Modafinil and In this column, Dr Andrade offers

practical knowledge, ideas, and tips in

Armodafinil in Schizophrenia psychopharmacology to JCP readers in
psychiatric and general medical settings.
Chittaranjan Andrade, MD

■■ Schizophrenia patients may sometimes require modafinil or armodafinil for

approved or off-label indications.
■■ Modafinil and armodafinil induce certain CYP enzymes and thereby reduce
levels of antipsychotics that are metabolized by these enzymes.
■■ The effects of reduced antipsychotic potency associated with the reduced
antipsychotic levels may not appear until long after the onset of the
pharmacokinetic changes induced by modafinil or armodafinil.

Clinical Problem
Mr P is an obese 52-year-old man with a 20-year history of schizophrenia.
He has recently been diagnosed with obstructive sleep apnea and experiences
excessive daytime drowsiness as a prominent symptom. His physician wishes to
treat him with modafinil or armodafinil to increase alertness during his waking
Department of Psychopharmacology,
hours. What might be the benefits and risks of such an action?
National Institute of Mental Health
and Neurosciences, Bangalore, India
What Might Be the Positive Spin-Offs (candrade@psychiatrist.com).
Associated With Modafinil or Armodafinil Use in This Patient? J Clin Psychiatry 2012;73(8):e1062–e1064
Racemic modafinil and its R-isomer armodafinil are approved treatments (doi:10.4088/JCP.12f07977)
© Copyright 2012 Physicians Postgraduate Press, Inc.
for the excessive daytime drowsiness associated with narcolepsy, shift work, and
obstructive sleep apnea1; therefore, either of these drugs could benefit Mr P.
In schizophrenia, modafinil and armodafinil have been prescribed,
studied, or suggested for off-label indications such as antipsychotic-induced
drowsiness,2–4 antipsychotic-related weight gain,5,6 negative symptoms,3,4,7,8 and
cognitive impairment.3,4,7,9,10 Favorable results for these off-label indications
have mostly been described in anecdotal reports; with a few exceptions, the
randomized controlled trials have generally found no advantage for these drugs
over placebo.
In summary, modafinil and armodafinil could be expected to improve
daytime alertness in Mr P, but, realistically, cognitive and negative symptoms
could improve only to the extent that they were worsened specifically by the
daytime drowsiness.

What Might Be the Risks Associated With

Modafinil or Armodafinil Use in This Patient?
Most antipsychotic drugs are metabolized by the cytochrome P450
(CYP) enzymes 1A2, 2D6, and 3A4. Modafinil induces CYP1A2 and 3A4.11
Armodafinil does not induce CYP1A2 but is a moderate inducer of CYP3A4.12
Thus, modafinil and armodafinil could reduce the blood levels and hence the
efficacy of antipsychotics that are metabolized by the induced enzymes.
Antipsychotic substrates of CYP1A2 include olanzapine, clozapine,
and asenapine. Antipsychotic substrates of CYP3A4 include quetiapine,
ziprasidone, sertindole, iloperidone, aripiprazole, and lurasidone and, to a
lesser extent, clozapine, asenapine, and risperidone, as well.13–18 There are few
pharmacokinetic data examining specific interactions between modafinil or
armodafinil and antipsychotic drugs. As an example, a 5-week study19 found
that armodafinil reduced the maximum concentration of quetiapine by 45% and

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 the area under the curve by 42%. However, this reduction What Are the Treatment Options for This Patient?
was not associated with an increase in positive or negative Given that the patient requires modafinil or armodafinil,
symptom ratings across 5 weeks of drug use. treatment would depend on whether the antipsychotic
that the patient is currently receiving is metabolized by
Are the Predicted Interactions CYP1A2 or 3A4 and, if it is a substrate of either or both of
Likely to Be Clinically Significant? these enzymes, whether the clinician prefers to continue the
Yes. For example, armodafinil reduced key pharmacokinetic same antipsychotic or switch medications. There are several
parameters for quetiapine by 40%–45%19; this is a substantial possibilities:
effect and could be expected to increase the risk of relapse in
a stable patient. Nevertheless, in a review of 6 clinical trials, •• Prefer armodafinil over modafinil. Armodafinil
Saavedra-Velez et al3 observed that psychosis exacerbation does not induce CYP1A212 and can be prescribed
was recorded in only 5 (6.0%) of 83 patients receiving to patients who receive 1A2 substrates such as
modafinil relative to 2 (2.9%) of 70 patients receiving placebo; olanzapine.
this difference did not reach statistical significance. Also, •• Switch to an antipsychotic drug that is not
recent placebo-controlled clinical trials3,4,7–10 of modafinil metabolized or minimally metabolized by the liver,
or armodafinil in schizophrenia did not find an increase in such as paliperidone, sulpiride, levosulpiride, and
psychopathology associated with active treatment. amisulpride.20
What might be the explanation for the apparent lack of •• Switch to an antipsychotic drug that is metabolized
risk? There are many possibilities. First, some trials recruited through pathways that do not appreciably involve
only patients who were receiving olanzapine, risperidone, CYP1A2 and 3A4. These drugs include risperidone14
or paliperidone, that is, antipsychotics that are not (or are and, to the extent that the topic has been studied,
minimally) metabolized by the study drug, armodafinil. many of the first-generation antipsychotics, as well.21
Next, all trials were short-term studies; for dose reduction •• Raise the dose of the current antipsychotic drug, if it
to be associated with a detectably increased risk of relapse, a is a substrate of CYP1A2 or 3A4. The difficulty lies
reasonable estimate is that at least 3–6 months of treatment in knowing how high to raise the dose. If facilities
is necessary. Finally, all studies were conducted with for therapeutic drug level monitoring are available,
small samples; none was adequately powered to identify a the dose could be increased until active moiety
significant risk of relapse. Therefore, there is no reassurance (parent antipsychotic and active metabolite) levels
to be obtained from the failure of existing trials to identify approximate those that antedated the introduction
a risk. of modafinil or armodafinil. Otherwise, the clinician
would need to be guided by a mixture of judgment,
Is There an Important Message Here? prudence, and luck, bounded by the patient’s
Yes. Clinicians generally expect pharmacokinetic tolerance of the higher dose.
interactions to manifest within days to a few weeks of the
introduction of a new drug. Given that many schizophrenia References
patients may not relapse until several months after
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