Brief report
Absence of mood switch with and tolerance to modafinil: A replication study from a large private practice

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Abstract

Background

Fatigue is a common symptom of depression, especially the bipolar type. Modafinil is a wake-promoting agent that can alleviate fatigue in depressed patients. Many stimulants used to treat fatigue carry the risk of a switch into mania or hypomania in bipolar patients as well as the risk for tolerance or abuse.

Method

A retrospective chart review was performed on all patients currently being seen in a large outpatient practice who received modafinil at some point during their treatment. Data collected included patient demographics, MiniSCID diagnoses, clinical diagnoses including history of substance abuse, and length and dosage of treatment with modafinil.

Results

Of the 191 patients who were given modafinil at some point during their treatment, 105 patients remained on it for 2 months or more and 37% of these patients were bipolar (18 BPI and 21 BPII). In addition, 86 patients were on modafinil for less than 2 months and 31% of these patients were bipolar(16% BPI and 15% BPII). No patients in any group demonstrated a switch into mania or hypomania while on modafinil. There was also no significant difference in final modafinil dosage between patients who had a positive history of chemical abuse/dependence (290 mg/day) and those who did not (258 mg/day).

Limitations

Retrospective chart review.

Conclusions

Adult affective disorder patients, whether unipolar or bipolar, can use modafinil to relieve symptoms of depression, including fatigue and sleepiness, without risking a switch in their mood or developing tolerance or abuse of this medication.

Introduction

Bipolar patients experience depression more often than mania (Judd et al., 2003). Fatigue has been reported as a possible clue for bipolarity when patients present with depression (Mitchell et al., 2001). Many stimulants or activating antidepressants used to address fatigue and depressed mood carry the risk of a switch into mania or hypomania in bipolar patients (Boerlin et al., 1998, Goldberg and Truman, 2003, Ghaemi et al., 2004).

Modafinil is a wake-promoting agent that is used to treat many conditions associated with fatigue, including depression (DeBattista et al., 2001, Nasr, 2004). Modafinil's mechanism of action is possibly mediated through the histamine receptors in the anterior hypothalamus without affecting the dopamine pathways associated with dependence and reward usually targeted by the stimulants (Lin et al., 1996). Modafinil, therefore, may be associated with a lower risk of mood switching in depressed patients.

Substance abuse is an additional contributing factor to mood switching. It is frequently comorbid with affective disorders raising additional concern for abuse of stimulants by bipolar patients. Modafinil is a class IV drug with the potential for risk of tolerance or abuse. However in previous studies of modafinil for depression augmentation, there were no reports of modafinil-induced mania in participants except for 4 single case reports of modafinil-induced recurrence of psychosis (Menza et al., 2000, DeBattista et al., 2001, Carlson et al., 2004, Nasr, 2004, Fava et al., 2005, Vorspan et al., 2005). There is also lack of evidence for its abuse potential even among cocaine dependent individuals (Warot et al., 1993).

The following study examines modafinil's effect on mood switching, dose stability, and abuse liability in a large series of affective disorder outpatients.

Section snippets

Method

A retrospective chart review was performed on all patients currently being seen in a private, rural, outpatient psychiatric office who received modafinil at some point during their treatment, usually as an adjunct to other medications. Data collected included patient demographics, MiniSCID diagnoses, clinical diagnoses including history of substance abuse, length and dosage of modafinil treatment, and concomitant use of mood stabilizers. Patients were monitored for manic or hypomanic symptoms

Results

Of approximately 1500 patient charts reviewed, 191 patients were given modafinil at some point during their treatment. There were 134 female patients, and 57 male patients. Over 95% of patients were Caucasian. The average age of all patients given modafinil was 49.3 (± 12.5, range: 20–82); 48.6 (± 13.4) for patients who quit within 2 months, and 49.8 (± 12.0) for patients who remained on at least 2 months. 31 patients had a clinical diagnosis of Bipolar I, 33 patients had a clinical diagnosis of

Discussion

The present findings indicated that modafinil did not induce manic/hypomanic switches or either tolerance or abuse in either unipolar or bipolar patients whether or not they had a positive history of chemical abuse/dependence.

Zis and Goodwin (1979) reported that cycle frequency increases with advancing age. This puts patients in this study at higher risk for mood switching yet 45 patients observed for 2 or more years did not show any mood cycling on modafinil (Zis and Goodwin, 1979).

Several

Conclusions

Modafinil can play an important role in the treatment of treatment-resistant depression and bipolar depression. This study demonstrates that adult affective disorder patients, whether unipolar or bipolar, can use modafinil to relieve symptoms of depression, including fatigue and sleepiness, without risking a switch in their mood or risk developing tolerance of this medication.

References (23)

  • C.A. Soutullo et al.

    Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment

    J. Affect. Disord.

    (2002)
  • H.L. Boerlin et al.

    Bipolar depression and antidepressant-induced mania: a naturalistic study

    J. Clin. Psychiatry

    (1998)
  • R.C. Bransfield

    Potential uses of modafinil in psychiatric disorders

    J. Appl. Res.

    (2004)
  • P.J. Carlson et al.

    Adjunctive stimulant use in patients with bipolar disorder: treatment of residual depression and sedation

    Bipolar Disord.

    (2004)
  • C. DeBattista et al.

    Modafinil as adjunctive in treatment of fatigue and hypersomnia in major depression

  • K. Doghramji et al.

    Adjunct modafinil for fatigue and wakefulness in MDD

  • R.S. El-Mallakh

    An open study of methylphenidate in bipolar depression

    Bipolar Disord.

    (2000)
  • M. Fava et al.

    A multicenter placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness

    J. Clin. Psychiatry

    (2005)
  • J. Fawcett et al.

    CNS stimulant potentiation of monomine oxidase inhibitors in treatment-refractory depression

    J. Clin. Psychopharmacol.

    (1991)
  • J.P. Feighner et al.

    Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression

    J. Clin. Psychiatry

    (1985)
  • S.N. Ghaemi et al.

    Antidepressant treatment in bipolar versus unipolar depression

    Am. J. Psychiatry

    (2004)
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