Augmentation of atypical antipsychotics with valproic acid. An open‐label study for most difficult patients with schizophrenia

Suzuki, Takefumi; Uchida, Hiroyuki; Takeuchi, Hiroyoshi; Nakajima, Shinichiro; Nomura, Kazuhiro; Tanabe, Akira; Yagi, Gohei; Watanabe, Koichiro; Kashima, Haruo

doi:10.1002/hup.1073

Cited by 53 publications

(29 citation statements)

References 44 publications

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“…HDAC inhibitors are also discussed as novel targets to treat schizophrenia (15)(16)(17). In fact, valproate given in combination with atypical antipsychotics shows beneficial effects in preclinical (18) and clinical (19) studies. These data have to be interpreted with care, however, because besides its action on HDACs, valproate affects many other cellular processes (20).…”

Section: Hdac1 Links Early Life Stress To Schizophrenialike Phenotypesmentioning

confidence: 99%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

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

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Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

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Section: Hdac1 Links Early Life Stress To Schizophrenialike Phenotypesmentioning

confidence: 99%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

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

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“…In addition, preclinical and clinical studies have found that VPA, a class I HDAC inhibitor, can augment the therapeutic effects of antipsychotics (Guidotti et al, 2009;Suzuki et al, 2009). To evaluate whether VPA can also restore the behavioral effects of HAL in aged mice, we used the CAR test and found that pretreatment with VPA restored the ability of HAL to suppress the avoidance response in aged mice and in a manner that was probably associated with the modulation of histone acetylation.…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

Montalvo-Ortiz

Keegan

Gallardo

et al. 2013

Neuropsychopharmacol

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Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL þ VPA and HAL þ MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.

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“…In addition to symptomatic perspectives, we believe that a 10-point change in global functioning represents a clinically pertinent one. 2 Patients in this study were fairly well controlled at baseline: their mean PANSS total score was less than 40, with good functioning as represented by a mean GAF score in the 70s. In this context, irreversibility of worsening in the intermittent treatment group is a concern.…”

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confidence: 67%