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Modafinil in the Treatment of Depression With Severe Comorbid Medical Illness

Key Words: Modafinil • Depression

TO THE EDITOR: Modafinil is a new FDA-approved anti-narcoleptic agent that is beginning to be used off label for the treatment of major depression.¹ This drug is a wakefulness-promoting agent that acts as a norepinephrine agonist in the human hypothalamus.² Its pharmacodynamic profile is quite different from other stimulating agents such as d-amphetamine or methylphenidate, both of which are global noradrenergic and dopaminergic agonists in the central nervous system and periphery.³ This profile may give modafinil a more favorable side effect profile with less resultant anxiety, hypertension, tachycardia, insomnia, and physical dependence when compared with stimulants.

Modafinil, theoretically, appears to be a good antidepressant augmentation agent, since it adds noradrenergic potential to an antidepressant combination strategy. Desipramine and bupropion have been used similarly in the past. These types of drug combinations have been used to treat resistant depressive episodes.³

Literature is scarce; currently, only one small case series (N=7) has shown improvement when modafinil was added to other antidepressant medication regimens.¹

We often use stimulant medication on the hospital inpatient psychiatric consultation and liaison service when treating depression in those patients with severe medical illness (e.g., end-organ/multisystem failure, stroke, congestive heart failure). Many of these patients are treated on intensive care units. Others have used stimulants as well to treat these comorbidly depressed patients.^4–7 This type of intervention usually requires an aggressive and quick response that is often needed to lower morbidity and mortality in these patients.

A problem with most currently available stimulant medications is their propensity to act peripherally on the cardiovascular system. Often, cardiac clearance to start stimulant medication is needed on the medical inpatient unit, since increases in blood pressure or heart rate may detrimentally worsen the patient's medical condition. Modafinil, given its different pharmacodynamic profile, may be better tolerated in this medically ill population. According to the package insert, there generally is a lack of peripheral vasopressor effect, cardiac arrhythmias, and tachycardia seen with modafinil treatment.

We report here five cases in which modafinil was used to treat depression in patients with concomitant severe medical illness because it was felt to be a safer agent. We routinely use the Hamiton Rating Scale for Depression in real time during clinical practice. Retrospective chart review allowed for assignment of Clinical Global Impression (CGI) scores as well.

All patients had received therapeutic doses of antidepressants and mood stabilizers (mirtazapine, sertraline, lithium, temazepam, gabapentin, zaleplon), but these agents failed to elicit an adequate response. As is common, a second agent was added to improve efficacy. In this case series, modafinil was used in place of a stimulant medication for augmentation purposes.

Four out of five patients experienced at least a minimal or better response as indicated by improvement in CGI or Hamilton depression scale scores. The average pretreatment Hamilton depression scale score was 22 compared with 16 posttreatment. Average improvement in Hamilton depression scale scores from baseline was 29% during an average of 33 treatment days. This drug was well tolerated except for one patient (whose lithium level was also being retitrated) who discontinued treatment because of anxiety and tremor. There were no modafinil-induced cardiovascular problems in these patients. This is in contrast to the side effects sometimes seen when typical stimulants are used in these patients.

Discussion

These patients represented a very difficult-to-treat depressed population because of the severity of overlapping medical conditions. A MEDLINE literature search revealed no similar reports or case series.

We suggest that modafinil may be a safer alternative to stimulant augmentation in those who are depressed and have other significant comorbid medical conditions. With regard to efficacy, it appears that this is a reasonable augmentation agent.

This case series is limited by its small study group size and its retrospective, nonrandomized, and uncontrolled nature. Future double-blind, placebo-controlled, randomized, prospective studies are required and may ultimately show that modafinil is a safe and effective augmentation strategy in treating depression.

REFERENCES

1. Menza MA, Kaufmann KR, Castellanos A: Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry 2000; 61:378-381[Medline]
2. McClellan KJ, Spencer CM: Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 1998; 9:311-324[CrossRef]
3. Stahl S: Essentials of Psychopharmacology: Neuroscientific Basis and Practical Applications (2nd ed). Cambridge, Cambridge University Press, 2000
4. Masand PS, Anand VS, Tanquary JF: Psychostimulant augmentation of second generation antidepressants: a case series. Depression & Anxiety 1998; 7(2):89-91
5. Masand PS, Tesar GE: Use of stimulants in the medically ill. Psychiatr Clin North Am 1996; 19:515-547[CrossRef][Medline]
6. Linet LS: Treatment of a refractory depression with a combination of fluoxetine and d-amphetamine (letter). Am J Psychiatry 1989; 146:803-804
7. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO: Methylphenidate augmentation of serotonin selective reuptake inhibitors: a case series. J Clin Psychiatry 1996; 57:72-76

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