Bipolar Disorder

Table 1: Approved Treatments for Bipolar Disorder in the US4–6

Mania/Mixed Depression Maintenance Episodes

Lithium

Anticonvulsants

Carbamazepine (extended rel.) X Lamotrigine Valproic acid

Antipsychotics (typical)

Chlorpromazine

Antipsychotics (atypical)

Aripiprazole Asenapine Olanzapine Quetiapine Risperidone Ziprasidone

Drug combinations

Olanzapine/fluoxetine

X

Xa Xb

X X X X X X

X X X

Xc Xd

X X

cortical and hypothalamic brain activation have also been demonstrated with modafinil compared with psychostimulants.23,29

This may confer a

number of advantages related to the treatment of bipolar depression symptoms, including improvements in attention, vigilance, subjective energy, and mood state in the absence of adverse cardiovascular effects32,33 and reduced addiction liability.34,35

These effects are consistent with the known role of both DA and NE in regulating mood and cognition.36,37

Clinical Studies

Studies in Non-bipolar Subjects

modafinil resulted in significantly greater increases in positive affect as assessed by the Positive and Negative Affect Schedule (PANAS).39

Modafinil has been shown to improve subjective alertness, energy level, and mood state in a wide variety of clinical samples and in healthy volunteers. For example, in a randomized, cross-over comparison of modafinil (400mg daily) and placebo involving 12 healthy subjects,38

However, modafinil also resulted in greater increases in subjective anxiety and arousal.

X

X = indication approved by the US Food and Drug Administration (FDA). a. Valproic acid extended-release (ER) formulation is FDA-approved for both mania and mixed episodes. The conventional formulation of valproic acid is approved for mania. b. FDA- approved for mania only. c. FDA-approved as an adjunctive treatment with lithium or valproic acid. d. Risperidone long-acting injectable formulation is FDA-approved for maintenance treatment as a monotherapy and as an adjunct to lithium or valproic acid.

Here, we summarize the available data that support a potential role for modafinil in the treatment of bipolar depression.

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

While modafinil has been shown to inhibit the DAT, the effect of modafinil at this site is much weaker than that of traditional psychostimulants,20,30 leading to significant but smaller elevations in DA levels.22,31 catecholaminergic effects and more selective (rather than widespread)

Weaker

12

Studies in Bipolar Depression

An early case series of modafinil effects in bipolar depression suggested that it may reduce fatigue and promote wakefulness without increasing risk of mood switching; however, patients in this small study had remitted rather than active core depressive symptoms.48

In addition, there were

subsequent isolated reports of rapid emergence of manic and mixed mood-switching in the setting of modafinil treatment.49-52

To formally test the hypothesis that modafinil used in conjunction with mood-stabilizing medications may result in clinically significant antidepressive effects without increasing risk for manic induction, Frye et al. conducted a multicenter, randomized study of modafinil in patients with bipolar disorder, depressed phase.53 Clinical Interview for DSM-IV (SCID)54

All subjects (n=85) had Structured -confirmed diagnoses of bipolar I or II

disorder and were on stable regimens of mood stabilizers and/or atypical antipsychotic drugs—with or without concomitant antidepressants (61% in the modafinil group, 55% in the placebo group). Patients were randomly assigned to receive adjunctive modafinil (n=41, mean dose 174.2mg/day) or placebo (n=44) for six weeks. The primary end-point was change in Inventory of Depressive Symptoms-Clinician Rated (IDS) scale scores.55 There was significantly greater improvement in depressive symptoms

US PSYCHIATRY

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 adjunct to lithium or valproic acid.18

Several studies have investigated the use of modafinil both in monotherapy and as an adjunct to antidepressants for patients with unipolar depression.40-42

Preliminary studies suggested that adjunctive

modafinil can reduce residual fatigue and sleepiness in antidepressant- treated patients with major depression.43,44

Direct effects of adjunctive

modafinil on mood were subsequently examined in a randomized, placebo-controlled trial in a sample of patients with major depression who were partially responsive to selective serotonin re-uptake inhibitor (SSRI) treatment and had residual, persisting fatigue and sleepiness.45

Adjunctive

modafinil resulted in significantly greater improvement in depressive symptoms than placebo. An extension study showed that these benefits were sustained over 12 weeks of follow-up for most patients.46

However,

in another multicenter, placebo-controlled add-on study involving unipolar depressed patients who were partially responsive to SSRI treatment, adjunctive modafinil did not result in significant improvement in mood.47 Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68