Dopaminergic and stimulant augmentation  Dopamine has received less attention than either serotonin or noradrenaline as a factor in the pathogenesis and treatment of depression, although preclinical and clinical evidence indicates that dopamine may have a role in the development of depression (Kapur and Mann 1992). Furthermore, stimulants and dopaminergic agents may be useful antidepressants either alone or as adjuncts for some depressed patients.

Dopaminergic agents  Bromocriptine, piribedil, amantadine, and pramipexole are dopamine agonists used to treat Parkinson’s disease. Four open trials on the antidepressant efficacy of bromocriptine showed that 57% of a mixed group of 56 mostly treatment-resistant depressed patients responded. Three double-blind trials (total N = 125), reviewed by B. G. Wells and Marken (1989), showed bromocriptine to be as effective as either imipramine or amitriptyline (Bouras and Bridges 1982; Theohar et al. 1982; Waehrens and Gerlach 1981). In addition, piribedil, which functions as a postsynaptic dopamine agonist at high doses, was found to be clinically effective in 36% of a group of unipolar and bipolar II depressed inpatients (N = 11) (Post et al. 1978). No studies are available on the antidepressant efficacy of amantadine.

Pergolide, a dopamine agonist 20-30 times more potent than bromocriptine, was found to be an effective adjunct in 55% (N = 20) of depressed patients (4 bipolar, 16 unipolar) who had not responded to either fluoxetine, TCAs, MAOIs, or trazodone (Bouckoms and Mangini 1993). Adverse drug reactions included nausea, dizziness, anxiety, and mania. Although clinicians are known to employ dopamine agonists such as bromocriptine, amantadine, and piribedil as adjuncts to antidepressants, no controlled studies address the question of efficacy.

Pramipexole is a dopaminergic agonist of the dopamine type 2 (D₂) subfamily of receptors but with preferential binding to dopamine type 3 (D₃) receptor subtypes (Piercey et al. 1996). Pramipexole (1.75-9.0 mg/day) was used as a primary antidepressant in an open study of 26 inpatients (Szegedi et al. 1997). Mean 17-item HAM-D scores went from 23.1 at baseline to only 16.0 after 28 days. Six (23%) were considered responders (50% reduction in baseline 17-question HAM-D score). The most common side effects were nausea, agitation, headache, and insomnia. Studies have yet to be published on the use of pramipexole as an antidepressant augmentation. Two cases of refractory bipolar depression that responded to pramipexole 0.75-1.0 mg were also reported (J. F. Goldberg et al. 1999). One retrospective study (Sporn et al. 2000) suggested the efficacy of this augmentation strategy by observing response in 8 (40%) of 20 unipolar patients.

Stimulants  Although in populations of patents with a history of substance abuse, amphetamine, methylphenidate, and pemoline have potential for abuse, these agents have been taken responsibly in stable doses for up to 20 years by depressed patients who experienced initial benefit (Chiarello and Cole 1987). With respect to the use of stimulants as antidepressant adjuncts, controlled trials are lacking. Case reports and series suggest that stimulants are effective when given to patients who do not respond to, but continue to take, fluoxetine (Linet 1989; Metz and Shader 1991), MAOIs alone, or MAOIs in combination with TCAs (Fawcett et al. 1991; Feighner et al. 1985). Two groups reported experience with d-amphetamine (dosage range = 5-40 mg/day), methylphenidate (dose range = 10-15 mg/day), and pemoline (dosage range = 18.75-112.5 mg/day) as adjuncts for a total of 45 severely treatment-resistant patients (Fawcett et al. 1991; Feighner et al. 1985). These groups reported that 8 of 14 (57%) responded to d-amphetamine, 3 of 5 (60%) responded to methylphenidate, and 13 of 26 (50%) responded to pemoline when these agents were added to failed aggressive trials of MAOIs alone and in combination with other psychotropic classes of medications. Of 32 patients in one group, 25 (78%) were considered to have a good response (Clinical Global Impressions Scale score of 2 or less), but only 10 (31%) maintained their improvement (Fawcett et al. 1991). Adverse events that led to discontinuation of pemoline included impotence, orthostatic hypotension, elevated blood pressure, and shakiness. Pemoline was also associated with reports of fatigue, unsteady gait, and weight gain, which were not severe enough to lead to discontinuation. Memory problems, parkinsonian symptoms, and weight gain were among the side effects leading to discontinuation of d-amphetamine. Six of the 32 patients (19%) developed either mania or hypomania in response to treatment with pemoline or d-amphetamine.

