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Letters to the Editor
March 2002

Is Psychosis Exacerbated by Modafinil?

Arch Gen Psychiatry. 2002;59(3):292-293. doi:

Modafinil (Provigil; Cephalon Inc, West Chester, Pa) is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. The stimulant drug methylphenidate, which promotes wakefulness, has been reported to be useful in treating severe and persistent sedation associated with clozapine treatment.1 However, controversy has surrounded the routine use of such stimulant drugs to treat clozapine-induced sedation because of the potential risk of exacerbating psychosis (due to the drugs' dopaminergic activity) and worsening movement disorders.2 We herewith report on the possible exacerbation of psychosis by modafinil in a clozapine-treated patient with schizophrenia.

Our patient was a 61-year-old African American woman with a history of undifferentiated schizophrenia and neurolepsy-induced akathisia, who was stable with a regimen of 100 mg of clozapine administered 3 times daily by mouth and 1 mg of lorazepam twice daily by mouth. She had a history of hypertension for which she was being treated with 10 mg of amlodipine 4 times daily by mouth. She complained of severe daytime sedation that persisted for 2 months after the initiation of the clozapine trial. To treat the intractable sedation, 200 mg of modafinil (4 times daily by mouth) was added to her preexisting medication regimen. During week 3 of modafinil treatment, she visited in an agitated state with extreme disorganization of speech, paranoid delusions, and auditory hallucinations necessitating inpatient psychiatric care. The serum clozapine level determined on admission (approximately 12-16 hours after last dose) was 646 ng/mL, confirming compliance. The patient stabilized within 2 weeks after the discontinuation of modafinil, while maintaining her previous medications (clozapine, lorazepam, and amlodipine) at the same dosages. The baseline and follow-up Positive and Negative Symptom Scale (PANSS), Epworth Sleepiness Scale (ESS), and Abnormal Involuntary Movement Scale (AIMS) scores are presented in Table 1.

Patient Scores*
Patient Scores*

Modafinil has an essentially unknown mechanism of action as a sleep inhibitor and perhaps a subtle behavioral activating agent; it seems not to be directly monoaminergic, unlike traditional stimulants. It has been hypothesized that modafinil might promote wakefulness indirectly by inhibiting the release of γ-aminobutyric acid (GABA) in the forebrain, perhaps through a serotonin-mediated process.3 The N-methyl-D-aspartate (NMDA) glutamate receptor hypofunction hypothesis of schizophrenia proposes that a hypofunctional NMDA receptor system causes loss of GABAergic inhibition, which in turn leads to a loss of inhibition over the excitatory pathways (cholinergic and glutamatergic) that convergently innervate vulnerable cerebrocortical neurons involved in psychotic symptom formation.4 It is plausible that modafinil, via its inhibition of GABA release, aggravated the already depressed level of GABAergic inhibition in our schizophrenic patient, leading to an acute exacerbation of psychosis. At least theoretically, it is possible that modafinil tipped the balance in favor of psychosis. The patient's psychosis may have been stabilized by clozapine through its potential to enhance the release of GABA via its 5-HT2 antagonism5; and lorazepam, by its enhancement of activity at the GABA receptors.6 One must keep in mind that the fundamental underpinnings behind this hypothesis are speculative and that these findings need to be replicated at the clinical and basic science levels before researchers can draw any firm conclusions. Nevertheless, this case report suggests that this new, centrally acting agent modafinil may not be any safer than stimulants in patients with schizophrenia. It also suggests the need for further research into the basic pharmacological mechanism of modafinil and its utility as a possible indirect probe to study the NMDA receptor hypofunction hypothesis in schizophrenia.

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