias, high risk of bias, and unclear risk of bias.

If the raters disagreed, the final rating was made by consensus with involvement of another member of the review group. Non‐congruence in quality assessment was reported as percentage disagreement.

Measures of treatment effect

All comparisons were performed between valproate and comparator drug or placebo as individual compound.

Dichotomous data

For dichotomous, or event‐like, data, the risk ratio (RR) was calculated with its 95% confidence interval (CI). 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) as the inverse of the risk difference.

Continuous data

For continuous data, mean differences (MDs) or standardised mean differences (SMDs) were calculated 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. Continuous data on clinical outcomes often are not normally distributed, and skewed data were presented descriptively. If papers reported a mean and a standard deviation (SD), as well as an absolute minimum possible value for the outcome, we divided the mean by the SD. If this value was less than two, then we concluded that some indication of skewness was present. If the value was less than one (i.e. the SD was bigger than the mean), then skewness was almost certainly present. If papers did not report the skewness and simply reported means, SDs and sample sizes, these numbers were used. Because these data may not have been properly analysed and can be misleading, analyses were conducted with and without these studies. If the data were log‐transformed for analysis, and the geometric means were reported, skewness was reduced. This is the recommended method for analysis of skewed data (Higgins 2011).

Unit of analysis issues

Cross‐over trials

A major concern of cross‐over trials is the carry‐over effect. It occurs when an effect (e.g. pharmacological, physiological, psychological) of the treatment in the first phase is carried over to the second phase. As a consequence, on entry to the second phase, participants can differ systematically from their initial state, even despite a wash‐out phase. For this reason, we planned to use only data from the first phase of the cross‐over studies. No cross‐over studies were identified for this version of the review. Given that cross‐over trials for which only first period data are available should be considered to be at risk of bias (Higgins 2011), careful attention will be paid to retrieve only unbiased data available from such studies in the next updates of this review.

Cluster‐randomised trials

No cluster randomised trials were found for this version of the review. Should they be identified in a future update, we will attempt to adjust for the effects of clustering using an intraclass correlation coefficient (ICC). In fact this is seldom available in published reports, so a common approach is to use external estimates obtained from similar studies; several resources are available that provide examples of ICC (Higgins 2011). We will conduct sensitivity analyses to investigate the robustness of our conclusions, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions.

Studies with multiple treatment groups

For a particular multi‐arm study, the intervention groups of relevance to a systematic review are all those that could be included in a pair‐wise comparison of intervention groups that, if investigated alone, would meet the criteria for inclusion of studies in the review. Each meta‐analysis addresses only a single pair‐wise comparison, so we first considered whether a study of each possible pair‐wise comparison of interventions in the study was eligible for the meta‐analysis. Then, several possible approaches to including a study with multiple intervention groups could be used in a particular meta‐analysis (Higgins 2011). For binary outcomes, we decided to combine all relevant experimental intervention groups of the study into a single experimental group, and to combine all relevant control intervention groups into a single control group. For continuous outcomes, we decided to combine means and standard deviations using methods described in Chapter 7 of the Cochrane Handbook for Systematic Review of Interventions.

Dealing with missing data

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. When standard deviations (SDs) were missing, we presented data descriptively. When SDs were not reported, authors were asked to supply the data. When only the standard error (SE) or t‐statistics or the P value was reported, we calculated SDs in accordance with Altman 1996.

Assessment of heterogeneity

Heterogeneity between studies was investigated by the I² statistic (Higgins 2003) (I² equal to or greater than 50% was considered indicative of heterogeneity) and by visual inspection of the forest plots. Given that the value of I² depends on the sample size of the included studies, the magnitude and direction of effects and the strength of evidence for heterogeneity, we used this arbitrary threshold to perform a preliminary evaluation. If the I² value fell below 50% but the direction and magnitude of treatment effects were suggestive of important heterogeneity, we investigated the potential sources of heterogeneity.

Assessment of reporting biases

Data from included studies were entered into a funnel plot (trial effect against trial variance) for investigation of small‐study effects (Sterne 2000). We planned to use the tests for funnel plot asymmetry only when at least 10 studies were included in the meta‐analysis (Higgins 2011). Funnel plot asymmetry may be noted for many possible reasons, so when evidence of small‐study effects was identified, all possible reasons for funnel plot asymmetry, including publication bias, were investigated.

Data synthesis

All analyses used a fixed‐effect model. We decided to use a fixed‐effect model as the primary analysis because by including only RCTs with standardised dose regimens, similar clinical management and narrow diagnostic inclusion criteria, we did not expect to see significant clinical heterogeneity. However, the robustness of this summary measure was routinely examined by checking the random‐effects model, which has the greatest generalisability in our empirical examination of summary effect measures for meta‐analyses (Furukawa 2002a). Material differences between the models were reported. A P value less than 0.05 and a 95% confidence interval (CI) were considered statistically significant.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses for primary outcomes when possible.

Studies examining rapid cycling bipolar disorder were to be considered separately. The efficacy of valproate in preventing/attenuating episodes in rapid cycling disorder was measured by recurrence of affective episodes; admission to hospital; institution of additional treatment for mood disorder; and length of the well period, expressed in cycle lengths.
Assessment of the effectiveness of valproate treatment in previous mood stabiliser non‐responders was considered.

Results were interpreted with caution because multiple comparisons can lead to false‐positive conclusions (Oxman 1992). If the CIs of RRs in the groups did not overlap, potential sources of heterogeneity were investigated. Given that no age restrictions were applied in the present review, in the next update we will conduct, if possible, subgroup analyses for age, as important differences between children/adolescents and adults could be seen in terms of clinical presentation.

Sensitivity analysis

The following sensitivity analyses for primary outcomes were planned a priori.

We excluded trials with unclear concealment of random allocation and/or unclear double blinding.
We excluded trials with a dropout rate greater than 20%.
We excluded studies with a discontinuation design. Data from these studies were to be analysed separately for assessment of the effects of valproate discontinuation.
The routine application of random‐effects and fixed‐effect models can be considered an additional form of sensitivity analysis.
The use of ITT analyses, when data have been imputed (by you or by the trialists), warrants sensitivity analyses. In future updates, we will undertake sensitivity analysis in the event that we will impute data for ITT analysis.

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies; and Characteristics of studies awaiting classification.

Results of the search

Initially, we identified 59 new references through the updated search. After the abstracts were read, 30 references were considered relevant for our review and were retrieved for more detailed evaluation (see Figure 1 for PRISMA flow diagram). Although the search was thorough, it is possible that unpublished studies may not have been identified.

Figure 1

Study flow diagram showing study selection process.