Pemoline (dosage range = 9.375-37.5 mg/day) was combined with fluoxetine in 21 patients with treatment-resistant depression, of whom 16 (76%) responded (Metz and Shader 1991). Adverse reactions included agitation, insomnia, anxiety, anorexia, and weight loss. One patient did not respond to robust treatment and subsequently responded to a combination of fluoxetine 60 mg/day and d-amphetamine 45 mg tid (Linet 1989).

Diagnostic issues: attention-deficit/hyperactivity disorder comorbidity  Is there a diagnostic subtype of depression that would specifically benefit from the addition of a stimulant? One possibility is depressed patients with a history of childhood and adult attention-deficit/hyperactivity disorder (ADHD) (T. Wilens, personal communication, March 1994). However, systematic treatment studies of patients with major depression and comorbid ADHD have not been conducted.

Instead, a group of depressed patients who were treated with fluoxetine were assessed for the presence of ADHD by DSM-III-R (American Psychiatric Association 1987) criteria (Alpert et al. 1996). The prevalence of probable or definite ADHD was about twice that expected in the general population. Rates of response to fluoxetine were the same for those with and without ADHD comorbidity.

Guidelines for the use of dopaminergic agents and stimulants as antidepressant adjuncts  Although the data supporting the use of dopaminergic agents and stimulants as antidepressant adjuncts are limited, clinicians have been prescribing these drugs when more conventional therapies have failed (J. O. Cole and J. Fawcett, personal communications, May 1992). Guidelines for the prescription of dopaminergic agents and stimulants are therefore based on clinical experience rather than on controlled trials.

Dose: Pergolide, bromocriptine, amantadine, and piribedil can be started in low dosages and increased to the maximum dose recommended for use in Parkinson’s disease (American Medical Association 1993). Pergolide should be started at 0.05 mg/day, with increases of 0.1-0.15 mg every 2-3 days, with a maximum of 5 mg/day in divided doses. Bromocriptine is started at 1.25 mg/day or bid and increased every 2 weeks by 1.25-mg increments up to 20 mg/day, although some patients may require up to 100 mg/day. Amantadine can be started at 25-50 mg/day (when given in syrup form) and increased up to 200 mg/day. d-Amphetamine and methylphenidate can be started at low dosages such as 2.5 mg/day and 5.0 mg/day, respectively, with gradual increases up to 60 mg/day in divided doses. Pemoline can be started at 18.75 mg/day and increased up to 112.5 mg/day. Pramipexole can be started at 0.125 mg twice a day and gradually titrated up to 5 mg/day.

Duration of treatment: In contrast to the 3-6 weeks necessary for both lithium and thyroid augmentation, the dopaminergic and stimulant agents seem to be effective within days.

Adverse drug reactions and precautions: Limited information is available to assess the risk of developing serious adverse reactions when dopaminergic agents or stimulants are combined with antidepressants. Dopaminergic agents by themselves can cause nausea, vomiting, orthostatic hypotension, and, at higher doses, confusion, delusions, hallucinations, and dyskinesias. Use of stimulants can result in nervousness, insomnia, anorexia, weight loss, restlessness, tachycardia, and psychosis. Tolerance may arise with long-term administration. Stimulants may also increase blood levels of other medications, so it may be necessary to monitor blood levels of TCAs. Extreme caution should be used when stimulants are combined with MAOIs; patients should be instructed about the risk and symptoms of a hypertensive crisis, and stimulants should be added at very low doses and increased gradually until optimum levels are reached.

Conclusion  Stimulants and dopaminergic agents may be effective as antidepressant adjuncts, but data from controlled studies are lacking. Stimulants are best avoided in patients with a history of substance abuse, particularly cocaine. Patients should be informed that there is an unlikely potential to develop tolerance with the usual antidepressant regimen but that stimulants are a controlled substance associated with risk of abuse in other populations. The duration of treatment for depressed patients who respond to dopaminergic and stimulant adjuvants remains to be determined.