Valproate for Catatonia: Need for Caution in Patients on SSRIs and Antipsychotics

SIR: I read with interest the report by Krüger and Bräunig¹ of successful intravenous valproic acid monotherapy in severe catatonic schizophrenia. This treatment may constitute an important addition to the therapeutic armamentarium for catatonia.

I would only wish to remind the readership that at present, it may be wise to select patients for this treatment who are free of selective serotonin reuptake inhibitors (SSRIs) and antipsychotics.

I previously reported the case of a patient with schizoaffective disorder receiving sertraline and risperidone wherein the addition of valproate resulted in seemingly paradoxical catatonia.² A review of the literature in that article suggested a nonparadoxical explanation. Aside from the capacity of antipsychotics such as risperidone to precipitate catatonia, valproate appears to be a less effective gamma-aminobutyric acid A (GABA_A) agonist than alprazolam,³ and its effect at GABA_A may be further reduced in a parkinsonian context⁴ fostered by risperidone and valproate.⁵ Resulting predominant GABA_B stimulation is associated with catatonia in mice,⁶ an effect that is enhanced by serotonin 5HT_1A receptor stimulation⁶ inducible by sertraline, perhaps compounded by 5HT₂ blockade engendered by risperidone. 5HT_1A stimulation may also be involved in catatonia observed in the serotonin syndrome.⁷ Thus, the pro-catatonigenic influences of GABA_B and 5HT_1A stimulation as well as dopamine D₂ and 5HT₂ blockade may have led to catatonia with this specific pharmacological combination.

Consequently, until further data are available, it may be wise at this time to avoid valproate administration in patients simultaneously on SSRIs and antipsychotics, perhaps especially the atypical antipsychotics.