Included studies

A total of six studies were identified, with a mean follow‐up duration ranging between 6 and 24 months. Attempts to contact trial authors for additional unpublished information were successful in five cases, and additional data were provided by the authors of three studies (Bowden 2000; Calabrese 2005; BALANCE 2010).

Study design

Most studies were reported to be double‐blind (Bowden 2000; Calabrese 2005; Findling 2005; Kemp 2009), apart from Altamura 2004 and BALANCE 2010, which were designed as open‐label studies. Only two studies were three‐arm trials (Bowden 2000; BALANCE 2010), and the remaining four were two‐armed studies (Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009).

Sample Size

Overall, 876 participants were included. The mean sample size per arm was 60.5 participants (range 10 to 187). Four studies recruited fewer than 100 participants (Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009), and only two studies recruited more than 200 participants overall (Bowden 2000; BALANCE 2010).

Setting/participants

Five trials enrolled only outpatients (Bowden 2000; Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009), and one study enrolled both inpatients and outpatients (BALANCE 2010). All participants had been given a formal diagnosis of bipolar disorder according to DSM‐IV (Calabrese 2005; Kemp 2009; BALANCE 2010) or DSM‐III‐R (Bowden 2000; Findling 2005); however, one study (Altamura 2004) recruited a few participants with schizoaffective disorder (3 of 23 randomly assigned participants). One study recruited children and adolescents only (Findling 2005), and two trials randomly assigned only participants with rapid cycling disorder (Calabrese 2005; Kemp 2009). In Kemp 2009, participants had co‐occurring substance abuse or dependence. About three‐fifths of the participants included in the study recruiting children and adolescents only (Findling 2005) were prescribed concomitant psychostimulants for attention deficit hyperactivity disorder (ADHD) symptoms (35 of 60, 58.3%), but randomisation was stratified on the basis of three factors: age (5 to 11 or 12 to 17 years), presence/absence of rapid cycling and whether the individual had comorbid ADHD. All studies employed a discontinuation design (randomly assigning participants before long‐term, relapse prevention treatment was provided).

Interventions and comparators

We found two studies (overall, 312 participants) that compared valproate with placebo (Bowden 2000; Kemp 2009), four studies (overall, 618 participants) comparing valproate with lithium (Bowden 2000; Calabrese 2005; Findling 2005; BALANCE 2010), one study (overall, 23 participants) comparing valproate with olanzapine (Altamura 2004) and one study (overall, 220 participants) comparing valproate with the combination of valproate plus lithium (BALANCE 2010). In the included studies, almost all participants used lithium or valproate within the therapeutic dose range. Valproate or divalproex as orally administered was used in all trials. Blood levels of valproate were monitored in all trials. The tapering discontinuation of medications in the run‐up to maintenance treatment was explicitly gradual in Bowden 2000 (two weeks), Calabrese 2005 (average six weeks), Findling 2005 (eight weeks) and Kemp 2009 and BALANCE 2010 (four weeks), presumably to avoid rebound. Altamura 2004 recruited participants who were euthymic at the moment of recruitment, with no run‐in phase. Rescue medications were allowed in all studies in accordance with a priori protocols.

Outcomes

Of the included six studies, all reported efficacy data and tolerability or acceptability data that were suitable for meta‐analysis. The included studies did not report on all outcomes prespecified in the protocol of this review. Outcomes of clear relevance to patients and clinicians, in particular, patients' and their relatives' attitudes towards treatment, patients' ability to return to work and resume normal social functioning, health‐related quality of life measures and costs of health care services, were not reported in the included studies.

Excluded studies

Of the 30 references retrieved for more detailed evaluation, 24 articles did not meet our inclusion criteria and were excluded for one of the following reasons: wrong/non‐randomised design (13 articles), review/case series (two articles), wrong comparison (five articles) and wrong diagnosis/population (four articles) (see Figure 1 for PRISMA flow diagram).

Ongoing studies

No ongoing studies were identified.

Studies awaiting classification

Two studies are awaiting classification. Bowden 2012 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. We require further information to assess NCT00071253. If we receive the required information we will be able to consider its eligibility when updating this review.

New studies found at this update

Five new studies were incorporated at this update: Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009; and BALANCE 2010.

Risk of bias in included studies

See Included studies, Figure 2 and Figure 3.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Risk of bias graph: review authors' judgements about all risk of bias items presented as percentages across all included studies.

Our judgement about the overall risk of bias in the individual studies is illustrated in Figure 2 and Figure 3. No disagreement between the raters occurred. The methodological quality of these included studies was questionable overall. Even though it is not possible to predict the direction or magnitude of bias associated with lack of adequate sequence generation or adequate allocation concealment (Odgaard‐Jensen 2011), this type of reporting has been associated with an overestimate of the effect of investigational drugs (Schulz 1995), and this should be considered when the review results are interpreted.

Allocation

In terms of random sequence generation, we found that all included studies were at low risk of bias, and most studies reported that the method of generating random sequence was “a computer originated schedule”. In terms of "allocation concealment", only one study reported enough details on the allocation concealment procedure (BALANCE 2010). We were not assured that bias was minimised during the allocation procedure in the other five studies (Bowden 2000; Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009), yet the great majority of them reported that participants allocated to each treatment group were “similar”, “the same”, “not significantly different”, “comparable” or “matched”.

Blinding

Four of six included studies described their design as “double‐blind” (Bowden 2000; Calabrese 2005; Findling 2005; Kemp 2009); however, no tests were conducted to ensure successful blinding. Two studies reported full details about blinding of participants and personnel and were rated at low risk of bias (Calabrese 2005; Kemp 2009), and two studies had been carried out in an open manner (Altamura 2004; BALANCE 2010). Blinding of outcome assessment was rated as "unclear" in five studies (Bowden 2000; Altamura 2004; Calabrese 2005; Findling 2005; Kemp 2009).

Incomplete outcome data

Only three studies were rated as at "low risk" of bias (Bowden 2000; Calabrese 2005; BALANCE 2010). Total dropout rate was high overall, ranging from 20.9% (BALANCE 2010) to 90% (Findling 2005). In four studies, the total dropout rates were higher than 50% (Bowden 2000; Calabrese 2005; Findling 2005; Kemp 2009). Two studies used a proper ITT analysis and were rated as "low risk" (Calabrese 2005; BALANCE 2010), and the remaining four did not provide clear information about analysis and were rated "unclear" (Bowden 2000; Altamura 2004; Findling 2005; Kemp 2009).

