Conclusion

While modafinil decreased the fatiguing side effects of clozapine, it also resulted in a 40-lb weight loss over 1 year and a 50-lb weight loss over 3 years. Additionally, following discontinuation of modafinil, significant weight gain was observed over several months. Upon reinstitution, weight loss again occurred in this patient. As there are few successful interventions for weight gain associated with atypical antipsychotic agents, the addition of modafinil to clozapine may be helpful in some patients. The potential mechanism of modafinil-associated weight loss in a clozapine-treated patient is unknown, but may be related to increased activity [17]. This may include non-aerobic activity such as activities of daily living, fidgeting, and posture movement.

Mr. B. noted a significant improvement in his fatigue and sedation while tolerating the combination of clozapine and modafinil. No worsening of psychotic or manic symptoms was observed. There are two cases reported in the literature of modafinil added to clozapine that resulted in an increase in psychotic symptoms [18],[19], possibly due to a decrease in clozapine blood levels. Modafinil may induce P450 1A and 3A4 isoenzymes, both important in the metabolism of clozapine. However, this was not evident in Mr. B.’s case as he experienced an improvement in fatigue and sedation, and without an exacerbation of psychotic symptoms from modafinil.

Antipsychotic agents may not only increase appetite leading to an increase in caloric intake, but may also reduce caloric expenditure by decreasing physical activity secondary to sedative and fatiguing side effects. The sedative and fatiguing effects of antipsychotic agents may contribute to reduced activity and exercise in schizophrenic patients. Weight gain and obesity in the chronically mentally-ill are contributing factors for medical disorders such as hypertension, diabetes mellitus, and cardiovascular disease. Modafinil may offer an approach to reduce or reverse weight gain and associated morbidity in antipsychotic- or psychotropic-treated patients. However, randomized placebo-controlled trials are necessary to evaluate the safety and efficacy of modafinil for clozapine-associated weight gain.