Valproate as an Adjunct to Neuroleptic Medication for the Treatment of Acute Episodes of Mania: A Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Müller‐Oerlinghausen, B.; Retzow, A; Henn, Fritz A.; Giedke, H.; Walden, J.

doi:10.1097/00004714-200004000-00012

Cited by 150 publications

(67 citation statements)

References 22 publications

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“…Very few studies have examined co-therapy in subjects who have not already failed on mood stabilizers and none met inclusion criteria for this analysis. Interestingly, one methodologically sound study comparing sodium valproate with placebo showed advantages for the addition of an antipsychotic to sodium valproate (29). Nonetheless, perhaps the single appropriate conclusion to draw from this metaanalysis is that in the treatment of mania, methodologically flawed studies uniformly indicate that co-therapy with an antipsychotic and mood stabilizer is more effective than a mood stabilizer alone in subjects showing inadequate response to unoptimized mood stabilizer monotherapy.…”

Section: Discussionmentioning

confidence: 97%

Acute bipolar mania: a systematic review and meta‐analysis of co‐therapy vs. monotherapy

Smith¹,

Cornelius²,

Warnock

et al. 2006

Acta Psychiatr Scand

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Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy Summations• Adjunct treatment with combined antipsychotics and mood stabilizers is more efficacious than mood stabilizers alone.• Combinations of some drugs are less well tolerated than mood-stabilizer monotherapy. Considerations• All studies included subjects who had already failed to respond to mood stabilizers alone.• The quality of study methods and reporting was variable.Smith LA, Cornelius V, Warnock A, Tacchi MJ, Taylor D. Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy.

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Section: Discussionmentioning

confidence: 97%

Acute bipolar mania: a systematic review and meta‐analysis of co‐therapy vs. monotherapy

Smith¹,

Cornelius²,

Warnock

et al. 2006

Acta Psychiatr Scand

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“…Valproate is an antiepileptic, mood-stabilizing drug that at therapeutic doses Table 1 for dose schedule). Each animal is indicated in a different color; the polymorphisms with respect to the Royaux et al (27) increases the brain GABAergic tone (33) and expresses a significant acceleration of the onset of the beneficial action of antipsychotics in the treatment of schizophrenia and bipolar disorder patients with psychosis (34,35). Recently it was reported that valproate, acting as an HDAC inhibitor, induces differentiation and reduces proliferation in cancer cells (29).…”

Section: Discussionmentioning

confidence: 99%

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

Tremolizzo

Carboni

Ruzicka

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

350

249

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Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical ␥-aminobutyric acid-ergic interneurons are downregulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this downregulation. Protracted L-methionine (6.6 mmol͞kg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD 67 mRNAs in both WT and heterozygous reeler mice. This effect of L-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of L-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulse͞startle interval increased in mice receiving L-methionine. Valproic acid (2 mmol͞kg for 15 days, twice a day) reverted L-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk. S tudies of heterozygous reeler mice (HRM) have provided preliminary evidence of a relationship between reelin haploinsufficiency, the decrease of dendritic spine expression density in frontal cortex (FC) pyramidal neurons and associated neuropil hypoplasticity, the down-regulation of glutamic acid decarboxylase (GAD) 67 expression, and the decrease in ␥-aminobutyric acid (GABA) turnover (1-3). Similar neurochemical and structural abnormalities were detected in the FC of schizophrenia postmortem brains (4-9). Hence, HRM may be a model to evaluate the efficacy of novel treatments for schizophrenia by monitoring drug actions on (i) reelin and GAD 67 mRNA expression, (ii) GABA turnover, and (iii) cortical neuropil plasticity including dendritic spine expression.The HRM model several aspects of the molecular neuropathology expressed in schizophrenia, although the mechanisms operative in these pathologies may be different. In fact, demographic studies of schizophrenia inheritance in identical twins show a concordance of Ϸ50%, which supports an epigenetic model but not gene haploinsufficiency of Mendelian origin. Investigation of a putative epigenetic mechanism attending schizophrenia vulnerability may therefore be in order (10). Along this line of thinking we have hypothesiz...

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“…In the only study of its type, valproate showed additive efficacy in the treatment of acute mania when added to a FGA. 51 Far fewer studies have compared the efficacy of a combination treatment to monotherapy in the maintenance phase of bipolar disorder. The few published controlled studies are marred by small sample sizes, large dropout rates or unrepresentative tertiary care patients.…”

Section: Combination Treatmentsmentioning

confidence: 99%

Treatment-resistant bipolar disorder

2006

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Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder. With the first report of lithium's efficacy in 1949 by Cade, bipolar disorder has the longest record of treatment efficacy among the major Axis I disorders. Furthermore, after more than half a century of clinical research, multiple agents from many different pharmacological classes have shown at least some efficacy, while many other agents (albeit without a consistent database demonstrating their utility) are prescribed regularly by clinicians. Yet, despite this plethora of choices, treatment of bipolar disorder remains suboptimal from the points of view of clinicians and patients alike. Whether measured by recovery time from manic or depressive episodes or preventive efficacy of maintenance treatments, bipolar disorder is characterized by sluggish responses, inadequate responses, poor compliance and recurrences in controlled cli...

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Valproate as an Adjunct to Neuroleptic Medication for the Treatment of Acute Episodes of Mania: A Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Cited by 150 publications

References 22 publications

Acute bipolar mania: a systematic review and meta‐analysis of co‐therapy vs. monotherapy

Acute bipolar mania: a systematic review and meta‐analysis of co‐therapy vs. monotherapy

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

Treatment-resistant bipolar disorder

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