Background
Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, and valproate is one of these.

Objectives
To examine whether:

1. valproate alone is an effective treatment for schizophrenia and schizoaffective psychoses; and

2. valproate augmentation of antipsychotic medication is an effective treatment for the same illnesses.

Search methods
We searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials (July 2002; February 2007; July 2012; March 04, 2016). We also contacted pharmaceutical companies and authors of relevant studies in order to identify further trials.

Selection criteria
We included all randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of people with schizophrenia or schizophrenia-like psychoses.

Data collection and analysis
We independently inspected citations and, where possible, abstracts, ordered papers, and re-inspected and quality-assessed these. At least two review authors independently extracted data. We analysed dichotomous data using risk ratio (RR) and its 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table.

Main results
The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported.

For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life.

Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I2 = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I2 = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I2 = 0).

Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I2 = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I2 = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I2 = 0, low-quality evidence). No study reported on the important outcome of quality of life.

Authors' conclusions
There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.

Valproate for schizophrenia.

Although the new generation of atypical antipsychotic agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians. Fortunately, many, if not most, cases of TD are mild. For patients with mild to moderate TD, therapeutic efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neuroleptics is probably small. Patients with moderate to severe forms of TD present greater challenges. These patients frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried with limited success. No treatment strategy has emerged that is clearly superior or even successful in most patients. Increasing doses of typical neuroleptics may be useful for short-term suppression; however, the long-term efficacy and risk of this strategy have not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive effects seem, at best, weak, but patients may improve with long-term treatment. Medications with relatively few side effects that may have suppressive efficacy for some patients include calcium channel blockers, adrenergic antagonists, and vitamin E. Gamma-amino-butyric acid agonists agents and dopamine depleters are frequently useful, but have troubling side effects of their own. A variety of other medications have been employed, but are not well studied. For patients with tardive dystonia, anticholinergic agents or botulinum toxin has been particularly effective. Efforts to understand the neurobiology of TD may shed light on this persistent clinical conundrum.

Treatment of Tardive Dyskinesia

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as trea

Comprehensive review of the psychiatric uses of valproate

Neuroleptic-induced akathisia (NIA) is a relatively common side effect of neuroleptics, in which patients complain of a subjective sense of restlessness usually referable to the legs and have characteristic motor movements. This paper will review: 1) history of spontaneously occurring syndromes of pathologic restlessness and NIA, 2) the clinical significance of NIA, 3) issues concerning the diagnosis and quantification of NIA, 4) treatments of NIA and 5) possible future directions for research in this area. Special attention will be paid to newer treatments for this syndrome, specifically beta-blockers.

Neuroleptic-induced akathisia: a review.

Akathisia is a frequent and common adverse effect of treatment with antipsychotic (neuroleptic) drugs. This syndrome consists of subjective (feeling of inner restlessness and the urge to move) as well as objective components (rocking while standing or sitting, lifting feet as if marching on the spot and crossing and uncrossing the legs while sitting). Antipsychotic-induced akathisia can be classified according to the time of onset in the course of antipsychotic treatment (acute, tardive, withdrawal and chronic akathisia). Reported prevalence rates vary widely between 5 and 36.8%. Numerous risk factors for acute akathisia have been described and the exact pathophysiology of akathisia is still unknown. Since akathisia is a drug-induced adverse effect, optimal management involves its prevention rather than treatment. Standardised titration and the use of novel antipsychotics are successful measures of prevention. This paper reviews different forms of therapeutic approaches for the treatment of akathisia. Based on the available literature, propranolol or other lipophilic β-blockers seem to be the most consistently effective treatment for acute akathisia. There is nothing in the literature to guide a clinician when treatment with β-blockers fails. Addition of benzodiazepines would appear to be a sensible next choice, especially if subjective distress persists. If all of these drugs are unsuccessful, amantadine or clonidine can be tried. Other agents that have been investigated include ritanserin, piracetam, valproic acid (sodium valproate) and tricyclic antidepressants. Evidence on the treatment of tardive akathisia is unsatisfactory.

Managing antipsychotic-induced acute and chronic akathisia.

Fifteen psychiatric patients participated in a double-blind cross-over study of the effect of sodium valproate (a GABA mimetic drug), biperiden (an anticholinergic drug) and placebo in neuroleptic-induced akathisia, parkinsonism and hyperkinetic movements. All patients had subjective and objective signs of akathisia, 11 had parkinsonism and 11 hyperkinesia, eight of which were tardive dyskinesia (TD) and three initial hyperkinesia. After a pretreatment washout period of 2 weeks, during which anticholinergic drugs, if any, were replaced by placebo, the patients were treated in three randomized periods of 4 weeks with sodium vaiproate, biperiden and placebo. Compared to placebo, sodium vaiproate (900–2400 mg/day, median 1700) had no significant effect on akathisia and parkinsonism, although akathisia was reduced in four patients (unchanged in 10 and increased in one) and parkinsonism was induced or aggravated in seven patients (unchanged in five and reduced in three). Sodium valproate, however, reduced hyperkinesia score (TD + initial hyperkinesia) from 1.6 to 1.2 (P < 0.05). Biperiden (6–18 mg/day, median 12) significantly reduced akathisia score from 1.4 to 0.6 (P < 0.01) and parkinsonism from 2.0 to 0.6 (P < 0.01), and increased TD score from 2.1 to 3.9 (P < 0.05). None of the drugs induced significant side effects. It is concluded that 1) sodium valproate has no significant effect on akathisia, but a slight beneficial effect in hyperkinetic movements, both TD and initial hyperkinesia, 2) sodium valproate may aggravate parkinsonism without necessarily aggravating akathisia, and 3) anticholinergic drugs like biperiden appear still to be the best treatment for akathisia.

T. Friis

Papers

Sodium valproate and biperiden in neuroleptic-induced akathisia, parkinsonism and hyperkinesia. A double-blind cross-over study with placebo.