Selective reporting

Two studies were rated as "low risk" (Calabrese 2005; BALANCE 2010) and one as "high risk" (Altamura 2004). The study protocol was available for only one study (BALANCE 2010), and some trials did not report in the published paper SDs for mean changes as continuous outcomes (Findling 2005; Kemp 2009).

Other potential sources of bias

One study was sponsored by a valproate manufacturer (Bowden 2000), one study reported no information about funding (Altamura 2004) and all remaining studies were funded by grants from independent bodies (e.g. the National Institutes of Health, the Stanley Medical Research Institute, or the Stanley Foundation, and the Nina Rahn Fund). In three of these studies, medications were provided by Abbott Laboratories or Abbott Pharmaceuticals, the manufacturer of valproate (Calabrese 2005; Findling 2005; Kemp 2009), and in the fourth study, all study drugs (both lithium carbonate and valproate semisodium) were donated by sanofi‐aventis (BALANCE 2010).

Effects of interventions

All six included studies contributed usable data for the efficacy, acceptability and tolerability analyses, but only one reported data about quality of life and global functioning (BALANCE 2010). No studies assessed other general health and social functioning issues, such as employment or separation/divorce, and no information about costs of healthcare services was provided in the included studies. All included studies excluded women who were pregnant (or were planning to become pregnant) and fertile women not on adequate contraceptive methods. No cases of teratogenicity were signalled. The results of the present systematic review are reported by comparison and by outcome, in accordance with the original review protocol. The forest plots are organised according to relevance of outcomes, as reported in the review protocol. For tolerability, adverse events are reported only when statistically significant (non–statistically significant results about adverse events are presented in Table 1).

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Table 1. Adverse events

Adverse event	Study	Valproate		Comparator		Risk Ratio, Fixed [95% CI]
Adverse event	Study	Events	Total	Events	Total	Risk Ratio, Fixed [95% CI]
*Valproate vs placebo*
Acne	Kemp 2009	0	15	2	16	0.21 [0.01, 4.10]
Akathisia	Bowden 2000	1	187	1	94	0.50 [0.03, 7.95]
Blurred vision	Kemp 2009	2	15	1	16	2.13 [0.22, 21.17]
Cognitive dysfunction	Kemp 2009	2	15	2	16	1.07 [0.17, 6.64]
Diarrhoea	Bowden 2000; Kemp 2009	69	202	34	110	1.11 [0.78, 1.56]
Dry mouth	Kemp 2009	3	15	0	16	7.44 [0.42, 132.95]
Fatigue	Kemp 2009	5	15	1	16	5.33 [0.70, 40.54]
Increased appetite	Kemp 2009	0	15	2	16	0.21 [0.01, 4.10]
Infection	Bowden 2000	51	187	18	94	1.42 [0.88, 2.29]
Nausea	Bowden 2000; Kemp 2009	81	202	32	110	1.32 [0.94, 1.86]
Polydipsia	Kemp 2009	6	15	5	16	1.28 [0.49, 3.33]
Polyuria	Bowden 2000	15	187	9	94	0.84 [0.38, 1.84]
Sedation	Bowden 2000	78	187	33	94	1.19 [0.86, 1.64]
Sexual dysfunction	Kemp 2009	2	15	2	16	1.07 [0.17, 6.64]
Tachycardia	Bowden 2000	1	187	1	94	0.50 [0.03, 7.95]
Thirst	Bowden 2000	11	187	7	94	0.79 [0.32, 1.97]
Tinnitus	Bowden 2000	12	187	1	94	6.03 [0.80, 45.69]
*Valproate vs lithium*
Akathisia	Bowden 2000	1	187	4	91	0.12 [0.01, 1.07]
Alopecia	Bowden 2000; Calabrese 2005; Findling 2005	30	245	9	153	1.74 [0.85, 3.56]
Balance problems	Calabrese 2005	2	28	1	32	2.29 [0.22, 23.88]
Cognitive difficulties	Calabrese 2005	0	28	1	32	0.38 [0.02, 8.95]
Decreased appetite	Findling 2005	3	30	3	30	1.00 [0.22, 4.56]
Dry eyes	Bowden 2000	0	187	3	91	0.07 [0.00, 1.34]
Fever	Findling 2005	1	30	4	30	0.25 [0.03, 2.11]
Gastrointestinal discomfort	Calabrese 2005	2	28	5	32	0.46 [0.10, 2.17]
Haematological dyscrasia	Findling 2005	1	30	0	30	3.00 [0.13, 70.83]
Headache	Calabrese 2005; Findling 2005	11	58	4	62	2.64 [0.96, 7.24]
Nausea	Bowden 2000; Findling 2005	81	217	46	121	0.89 [0.68, 1.18]
Serious adverse events	BALANCE 2010	7	110	5	110	1.40 [0.46, 4.28]
Sore throat	Findling 2005	3	30	1	30	3.00 [0.33, 27.23]
Speech	Calabrese 2005	0	28	1	32	0.38 [0.02, 8.95]
Stomach pain	Findling 2005	7	30	3	30	2.33 [0.67, 8.18]
Tachycardia	Bowden 2000	1	187	4	91	0.12 [0.01, 1.07]
Tremor	Bowden 2000; Calabrese 2005; Findling 2005	83	245	53	153	0.86 [0.65, 1.14]
Upper respiratory congestion	Findling 2005	3	30	2	30	1.50 [0.27, 8.34]
Visual impairment	Calabrese 2005	0	28	3	32	0.16 [0.01, 3.02]
Vomiting	Findling 2005	3	30	9	30	0.33 [0.10, 1.11]
Weight gain	Bowden 2000; Calabrese 2005	41	215	13	123	1.60 [0.89, 2.85]

Comparison 1: valproate versus placebo

Primary outcome

1.1 Efficacy in preventing/attenuating further episodes of affective disorder

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; P = 0.02; NNTB 8, 95% CI 5 to 50; 2 RCTs, 312 participants) or to a depressive episode alone (RR 0.46, 95% CI 0.24 to 0.89; P = 0.02; NNTB 13, 95% CI 7 to 100; 2 RCTs, 312 participants) (Analysis 1.1; Figure 4). No strong evidence suggested that valproate was superior to placebo in reducing study withdrawals due to manic episodes (RR 0.77, 95% CI 0.48 to 1.25; P = 0.29; 2 RCTs, 312 participants) (Analysis 1.1; Figure 4). When study data were analysed using the random‐effects model, valproate was still seen to more effective than placebo in preventing study withdrawal due to any mood episode, but results were no more statistically significant (RR 0.71, 95% CI 0.49 to 1.02; P = 0.07).

Figure 4

Forest plot of comparison: 1 Valproate versus placebo, outcome: 1.1 Study withdrawal due to episode of mood disorder.

