Fischer and Weiner reported a case in which clozapine levels were lowered by modafinil [Fischer and Weiner, 2008]. DeQuardo poses the inhibition by modafinil of hepatic metabolism involving isoenzyme cytochrome

P450 2C19 activity [Robertson et al. 2000] is involved [DeQuardo, 2002]. Since clozapine is metabolized partially by isoenzyme cytochrome P450 2C19 [Baldessarini and Frankenburg, 1991], the lowering of clozapine levels after adding modafinil, Inhibitors,research,lifescience,medical as reported by Fischer and Weiner, can be explained by modafinil induction of hepatic metabolization by isoenzyme cytochrome P450 1A2 [Robertson et al. 2000]. Isoenzyme cytochrome P450 1A2 is also involved in the hepatic metabolism of clozapine [Pirmohamed et al. 1995]. Agitation, insomnia and dry mouth were mentioned as side effects observed after modafinil administration in the study of Sevy and PI 103 colleagues [Sevy et al. 2005]. Turner and colleagues reported no effects Inhibitors,research,lifescience,medical of modafinil on systolic blood pressure, diastolic blood pressure or heart rate [Turner et al. 2004]. Armodafinil was also generally well tolerated in both conducted RCTs. Reported side effects of armodafinil in by schizophrenia patients included diarrhoea, headache, muscle Inhibitors,research,lifescience,medical spasms, dizziness, dry mouth, insomnia, folliculitis, hostility and restlessness

[Kane et al. 2010]. In the RCT of Bobo and colleagues the auditory hallucinations of one patient in the armodafinil group worsened [Bobo et al. 2011]. Dosage Dosages of modafinil in the studies varied Inhibitors,research,lifescience,medical from 100 to 300 mg/day. The dosages usually started at 100 mg and were raised to 200 mg if modafinil was tolerated. Mean dosages reported by the RCT of Freudenreich and colleagues was 250 mg modafinil a day [Freudenreich et al. 2009], and by the RCT of Pierre and colleagues was 180 mg [Pierre et al. 2007]. Dosages of Inhibitors,research,lifescience,medical armodafinil ranged from 50 to 200 mg/day [Bobo et al. 2011; Kane et al. 2010]. Discussion Evidence for the use of modafinil and armodafinil as add-on therapy to antipsychotic drugs to alleviate fatigue, sleepiness and inactivity is inconclusive. One cohort study and one out of two

single-dose crossover RCTs in which modafinil addition was studied could demonstrate a positive effect. All five RCTs of modafinil (3 RCTs) and armodafinil (2 RCTs) addition with a longer study duration could not demonstrate a positive effect. With Ribonucleotide reductase respect to cognitive disturbances, animal models of cognitive deficits show clear improvements by modafinil. In RCTs with a study duration of 4 weeks or more, however, no positive effect could be demonstrated on cognitive functioning by modafinil or armodafinil addition. Yet, four single-dose crossover RCTs on modafinil addition show significant positive effects on executive functioning, verbal memory span, visual memory, working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition.