Major depressive disorder (MDD) is a highly prevalent and disabling mood disorder estimated to affect over 300 million people globally. While first-line antidepressants like selective serotonin reuptake inhibitors (SSRIs) demonstrate efficacy in acute treatment, almost 30-40% patients show partial or non-response even after adequate therapeutic trials.

Among non-remitters, a sizeable proportion present with persistent lack of energy, amotivation, concentration difficulties and loss of ability to experience pleasure also termed anhedonia. This subset characterized by motivational and psychomotor deficits remains at substantially higher risk of relapse, suicide as well as impaired occupational and interpersonal functioning .

From a neurobiological perspective, dysfunction of mesocorticolimbic dopamine mediated reward processing pathways closely tied to the ventral striatum seems relevant to the pathophysiology of depressive anhedonia . Agents enhancing dopaminergic neurotransmission like psychostimulants have shown robust albeit temporary effects while small trials assessing dopamine receptor agonists as adjuncts to first-line antidepressants demonstrate more sustained benefits .

Pramipexole is an FDA approved dopamine agonist for managing Parkinson’s disease (PD) symptoms with preferential affinity for dopamine D3 auto receptors highly expressed in mesolimbic areas. 

Despite mood alleviation with first-line antidepressants in majority MDD patients, almost 30-40% show non-response, particularly those exhibiting amotivation, fatigue and anhedonia pointing to dysregulation of neurobiological underpinnings of reward processing pathways. Dopamine agonists like pramipexole enhancing mesolimbic dopaminergic tone hold promise but lack systematic trial evidence.

Our proposed trial aims to evaluate its antidepressant augmentation efficacy along with safety and dose-response characteristics in SSRI depressed patients exhibiting persistent amotivation and anhedonia.

Objectives: 

Primary objective:

To assess efficacy of pramipexole versus placebo augmentation of SSRI antidepressants for MDD patients with persistent amotivation and anhedonia

Secondary objective: 

To evaluate effects on fatigue, psychomotor symptoms and concentration/decision making difficulties

To assess safety and tolerability of pramipexole adjuvant therapy