Secondary outcomes

1.2 Acceptability of treatments

Valproate was more effective than placebo in preventing all‐cause study withdrawal (RR 0.82, 95% CI 0.71 to 0.95; P = 0.01; NNTB 8, 95% CI 5 to 34; 2 RCTs, 312 participants) (Analysis 1.2), but it was associated with a greater number of participants dropping out of treatment as the result of intolerance or non‐compliance (RR 1.87, 95% CI 1.01 to 3.47; P = 0.05; NNTH 10, 95% CI 6 to 100; 1 RCT, 281 participants) (Analysis 1.3). No data were provided about participant reports of satisfaction or otherwise with treatment.

1.3 Adverse effects

People allocated to valproate were more likely to have tremor (RR 2.41, 95% CI 1.58 to 3.67; P < 0.0001; NNTH 10, 95% CI 6 to 34; 2 RCTs, 312 participants; I² = 90%) (Analysis 1.4), weight gain (RR 2.04, 95% CI 1.07 to 3.86; P = 0.03; NNTH 4, 95% CI 3 to 7; 2 RCTs, 312 participants; I² = 80%) and alopecia (RR 2.51, 95% CI 1.15 to 5.51; NNTH 10, 95% CI 6 to 34; P = 0.02; 2 RCTs, 312 participants). However, the differences in tremor and weight gain disappeared when the random‐effects model was used (RR 1.85, 95% CI 0.54 to 6.33; P = 0.33 and RR 1.25, 95% CI 0.19 to 7.94; P = 0.82, respectively).

1.4 General health and social functioning

No studies reported on this outcome for this comparison.

1.5 Mortality rates and deliberate self‐harm

No data about mortality or suicide were reported.

Comparison 2: valproate versus lithium

Primary outcome

2.1 Efficacy in preventing/attenuating further episodes of affective disorder

No strong evidence indicated that valproate was inferior or superior to lithium in preventing study withdrawals due to episodes of mood disorder (any mood episode or manic, depressive hypomanic or mixed episode alone) (Analysis 2.1; Figure 5). One study (BALANCE 2010) reported detailed information about other dichotomous efficacy outcomes, such as number of hospital admissions (Analysis 2.2) or new treatment for mood episode (Analysis 2.3). No difference was found between valproate and lithium on these outcomes, with the exception of "new treatment for depressive episode", for which valproate was noted to be inferior to lithium (RR 1.43, 95% CI 1.02 to 2.01; P = 0.04; NNTH 8, 95% CI 4 to 100; 1 RCT, 220 participants) (Analysis 2.3). Another study reported the continuous outcome "time to relapse" (Findling 2005), but we do not know whether valproate was better than lithium in terms of time to median survival (as measured in days) for participants who relapsed because of the presence of mood symptoms (MD ‐2.00, 95% CI ‐7.24 to 3.24; P = 0.45: 1 RCT, 60 participants) (Analysis 2.4).

Figure 5

Forest plot of comparison: 2 Valproate versus lithium, outcome: 2.1 Study withdrawal due to episode of mood disorder.

Secondary outcomes

2.2 Acceptability of treatments

When compared with lithium, valproate was associated with a lesser number of participants dropping out of treatment for any cause (RR 0.87, 95% CI 0.77 to 0.98; P = 0.02; 4 RCTs, 618 participants) (Analysis 2.5) and because of intolerance or non‐compliance (RR 0.67, 95% CI 0.49 to 0.93; P = 0.02; 4 RCTs, 618 participants) (Analysis 2.6).

2.3 Adverse effects

People allocated to valproate were less likely to have diarrhoea (RR 0.74, 95% CI 0.55 to 0.99; NNTB 10, 95% CI 5 to ∞; P = 0.04; 2 RCTs, 338 participants), polyuria (RR 0.31, 95% CI 0.16 to 0.58; P = 0.0003; NNTB 7, 95% CI 5 to 15; 2 RCTs, 338 participants; I² = 63%), increased thirst (RR 0.32, 95% CI 0.15 to 0.65; P = 0.002; NNTB 9, 95% CI 6 to 25; 2 RCTs, 338 participants) or enuresis (RR 0.22, 95% CI 0.05 to 0.94; P = 0.04; NNTB 5, 95% CI 3 to 20; 1 RCT, 60 participants) but were more likely to have sedation (RR 1.45, 95% CI 1.00 to 2.10; P = 0.05; NNTH 9, 95% CI 5 to 100; 2 RCTs, 338 participants; I² = 59%) or infection (RR 2.07, 95% CI 1.16 to 3.68; P = 0.01; NNTH 8, 95% CI 5 to 20; 1 RCT, 278 participants) (Analysis 2.7). However, the differences for sedation and polyuria disappeared when the random‐effects model was used (RR 0.93, 95% CI 0.20 to 4.44; P = 0.93 and RR 0.21, 95% CI 0.02 to 1.89; P = 0.16, respectively).

2.4 General Health and Social Functioning

Only one study (BALANCE 2010) reported data about quality of life and global functioning, but the results were inconclusive (Analysis 2.8; Analysis 2.9).

2.5 Mortality rates and deliberate self harm

Only one study (BALANCE 2010) reported data about mortality and deliberate self‐harm (DSH). We do not know whether valproate was worse than lithium in terms of DSH (RR 2.50, 95% CI 0.50 to 12.61; P = 0.27; 1 RCT, 220 participants; Analysis 2.10) or number of deaths (RR 1.50, 95% CI 0.26 to 8.80; P = 0.65; 1 RCT, 220 participants) (Analysis 2.11). None of the deaths was caused by suicide.

Comparison 3: valproate versus olanzapine

Primary outcome

3.1 Efficacy in preventing/attenuating further episodes of affective disorder

We do not know whether valproate was better than olanzapine in terms of numbers of participants experiencing syndromic recurrence of any mood episode (meeting DSM‐IV criteria) (RR 0.74, 95% CI 0.30 to 1.85, P = 0.52; 1 trial, 23 participants) (Analysis 3.1). No strong evidence suggested that valproate was inferior or superior to olanzapine in preventing study withdrawals due to episodes of mood disorder (manic or depressive episodes) (Analysis 3.1).

Secondary outcomes

3.2 Acceptability of treatments

In the included study (Altamura 2004), all dropouts left the study because of side effects, and all belonged to the olanzapine group. However, it is unclear whether there was a difference between valproate and olanzapine in terms of numbers of participants withdrawing from treatment (RR 0.18, 95% CI 0.01 to 3.16, P = 0.24; 1 trial, 23 participants) (Analysis 3.2; Analysis 3.3).

