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

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

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


Objective: Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials. Methods: Very challenging patients received open-label treatment with atypical antipsychotics concurrently augmented with valproic acid. The primary outcome was the newly developed Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz). Patients improving more than 20 points were classified as responders. Results: Mean age and illness duration of 28 participants (22male) were 42 y.o. and 20 years, respectively. They had spent a half of their life admitted after the onset. The average Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) were very severe at 79 and 6.1, respectively, with the baseline Global Assessment of Functioning (GAF) of as low as 21. As a result of augmentation, there were nine responders, 12 partial responders, and seven non-responders including only two patients who got worse. The main antipsychotics were mostly either risperidone or olanzapine. Mean maximum oral dose and blood level of valproic acid were 1907 mg and 91.7μg/ml, respectively. Overall significant improvements whilst to an inadequate degree were noted in clinical parameters. Valproate augmentation was generally well tolerated but serious adverse effects included thrombocytopenia, anaemia and sedation/falls. Conclusions: While these preliminary results need to be tested against tenacious monotherapy or polypharmacy involving clozapine, augmenting atypical antipsychotics with valproic acid can be useful for very severe schizophrenia.

Original languageEnglish
Pages (from-to)628-638
Number of pages11
JournalHuman Psychopharmacology
Issue number8
Publication statusPublished - 2009


  • Atypical antipsychotics
  • Augmentation
  • Schizophrenia
  • Valproic acid

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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