PHILADELPHIA — Pramipexole (Mirapex, Boehringer Ingelheim Pharmaceuticals, Inc), which is used to treat Parkinson's disease, can significantly improve symptoms of treatment-resistant depression, provided patients can tolerate the doses needed to achieve a therapeutic effect, new research suggests.
"These were quite treatment-refractory patients who did remarkably better on an adequately dosed dopamine agent," session co-chair Steven Hollon, PhD, Vanderbilt University, Nashville, Tennessee, told Medscape Medical News.
"The take-home message from this talk is that we should use a dopamine agent like pramipexole to deal with anhedonic treatment-refractory patients."
The findings, which were originally scheduled to be presented by study investigator Jan Fawcett, professor of psychiatry, University of New Mexico School of Medicine, Albuquerque, were instead delivered by Dr Hollon on his behalf.
The study, which was published in the February issue of the American Journal of Psychiatry, included 42 outpatients, 24 of whom had major depressive disorder; the remaining 18 had bipolar depression.
All patients had treatment-resistant depression, defined as failure to respond to at least four adequate antidepressant medical trials. The mean number of failed trials was six. Moreover, 8 of the 42 patients had failed to respond to one or more courses of electroconvulsive therapy.
"All patients began pramipexole while on other medications, because it was not known whether adding pramipexole would be helpful," the investigators note.
Dosing was initiated at 0.25 mg/day for patients younger than 45 years and was increased every 3 days in 0.25-mg increments. The initial goal was to reach a dose of 2 mg/day. The dose of pramipexole was increased if patients had not achieved remission after receiving treatment for 2 to 3 weeks.
Dosing started at 0.5 mg/day for patients older than 45 years and again was increased in increments of 0.5 mg, after which the same treatment plan was followed as for younger patients.
"For all patients, if intolerance was encountered with a dosage increase, the dosage was reduced to the prior level for 1-2 weeks and then raised again if remission was not achieved," the investigators write.
The mean dose of pramipexole for those who responded to treatment or experienced remission was 2.46 mg/day.
"Seventy-six percent responded with at least a 50% reduction in symptoms, of whom 48% remitted and were fully asymptomatic. Twenty-four percent did not respond or remit — largely because they could not tolerate the higher dose of the medication," the authors report.
Of the 32 patients who responded or experienced remission, only two patients relapsed after receiving pramipexole for an average of 15.9 months.
Importantly, seven patients who responded or underwent remission initially had to discontinue treatment for various reasons. In five of these patients, symptoms returned within 1 to 2 weeks of discontinuance; of the few who resumed pramipexole therapy, prior response or remission returned within 1 to 2 weeks after an effective dose had been reestablished.
No difference in treatment response was seen between patients with unipolar vs bipolar depression.
"Nausea was the biggest obstacle to adequate dosing," he said. To counter this side effect, the investigators advised physicians to dose only once a day at bedtime.
They also suggested that patients be given the last dose they could tolerate before developing nausea. This dose could be maintained for 1 to 2 weeks, during which time the patient becomes stable, after which dose escalation can be resumed.
Neuroleptics and antihistamines can also be used as adjunctive therapy to minimize nausea. Interestingly, older patients appear to tolerate pramipexole better than younger patients, the investigators note.
"Depressions associated with severe anhedonia, lack of motivation, inability to initiate behaviors, and unreactive mood are likely good candidates for pramipexole.... If it occurs, the expected benefit should be seen by 4 weeks at the maximally tolerated dose."
The researchers also warn against abrupt discontinuation of pramipexole, because it increases risk for dopamine agonist withdrawal syndrome, which is characterized by autonomic instability, anxiety, insomnia, fatigue, and motor symptoms.
Dr Hollon pointed out that the case series described by Dr Fawcett and colleagues is an open trial, so findings will have to be confirmed in one or more placebo-controlled trials.
Nevertheless, he characterized Dr Fawcett's data as the kind that "knock your socks off" and are a clear demonstration that treatment-resistant anhedonic patients can be successfully treated by targeting the dopaminergic system.
Pramipexole is a relatively selective dopamine D3 receptor agonist. D3 receptors are found in the mesolimbic system, which has been implicated in the motoric and hedonic deficits associated with depression.
Dr Fawcett has received speaking fees from the American Psychiatric Association and the Nevada Psychiatric Association and serves on a data review board for Amgen. He has also received remuneration as co–principal investigator of an NIMH-funded study. Dr Hollon reports no relevant financial relationships.