3.3 Adverse effects

No clear data were available in the paper that reported only that adverse events causing premature discontinuation for three participants allocated to olanzapine were weight gain and sedation.

3.4 General Health and Social Functioning

No studies reported on this outcome for this comparison.

3.5 Mortality rates and deliberate self harm

No deaths during the treatment period were reported in the included study (Altamura 2004).

Comparison 4: valproate plus lithium versus lithium alone

Primary outcome

4.1 Efficacy in preventing/attenuating further episodes of affective disorder

There was no evidence that valproate plus lithium was superior to lithium alone in preventing study withdrawals due to episodes of mood disorder (Analysis 4.1). No differences were found between valproate plus lithium and lithium alone in terms of hospital admission or new drug treatment for mood episode (Analysis 4.2; Analysis 4.3).

Secondary outcomes

4.2 Acceptability of treatments

Even though it was not clear whether there was a difference between the combination of lithium and valproate and lithium alone in terms of all‐cause dropout (Analysis 4.4), lithium alone was associated with dropout from treatment of a lesser number of participants as the result of intolerance or non‐compliance when compared with lithium and valproate, but results were inconclusive (RR 1.83, 95% CI 0.70 to 4.78; P = 0.22; 1 RCT, 220 participants) (Analysis 4.5).

4.3 Adverse effects

No evidence indicates that valproate plus lithium differed from lithium alone in causing serious adverse events (Analysis 4.6).

4.4 General health and social functioning

No difference was found between lithium and valproate in terms of quality of life or global functioning (Analysis 4.7; Analysis 4.8).

4.5 Mortality rates and deliberate self‐harm

Fewer participants in the lithium alone group committed DSH, but the results were inconclusive (RR 2.00, 95% CI 0.37 to 10.70; P = 0.42; 1 RCT, 220 participants) (Analysis 4.9). Three participants died: one in the combination arm and two in the lithium alone arm (Analysis 4.10).

Comparison 5: valproate plus lithium versus valproate alone

Primary outcome

5.1 Efficacy in preventing/attenuating further episodes of affective disorder

Valproate plus lithium was superior to valproate alone in prevention of study withdrawals due to episodes of mood disorder (RR 0.78, 95% CI 0.63 to 0.96; P = 0.02; NNTB 7, 95% CI 4 to 34; 1 RCT, 220 participants) (Analysis 5.1; Figure 6); this combination also resulted in lesser numbers of participants who required new treatment for any mood episode (RR 0.77, 95% CI 0.62 to 0.96; P = 0.02; NNTB 7, 95% CI 4 to 34; 1 RCT, 220 participants) or for mania alone (RR 0.61, 95% CI 0.42 to 0.89; P = 0.009; NNTB 6, 95% CI 4 to 20; 1 RCT, 220 participants) (Analysis 5.3). The combination of lithium and valproate was also more effective than valproate alone in terms of hospital admissions or new drug treatments for depression, but these results were inconclusive (Analysis 5.2; Analysis 5.3).

Figure 6

Forest plot of comparison: 5 Valproate plus lithium versus valproate alone, outcome: 5.1 Study withdrawal due to episode of mood disorder.

Secondary outcomes

5.2 Acceptability of treatments

Even though it was not clear whether there was a difference between the combination of lithium and valproate and valproate alone in terms of all‐cause dropout (Analysis 5.4), valproate alone was associated with lesser numbers of participants dropping out of treatment as the result of intolerance or non‐compliance when compared with the combination of lithium and valproate, but the results were inconclusive (RR 2.75, 95% CI 0.90 to 8.37; P = 0.07; 1 RCT, 220 participants) (Analysis 5.5).

5.3 Adverse effects

No evidence indicated that valproate plus lithium was more likely than valproate alone to cause serious adverse events (Analysis 5.6).

5.4 General health and social functioning

No difference between combination lithium plus valproate and valproate alone was noted in terms of quality of life or global functioning (Analysis 5.7; Analysis 5.8).

5.5 Mortality rates and deliberate self‐harm

Fewer participants in the combination group died, but the results were inconclusive (RR 0.33, 95% CI 0.04 to 3.16; P = 0.34; 1 RCT, 220 participants) (Analysis 5.10). Nine participants committed DSH: four in the combination arm and five in the valproate alone arm (Analysis 5.9).

Subgroup analyses

1) Rapid cycling bipolar disorder

We did not find enough studies to investigate the issue about rapid cycling disorder as reported in the review protocol because, of the two small trials randomly assigning participants with rapid cycling disorder only, one compared valproate as add‐on treatment with placebo (Kemp 2009), and the second compared valproate as monotherapy with lithium (Calabrese 2005).

2) Effectiveness of valproate treatment in previous mood stabiliser non‐responders

Information about participants who did not respond to other mood stabilisers, as reported in the included studies, was not sufficient to allow a proper statistical analysis.

Funnel plot analysis

For all comparisons, the presence of publication bias was not examined because trials were insufficient to allow meaningful formal assessment with the use of funnel plots.

Sensitivity analyses

1) Excluding trials with unclear concealment of random allocation and/or unclear double blinding

This sensitivity analysis was not performed because only one study reported clear details on concealment of random allocation (BALANCE 2010), and of four double‐blind studies, two studies reported full details on blinding, but one compared valproate with lithium (Calabrese 2005) and the other one compared valproate with placebo (Findling 2005).

2) Excluding trials whose dropout rate was greater than 20%

This sensitivity analysis was not performed because in all studies, the dropout rate was greater than 20%.

3) Excluding trials with a discontinuation design

This sensitivity analysis was not performed because five of six included studies had a discontinuation design, and only Altamura 2004 recruited participants who were euthymic at the moment of recruitment with no run‐in phase.

Discussion

Summary of main results

This systematic review of six randomised controlled trials comparing valproate with placebo or other active drugs in the maintenance treatment of bipolar disorder showed that valproate is more effective than placebo in preventing study withdrawals due to an episode of mood disorder (especially, depressive episode), but it is not materially different from lithium in terms of overall efficacy. However, only two studies compared valproate with placebo, and in the study that had the larger sample, valproate was no better than placebo on the primary efficacy measure. No reliable evidence suggested a difference between valproate and lithium (pooled RR 1.02, 95% CI 0.87 to 1.20), although the confidence interval is consistent with a 13% relative reduction in the risk in favour of valproate and a 20% reduction in the risk consistent with lithium. No statistically significant difference was noted between valproate and lithium in terms of prevention of manic episodes (RR 1.14, 95% CI 0.90 to 1.44) or depressive episodes (RR 1.12, 95% CI 0.84 to 1.49). In both cases, however, the direction of the effect favoured lithium, and a post hoc sensitivity analysis, including or excluding Findling 2005 (which used slightly different definitions of outcome), had no material effect on the overall estimate. The apparent benefit of valproate compared with placebo was of a similar size to the advantage of valproate plus lithium compared with lithium monotherapy. Taken together, these suggest that valproate has some preventative efficacy in bipolar disorder. However, when compared with combination therapy with lithium, valproate alone did not show any clinical advantage, as combination therapy was more likely to prevent relapse than was monotherapy with valproate. Even though it was associated with a higher incidence of adverse events such as alopecia, tremor and weight gain than placebo, valproate was more acceptable than lithium, as it was associated with a lower risk for participants to withdraw from treatment.

