Treatment-Resistant Unipolar Depression Treatment - Dopaminergic and stimulant augmentation

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.