Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study

Abstract

Background: Hypersomnia is a cardinal symptom of seasonal affective disorder/winter depression. This open-label pilot study assessed modafinil, a novel wake-promoting agent, as treatment for seasonal affective disorder/winter depression. Methods: Total daily modafinil dose was 100 mg (all patients week 1), and 100 mg or 200 mg split dose (weeks 2–8). Efficacy assessments (weeks 1, 2, 5, and 8) included the Structured Interview Guide for the Hamilton Depression (HAM-D) Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impression of Change (CGI-C), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS). Results: Thirteen patients (11 women; mean age, 41 years) were enrolled, 12 were evaluable for efficacy (100 mg dose, five patients; 200 mg dose, seven patients), and nine completed treatment. Modafinil significantly improved winter depression as shown by reductions from baseline in mean SIGH-SAD at week 1 (P<0.01) through week 8 (P<0.001 weeks 2–8) and MADRS total scores from week 2 through week 8 (P<0.01 for all). At week 8, mean SIGH-SAD total score was 17.1 (versus 37.2 at baseline, P<0.001), and mean MADRS total score was 13.3 (versus 26.9 at baseline, P<0.01). Modafinil significantly improved overall clinical condition at all time points (P<0.001). The response rate was 67% on the SIGH-SAD (29 item), HAM-D (21 item), and MADRS, and 100% on eight atypical SIGH-SAD items. Modafinil significantly reduced fatigue (FSS) and improved wakefulness (ESS) from weeks 2 through 8 (P<0.01). Modafinil was well tolerated. Limitations: This was an open-label, single site study. Conclusions: Modafinil may be an effective and well-tolerated treatment in patients with seasonal affective disorder/winter depression.

Introduction

Seasonal affective disorder is a clinical subtype of Major Depressive Disorder or the depressive phase of Bipolar Disorder in which the onset and remission of depressive episodes recur at certain times of the year (DSM-IV; American Psychiatric Association, 1994).The prevalence rates reported for seasonal affective disorder vary widely, ranging from <1 to 9.7% (Magnusson, 2000). Seasonal affective disorder is typically manifested as winter depression, in which patients experience depressive episodes during the fall and winter, with full remission during the spring and summer. Cardinal symptoms of seasonal affective disorder include depressed mood, profound lack of energy, hypersomnia, and weight gain (Partonen and Lonnqvist, 1998, Rosenthal et al., 1984).

Patients with seasonal affective disorder experience an exacerbation of symptoms as hours of daylight decrease. This may be associated with inadequate morning light exposure, eventually leading to misalignment of the internal circadian rhythms responsible for promoting sleep and wakefulness and the habitual sleep–wake schedule. Daily bright-light treatment sessions are utilized as a first-line treatment for seasonal affective disorder (Terman and Terman, 1999). While a positive clinical response can appear within 1 week of initiation of phototherapy, this treatment has limitations associated with inconvenience and need for optimization to maintain effect. Side effects associated with bright-light treatment (>5%) include nausea, jitteriness, headache, and eye irritation (Terman and Terman, 1999).

Antidepressant therapy is an alternative treatment that affords logistical advantages over phototherapy, with apparently comparable therapeutic benefit (Ruhrmann et al., 1998). Fluoxetine, moclobemide, and reboxetine have shown efficacy in patients with winter depression (Lam et al., 1995, Partonen and Lonnqvist, 1996, Hilger et al., 2001). Although antidepressants present an effective alternative to bright light treatment, no pharmacotherapy targeting the cardinal symptoms of seasonal affective disorder has emerged as a first-line treatment.

The novel wake-promoting agent modafinil may represent an alternative to both bright light and antidepressant therapy. Based on data from animal models, modafinil is thought to work selectively through the sleep–wake centers of the brain to promote wakefulness (Scammell et al., 2000). Modafinil has been shown to significantly improve wakefulness without adversely affecting nighttime sleep in a number of clinical models, including narcolepsy (US Modafinil in Narcolepsy Multicenter Study Group, 2000), and to improve wakefulness or reduce fatigue in major depressive disorder (DeBattista et al., 2001, DeBattista et al., 2003, Menza et al., 2000).

The wake-promoting and fatigue-reducing effects of modafinil in patients with major depressive disorder and residual fatigue or sleepiness suggest that modafinil may be useful in managing the hypersomnolence, fatigue, and perhaps other atypical symptoms that characterize seasonal affective disorder. The objective of the present study was to evaluate the efficacy and safety of modafinil in patients with seasonal affective disorder/winter depression.