Overall completeness and applicability of evidence

Retrieved randomised evidence compared valproate with a selection of possible comparator drugs, but only a few studies were found per comparison. The evidence that valproate is more effective than placebo was derived from only one moderately sized RCT and one very small RCT. By contrast, for the comparison between valproate and lithium, results were numerically more robust, as we found four RCTs. The identified studies were sufficient to address many, but not all, of the outcomes originally specified in the review protocol.

In this review, we included only RCTs, and one of the main limitations of efficacy trials involves including participants far from the “real world”. Proper randomisations and reliable inclusion and exclusion criteria may help create two or more groups that do not differ. However, the external validity of study findings might be limited (Cipriani 2009a). Generalisability of these findings can be extended only to patients who are likely to be enrolled in a randomised trial, and results from systematic reviews of RCTs should be integrated with available high‐quality observational evidence, which may inform better about the adverse events that cannot be fully assessed in RCTs only.

Quality of the evidence

With summary statistics, the quality of information is important for interpreting results and for usefulness of results in practice. Use of high‐quality research evidence is relevant for reviewing results and facilitating the translation of research in a way that can answer clinically relevant questions. However, the quality of RCTs is not easy to assess. Despite the fact that randomised clinical trials provide the best research design by which to answer questions about efficacy and acceptability of treatments (Cipriani 2009b), the six studies included in this review (876 participants overall) failed to report key methodological issues. For example, a great majority of trials still do not report adequate information about allocation concealment. Meta‐analyses of poor‐quality studies may be seriously misleading (Ioannidis 2005) because the bias associated with defects in the conduct of primary studies can seriously affect overall estimates of intervention. Even though reporting of outcomes in the included studies was sometimes unclear or incomplete (only graphs, no SDs), and the figures used for the analyses were not immediately understandable, the scant information about allocation concealment may be more a matter of reporting in the text than of real defects in study design.

Potential biases in the review process

Although the search was thorough, it is possible that unpublished studies have not been identified, but the small number of trials identified per comparison hinders the detection of any publication bias. We are also aware that a number of further randomised controlled trials comparing valproate with other drugs are currently being conducted and will be included in future updates of the review.

For several comparisons, the data came from just one study (e.g. valproate vs olanzapine, valproate plus lithium vs valproate alone), and results from this review should be interpreted with caution.

We found only one large placebo‐controlled RCT that investigated the efficacy and acceptability of valproate maintenance treatment in bipolar disorder. This study (Bowden 2000) is one of the largest trials of maintenance therapy in bipolar disorder ever undertaken; however, the results are equivocal. The practical difficulties caused by the inclusion of a placebo‐treated group led to the inclusion of a less severely affected group of participants than is generally found in clinical practice. A higher relapse rate was anticipated than was actually found, which meant that the study had insufficient power to detect reliably a moderate, but clinically important, treatment effect. Moreover, a 52‐week follow‐up was probably rather short for a maintenance study. Despite its short duration, a large number of participants withdrew from the study, especially in the lithium group. Finally, during the up to 3‐month run‐in phase, the index manic episode was treated at the discretion of the investigator, and 117 participants had been treated with valproate only (31.5%), 124 with lithium only (33.3%), 50 with both drugs (usually sequentially) (13.4%) and 81 with neither drug (21.8%). Given that 187 participants were subsequently randomly assigned to valproate, 91 to lithium and 94 to placebo (2:1:1 randomisation scheme), and that participants taking valproate or lithium on the day of randomisation had the drug gradually withdrawn over a 2‐week time, this design might have favoured valproate over placebo and lithium. The primary analysis used in Bowden 2000 was a comparison of survival curves in the treatment arms. This primary analysis found no significant differences between treatment groups, although the comparison between lithium and valproate tended to favour the latter. In our analysis, without access to individual participant data, we simply used the number of participants leaving the study because of recurrence during the study. We found a statistically significant benefit for valproate compared with placebo. This result is rather surprising because the time‐to‐event analysis is more efficient. In other words, because it makes fuller use of the data, other things being equal, it is more likely to detect an effect should one exist. It is possible that the discrepancy is explained by the large number of dropouts, which occurred at different rates in each arm, and the number of censored observations. Therefore, although our analysis suggests that valproate is more efficacious than placebo in preventing mood episodes, the effect is not robust to the choice of analysis, and the true efficacy of valproate therefore remains uncertain.

According to review protocol, we included non‐blind studies (Altamura 2004; BALANCE 2010). As all RCTs used an open‐label design, outcome assessment should be done very carefully to reduce the risk of performance and ascertainment biases. In BALANCE 2010, this risk was managed by restriction of randomisation to participants for whom there was no strong treatment preference on the part of the participant or the clinician and by careful verification of outcomes: All outcome events were considered by the trial management team, who were masked to treatment assignment, and in the case of any doubt, a description of the event was sent to an independent adjudication team.

We considered the all‐cause discontinuation rate as a measure of acceptability of treatment. Even though it has been employed in many other systematic reviews in the field of long‐term treatment for bipolar disorder (Cipriani 2009d; Cipriani 2010) and also for unipolar depression (Nakagawa 2009; Cipriani 2009c; Omori 2010; Watanabe 2011; Cipriani 2012), this choice might be questioned. We believe that early drug discontinuation is highly clinically relevant from a clinical point of view because it is one of the most important things the psychiatrist wants to know when starting the prescription of an effective long term treatment.

Our decision to use fixed‐effect meta‐analysis could have introduced a bias in the review process, as there was some visual indication of heterogeneity, although this was rarely statistically significant and so could simply indicate random error. Overall, we believe that the fixed‐effect average is probably the best estimate for guiding clinical practice. The two largest studies (Bowden 2000; BALANCE 2010) reported conflicting estimates, which contributed to the final heterogeneity (I² = 25%). However, this result was robust to the choice of statistical method because no material differences were noted between the random‐effects models and the fixed‐effect models.

