Pramipexole augmentation helps in treatment-resistant depression, but side effects noted

Augmenting antidepressants with pramipexole substantially improves treatment-resistant depression, although it comes with some adverse effects, according to the results of a randomized controlled trial.

Compared with placebo, pramipexole yielded a significant reduction in the primary outcome of total score on the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR₁₆) at week 12 (–6.4 vs –2.4; mean difference, −3.91, 95 percent confidence interval [CI], −5.37 to −2.45; p<0.0001). [Lancet Psychiatry 2025;doi:10.1016/S2215-0366(25)00194-4]

The QIDS-SR₁₆ response rate at week 12 was 44.1 percent in the pramipexole group and 16.4 percent in the placebo group (relative risk [RR], 2.72, 95 percent CI, 1.49–4.95; p=0.0011), with remission occurring in 27.9 percent and 7.5 percent of participants in the respective groups (RR, 3.94, 95 percent CI, 1.61–9.64; p=0.0026).

Results for other outcomes at week 12 also favoured the pramipexole group. These included total scores on the Quick Inventory of Depressive Symptoms (mean change, –6.1 vs –3.0; p<0.0001), the Snaith Hamilton Pleasure Scale (mean change, –3.8 vs –1.5; p=0.0003), and the General Anxiety Disorder-7 scale (mean change, –4.1 vs –1.5; p=0.0007). The mean dose of pramipexole received at week 12 was 2.3 mg.

By the end of treatment at week 48, the reduction in QIDS-SR₁₆ total score was maintained in the pramipexole group (mean, –6.1). On the other hand, the placebo group showed continued improvement, with the change in scores at week 48 (mean, 4.0) being greater than that seen at week 12.

Treatment satisfaction, measured using global scores on the Treatment Satisfaction Questionnaire for Medication, was significantly higher in the pramipexole group than in the placebo group (mean difference, 26.41, 95 percent CI, 14.94–37.88; p<0.0001).

“The results of this study have shown that pramipexole can be a useful adjunctive medication in patients with major depressive disorder whose episodes of illness are characterized by long duration and lack of response to conventional treatments,” the investigators said.

“Relative to placebo, the standardized antidepressant effect size of pramipexole in this study compares favourably with those estimated by meta-analyses for other commonly used augmentation treatments in treatment-resistant depression, [such as] atypical antipsychotics or esketamine,” they added. [Int J Neuropsychopharmacol 2015;18:pyv060; J Clin Psychiatry 2020;81:19r12889; JAMA Netw Open 2021;4:e2125531]

Tolerability issues

However, the investigators also acknowledged that tolerability is an important concern in the prescription of pramipexole.

Safety data from the present study showed that a higher number of participants in the pramipexole group than in the placebo group discontinued treatment due to adverse events (AEs) (20 percent vs 5 percent). The most common AEs reported in the pramipexole group were consistent with its known side effects and included nausea, headache, and sleep disturbance or somnolence.

With respect to AEs of special interest, impulse control disorder occurred in two participants in the pramipexole group, which remitted after lowering the dose of the drug. One patient had substance-induced psychotic symptoms, an event that involved steroid treatment.

Serious adverse events occurred in 5 percent of participants in the pramipexole group and in 3 percent in the placebo group, none of which were deemed related to treatment.

“Pramipexole's well-characterized adverse effect profile was generally similar to that reported in patients with Parkinson’s disease and led to 20 percent of participants discontinuing the medication. This equates to a number-needed-to-harm (ie, the number of patients treated for one extra person to stop the medication due to side-effects across 48 weeks of treatment) of 7,” the investigators said.

“The most problematic adverse effects of pramipexole are behavioural, particularly impulse control disorders such as pathological gambling and compulsive shopping, which occur in about 15 percent of people receiving dopamine receptor agonist treatment for Parkinson's disease. The current data suggest that the prevalence of impulse control difficulties might be less in patients with depression receiving pramipexole (about 3 percent), as previously reported in observational work,” they added. [Neurology 2006;67:1254-1257; Prog Neuropsychopharmacol Biol Psychiatry 2022;112:110425]

Taken together, the findings of the study underscore the potential of pramipexole, along with other dopaminergic agents, as a clinically useful treatment option for patients with depression who have not responded to initial treatments, particularly if strategies to improve tolerability are implemented, according to the investigators.

The study included 15 adults (mean age 44.9 years, 56 percent female, mean BMI 30.2 kg/m²) who met diagnostic criteria for moderate, severe, or very severe depression; were currently taking an antidepressant medication that they were willing to continue; and had no response to at least two pharmacological antidepressant regimens, each administered for a minimum of 4 weeks.

The participants were randomly assigned to receive pramipexole at a target dose of 2.5 mg (n=75) or placebo (n=75) daily for 48 weeks. Pramipexole was given at a starting dose of 0.25 mg, which was then increased every 3 days over 4 weeks until the target dose was reached. If side effects occurred, the dose could be lowered to the highest tolerated amount.