Modafinil as an Adjunctive Treatment for Bipolar Depression

William V Bobo, Richard C Shelton
European Psychiatric Review, 2010;3(2):49-52
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Abstract

Bipolar depression represents a critical unmet need in our field. Traditional mood stabilisers, such as lithium and valproic acid, are less effective for the treatment of bipolar depression compared with mania, and treatment studies of lamotrigine in acute bipolar depression have yielded mixed results. Two clearly effective options for the treatment of acute bipolar depression are approved by the US Food and Drug Administration: the olanzapine/fluoxetine combination and quetiapine. However, metabolic adverse effects may limit their long-term use. Modafinil is a psychostimulant with a novel mechanism of action that is approved in the US for the treatment of excessive somnolence associated with narcolepsy, obstructive sleep apnoea syndrome, and shiftwork sleep disorder. Modafinil has shown promise as a pharmacological adjunct to lithium or valproic acid in one six-week randomised, placebo-controlled, multicentre trial of bipolar depressed patients without apparent increase in risk of mood switching. Adjunctive use of modafinil is endorsed as a second-line pharmacological option in one very recently updated clinical practice guideline for treatment of bipolar depression. However, results from replication studies are unavailable, and long-term effectiveness studies in bipolar depression are lacking. Given the limited options available for the treatment of bipolar depression, adjunctive modafinil may be considered if other approved options are exhausted or are unfeasible. Monitoring modafinil-treated bipolar patients for drug–drug interactions, mood switching, and abuse during follow-up is warranted, although preliminary evidence suggests a low propensity for these complications.
Keywords
Modafinil, bipolar disorder, bipolar depression, adjunctive therapy
Disclosure William V Bobo has received grants/research support from Cephalon, Inc. Richard C Shelton has no conflicts of interest to declare.
Received: January 09, 2010 Accepted February 26, 2010
Correspondence: William V Bobo, 1500 21st Ave South, Suite 2200, Village at Vanderbilt, Nashville, TN 37212, US. E: william.v.bobo@vanderbilt.edu

Bipolar depression represents a critical unmet need in our field. Recent research concerning the longitudinal course of bipolar disorder has consistently shown that mood problems are more chronic and persisting than was once believed, and that bipolar patients are significantly depressed for the majority of the duration of their illness.1,2 However, clinical trials for the treatment of bipolar depression are relatively few compared with those of acute mania.3 Currently, nine drugs are approved in the US for the treatment of acute mania,4,5 while only two – the fluoxetine plus olanzapine combination and quentiapine monotherapy – are approved for use in acute bipolar depression (see Table 1).6Long-term use of these agents is limited by their well-known adverse effects on bodyweight and metabolic profile.7 To date, there are few other effective options for bipolar depression. Traditional mood stabilisers, such as lithium and valproic acid, are less effective for the treatment of bipolar depression compared with mania.3 While lamotrigine is clearly effective during the maintenance-phase treatment of bipolar disorder, results of acute bipolar depression studies are mixed.8 Similarly, while some studies support the effectiveness of antidepressants,9 typically in combination with traditional mood stabilisers, the recent large-scale Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study showed that adjunctive sertraline or bupropion showed no benefit over placebo for the treatment of bipolar depression.10 These results were consistent with prior reports showing a general lack of benefit from antidepressants in bipolar depression.11 Furthermore, adjunctive use of antidepressants in bipolar patients has been associated with greater risk of polar mood switching, induction of mania, and mood-cycle acceleration, although the risk of these outcomes may be limited when antidepressants are used concomitantly with mood stabilisers.12 Safe and effective augmenting agents in bipolar depression are urgently needed.

Modafinil is a psychostimulant with a novel mechanism of action that is approved in the US for the treatment of excessive somnolence associated with narcolepsy, obstructive sleep apnoea syndrome, and shiftwork sleep disorder.13 Similarly to traditional psychomotor stimulants (e.g. dextroamphetamine, methylphenidate), pro-cognitive and mood-enhancing effects have also been demonstrated with modafinil in healthy volunteers, in patients with attention-deficit–hyperactivity disorder, and in those with unipolar depression.14 Unlike traditional psychostimulants, modafinil may achieve these effects without increased risk of drug-induced mania or abuse.15-17 In preliminary studies, modafinil has shown promise as a pharmacological adjunct to mood stabilisers for the treatment of bipolar depression (reviewed below). At least one very recently published guideline recommends its use as a second-line option for bipolar depression as a pharmacological

Modafinil – Mechanism of Action and Pharmacological Effects
Modafinil interacts with a wide variety of neurotransmitter systems,19 but the precise mechanism of action regarding its wake-promoting and putative antidepressive effects is unknown. Modafinil inhibits dopamine and norepinephrine transporters (DAT and NET, respectively),20 leading to increased extracellular levels of dopamine (DA) and norepinephrine (NE), effects shared by some antidepressant medications.21,22 There are no established direct interactions at any specific neuroreceptor sites. That said, modafinil has been shown to increase levels of serotonin, dopamine, glutamate, orexin, and histamine in the central nervous system (CNS), and to decrease central gamma-aminobutyric acid (GABA) neurotransmission.14,23 These effects appear to occur through an indirect mechanism. The wakefulness-promoting activity of modafinil appears to depend, at least to some degree, on dopamine activation.24,25 In addition, modafinil’s activating effects on orexin and histamine pathways, and weak DA release secondary to reduced GABA transmission, have also been proposed as underlying mechanisms for the drug’s wakefulness- and vigilance-promoting effects.26–29

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