The relative risk of serious adverse events or death between valproate and other agents or placebo was not significant; however, included trials were not powered to detect any mortality difference. Because of the low numbers of events, random error is substantial, and estimates of treatment effect are consequently unstable with wide confidence intervals. Systematic reviews of randomised controlled trials may increase statistical power, but absolute numbers of participants who have rare adverse events such as completed or attempted suicide are low (Cipriani 2005a), and a few events in one direction or another can completely change the overall outcome (Cipriani 2005b).

It is known that Axis I and Axis II psychiatric comorbidity is of clinical interest, especially for bipolar disorder and borderline personality disorder (Bassett 2012). However, evidence suggests that bipolar disorder and borderline personality disorder are most likely separate disorders and that benefits of mood stabilisers are more predictable in bipolar disorder than in borderline personality disorder (Paris 2007). Therefore, we decided to exclude studies that recruited participants with Axis II comorbidity. Even though our inclusion criteria were aimed at higher internal validity (Cipriani 2009a), our choice might have limited the external validity of review findings because In clinical practice, patient populations are usually highly heterogeneous.

We found no reports of teratogenic effects, but randomised controlled trials are not intended or designed to evaluate this very important aspect of treatment. Treatment guidelines recommend that valproate should not be routinely used in women of child‐bearing potential in primary or secondary care (Goodwin 2009). If no effective alternative treatment to valproate can be used, then the patient should be made aware of the risks of taking valproate in pregnancy, and effective contraception should be used (NICE 2006).

Agreements and disagreements with other studies or reviews

Despite the increasingly widespread use of valproate in bipolar disorder (Hayes 2011), only one systematic review about the long‐term treatment of bipolar disorder has been published in the scientific literature since the first publication of the present review in 2001. The review by Soares and colleagues was published in 2007 and included a total of seven randomised or quasi‐randomised trials that investigated the efficacy of valproate (Soares‐Weiser 2007). Three studies included in Soares‐Weiser 2007 were excluded from the present review because we specifically included only randomised trials with a relapse prevention design, which did not recruit acutely ill patients for long‐term treatment. Notwithstanding these differences in inclusion/exclusion criteria, results from these two systematic reviews are consistent overall. Valproate was found to be effective as maintenance therapy for the prevention of relapse in bipolar disorder, but it was possibly more efficacious for the prevention of depressive relapses rather than manic relapses.

Figure 1

Study flow diagram showing study selection process.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Risk of bias graph: review authors' judgements about all risk of bias items presented as percentages across all included studies.

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Figure 4

Forest plot of comparison: 1 Valproate versus placebo, outcome: 1.1 Study withdrawal due to episode of mood disorder.

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Figure 5

Forest plot of comparison: 2 Valproate versus lithium, outcome: 2.1 Study withdrawal due to episode of mood disorder.

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Figure 6

Forest plot of comparison: 5 Valproate plus lithium versus valproate alone, outcome: 5.1 Study withdrawal due to episode of mood disorder.

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Analysis 1.1

Comparison 1 Valproate versus placebo, Outcome 1 Study withdrawal due to episode of mood disorder.

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Analysis 1.2

Comparison 1 Valproate versus placebo, Outcome 2 Participant withdrawal from treatment—any cause.

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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.

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Analysis 2.1

Comparison 2 Valproate versus lithium, Outcome 1 Study withdrawal due to episode of mood disorder.

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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.

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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.

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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.

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Analysis 3.1

Comparison 3 Valproate versus olanzapine, Outcome 1 Study withdrawal due to episode of mood disorder.

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Analysis 3.2

Comparison 3 Valproate versus olanzapine, Outcome 2 Participant withdrawal from treatment—any cause.

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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.

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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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Analysis 4.5

Comparison 4 Valproate plus lithium versus lithium alone, Outcome 5 Participant withdrawal from treatment due to intolerance or non‐compliance.

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Analysis 4.6

Comparison 4 Valproate plus lithium versus lithium alone, Outcome 6 Serious adverse events.

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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 not responding at 24 months.

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Analysis 4.9

Comparison 4 Valproate plus lithium versus lithium alone, Outcome 9 DSH—number of participants with at least one episode of deliberate self‐harm.

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Analysis 4.10

Comparison 4 Valproate plus lithium versus lithium alone, Outcome 10 Death.

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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.

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Analysis 5.3

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 3 New drug treatment for mood episode.

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Analysis 5.4

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 4 Participant withdrawal from treatment—any cause.

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Analysis 5.5

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 5 Participant withdrawal from treatment due to intolerance or non‐compliance.

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Analysis 5.6

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 6 Serious adverse events.

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Analysis 5.7

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 7 GAF—number of participants not responding at 24 months.

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Analysis 5.8

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 8 Quality of life—number of participants not responding at 24 months.

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Analysis 5.9

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 9 DSH—number of participants with at least one episode of deliberate self‐harm.

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Analysis 5.10

Comparison 5 Valproate plus lithium versus valproate alone, Outcome 10 Death.

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Table 1. Adverse events

Adverse event	Study	Valproate		Comparator		Risk Ratio, Fixed [95% CI]
Adverse event	Study	Events	Total	Events	Total	Risk Ratio, Fixed [95% CI]
*Valproate vs placebo*
Acne	Kemp 2009	0	15	2	16	0.21 [0.01, 4.10]
Akathisia	Bowden 2000	1	187	1	94	0.50 [0.03, 7.95]
Blurred vision	Kemp 2009	2	15	1	16	2.13 [0.22, 21.17]
Cognitive dysfunction	Kemp 2009	2	15	2	16	1.07 [0.17, 6.64]
Diarrhoea	Bowden 2000; Kemp 2009	69	202	34	110	1.11 [0.78, 1.56]
Dry mouth	Kemp 2009	3	15	0	16	7.44 [0.42, 132.95]
Fatigue	Kemp 2009	5	15	1	16	5.33 [0.70, 40.54]
Increased appetite	Kemp 2009	0	15	2	16	0.21 [0.01, 4.10]
Infection	Bowden 2000	51	187	18	94	1.42 [0.88, 2.29]
Nausea	Bowden 2000; Kemp 2009	81	202	32	110	1.32 [0.94, 1.86]
Polydipsia	Kemp 2009	6	15	5	16	1.28 [0.49, 3.33]
Polyuria	Bowden 2000	15	187	9	94	0.84 [0.38, 1.84]
Sedation	Bowden 2000	78	187	33	94	1.19 [0.86, 1.64]
Sexual dysfunction	Kemp 2009	2	15	2	16	1.07 [0.17, 6.64]
Tachycardia	Bowden 2000	1	187	1	94	0.50 [0.03, 7.95]
Thirst	Bowden 2000	11	187	7	94	0.79 [0.32, 1.97]
Tinnitus	Bowden 2000	12	187	1	94	6.03 [0.80, 45.69]
*Valproate vs lithium*
Akathisia	Bowden 2000	1	187	4	91	0.12 [0.01, 1.07]
Alopecia	Bowden 2000; Calabrese 2005; Findling 2005	30	245	9	153	1.74 [0.85, 3.56]
Balance problems	Calabrese 2005	2	28	1	32	2.29 [0.22, 23.88]
Cognitive difficulties	Calabrese 2005	0	28	1	32	0.38 [0.02, 8.95]
Decreased appetite	Findling 2005	3	30	3	30	1.00 [0.22, 4.56]
Dry eyes	Bowden 2000	0	187	3	91	0.07 [0.00, 1.34]
Fever	Findling 2005	1	30	4	30	0.25 [0.03, 2.11]
Gastrointestinal discomfort	Calabrese 2005	2	28	5	32	0.46 [0.10, 2.17]
Haematological dyscrasia	Findling 2005	1	30	0	30	3.00 [0.13, 70.83]
Headache	Calabrese 2005; Findling 2005	11	58	4	62	2.64 [0.96, 7.24]
Nausea	Bowden 2000; Findling 2005	81	217	46	121	0.89 [0.68, 1.18]
Serious adverse events	BALANCE 2010	7	110	5	110	1.40 [0.46, 4.28]
Sore throat	Findling 2005	3	30	1	30	3.00 [0.33, 27.23]
Speech	Calabrese 2005	0	28	1	32	0.38 [0.02, 8.95]
Stomach pain	Findling 2005	7	30	3	30	2.33 [0.67, 8.18]
Tachycardia	Bowden 2000	1	187	4	91	0.12 [0.01, 1.07]
Tremor	Bowden 2000; Calabrese 2005; Findling 2005	83	245	53	153	0.86 [0.65, 1.14]
Upper respiratory congestion	Findling 2005	3	30	2	30	1.50 [0.27, 8.34]
Visual impairment	Calabrese 2005	0	28	3	32	0.16 [0.01, 3.02]
Vomiting	Findling 2005	3	30	9	30	0.33 [0.10, 1.11]
Weight gain	Bowden 2000; Calabrese 2005	41	215	13	123	1.60 [0.89, 2.85]

Table 1. Adverse events

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Comparison 1. Valproate versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Study withdrawal due to episode of mood disorder Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Any mood episode	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.49, 0.93]
1.2 Manic episode	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.48, 1.25]
1.3 Depressive episode	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.24, 0.89]
2 Participant withdrawal from treatment—any cause Show forest plot	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.71, 0.95]

3 Participant withdrawal from treatment due to intolerance or non‐compliance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4 Adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Alopecia	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	2.51 [1.15, 5.51]
4.2 Tremor	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	2.41 [1.58, 3.67]
4.3 Weight gain	2	312	Risk Ratio (M‐H, Fixed, 95% CI)	2.04 [1.07, 3.86]

Comparison 1. Valproate versus placebo

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Comparison 2. Valproate versus lithium

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Study withdrawal due to episode of mood disorder Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Any mood episode	4	618	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.87, 1.20]
1.2 Manic episode	4	618	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.90, 1.44]
1.3 Depressive episode	4	618	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.84, 1.49]
1.4 Hypomanic episode	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.18, 2.61]
1.5 Mixed state	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 8.95]
2 Number of hospital admissions Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 New drug treatment for mood episode Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Any mood episode	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Mania	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Depression	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Time to relapse (days) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Participant withdrawal from treatment—any cause Show forest plot	4	618	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.77, 0.98]

6 Participant withdrawal from treatment due to intolerance or non‐compliance Show forest plot	4	618	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.49, 0.93]

7 Adverse events Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Diarrhoea	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.55, 0.99]
7.2 Sedation	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [1.00, 2.10]
7.3 Polyuria	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.16, 0.58]
7.4 Increased thirst	2	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.15, 0.65]
7.5 Infection	1	278	Risk Ratio (M‐H, Fixed, 95% CI)	2.07 [1.16, 3.68]
7.6 Enuresis	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.05, 0.94]
8 GAF—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 Quality of life—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 DSH—number of participants with at least one episode of deliberate self‐harm Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

11 Death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 2. Valproate versus lithium

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Comparison 3. Valproate versus olanzapine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Study withdrawal due to episode of mood disorder Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Any mood episode	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Manic only	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Depressive only	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Participant withdrawal from treatment—any cause Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Participant withdrawal from treatment due to intolerance or non‐compliance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. Valproate versus olanzapine

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Comparison 4. Valproate plus lithium versus lithium alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Study withdrawal due to episode of mood disorder Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Number of hospital admissions Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 New drug treatment for mood episode Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Any mood episode	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Mania	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Depression	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Participant withdrawal from treatment—any cause Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Participant withdrawal from treatment due to intolerance or non‐compliance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Serious adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7 GAF—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Quality of life—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 DSH—number of participants with at least one episode of deliberate self‐harm Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. Valproate plus lithium versus lithium alone

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Comparison 5. Valproate plus lithium versus valproate alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Study withdrawal due to episode of mood disorder Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Number of hospital admissions Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 New drug treatment for mood episode Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Any mood episode	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Mania	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Depression	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Participant withdrawal from treatment—any cause Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Participant withdrawal from treatment due to intolerance or non‐compliance Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6 Serious adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7 GAF—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8 Quality of life—number of participants not responding at 24 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9 DSH—number of participants with at least one episode of deliberate self‐harm Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

10 Death Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. Valproate plus lithium versus valproate alone

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Cochrane Review language

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Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICOs

PICOs

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

Valproato para mantener controlados a los pacientes con trastorno bipolar, luego de episodios relacionados con el estado de ánimo

Visual summary

Authors' conclusions

Implications for practice

Implications for research

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Experimental intervention

Comparator intervention

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

CCDAN's specialised register (CCDANCTR)

International trial registries

Regulatory agencies

Searching other resources

Personal communication

Reference checking

Data collection and analysis

Selection of studies

Data extraction and management

Main comparisons

Assessment of risk of bias in included studies

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cross‐over trials

Cluster‐randomised trials

Studies with multiple treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Study design

Sample Size

Setting/participants

Interventions and comparators

Outcomes

Excluded studies

Ongoing studies

Studies awaiting classification

New studies found at this update

Risk of bias in included studies

Allocation

Blinding