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New research moves pramipexole up in the algorithm for treatment resistant depression.
Publication Date: 02/23/2026
Duration: 13 minutes, 41 seconds
Transcript:
KELLIE NEWSOME: We look at the hidden gems of psychopharmacology, starting with pramipexole. Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003.
CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.
KELLIE NEWSOME: And I'm Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
CHRIS AIKEN: In 2003, I opened a psychotherapy practice in Western North Carolina. I didn't set out to focus on treatment-resistant depression, but the problem came to my door in patient after patient, as it does for many in our field. In most towns, people get their first line psychiatric treatment, the SSRI, from primary care and only come to us if that doesn't work; and for a lot of people, it doesn't work. Somewhere between 30 and 60% of patients do not reach full recovery after two or more antidepressant trials. That 30 to 60% range comes from different interpretations of the STAR*D trial. The fact that it is such a wide range tells us something important. Defining meaningful recovery is not an exact science; these patients with treatment-resistant depression are really a varied bunch. They include older adults with vascular disease, patients with bipolar features, inflammation, insulin resistance, dysthymic temperament, childhood trauma, and chronic stress. And I learned pretty quickly in the 2000s that the algorithms we had to treat them, raise the antidepressant, switch the class, add bupropion, buspirone, or a stimulant, were not meeting their needs. This wasn't like antibiotic resistance, where they just need IV vancomycin or some other magic bullet. These depressions I was seeing were complex and needed an approach from many angles: lifestyle, nutrition, sleep, medication, psychotherapy, and sometimes neuromodulation.
KELLIE NEWSOME: The STAR*D trial has a step by step algorithm for treatment-resistant depression that reflects how psychiatry was practiced in the 1990’s. The problem is, most of the steps in that algorithm have failed in large, randomized controlled trials. John Rush, who lead the STAR*D trial, has since turned away from that approach. He proposed a new title to replace treatment-resistant depression: Difficult to Treat Depression. And that is the title Dr. Aiken took for his new book, which we’re going to read an excerpt from today. The book covers psychotherapy, lifestyle, neuromodulation, and CAM approaches like light therapy, omega-3, and probiotics, and medications: lithium, antipsychotics, thyroid, as well as novel agents that have new support from randomized controlled trials: Amantadine, minocycline, celecoxib, d-cycloserine, and pramipexole.
CHRIS AIKEN: In the past two decades, I've tried just about everything with a randomized trial in treatment-resistant depression, and pramipexole has been one of the most useful, but as I set out to write this book on difficult-to-treat depression, I hesitated. My own experience might be biased here. Pramipexole works in both unipolar and bipolar depression, and I'm a bipolar specialist. Pramipexole works better in depressed patients with high inflammation, and my practice borders on the region of the US with the highest rates of inflammatory conditions like obesity, metabolic syndrome, and vascular disease near the Appalachian Mountains. So I had reason to doubt that my own experience with this dopamine agonist would translate to the rest of the country. But as I finished the book, a new trial came out from England that forced me to bump pramipexole up from third line to second line for treatment-resistant depression.
KELLIE NEWSOME: The study was unlike any other we had seen in treatment-resistant depression. 70% of the trials that supposedly look at treatment-resistance enroll patients after just one antidepressant failure, not the two failures the definition requires. This study got it right, with an average of 3.5 antidepressant failures, and 21% had failed augmentation trials as well. It was also large, enrolling 150 patients. Dr. Aiken found that many popular strategies for treatment resistance worked in small or uncontrolled trials, but then failed to make a difference in large, placebo-controlled trials, strategies like augmenting with mirtazapine, bupropion, buspirone, or stimulants. Finally, this study tested the drug against placebo for a full year, and it held up for the entire year with a large effect size. Very few augmentation strategies have that long-term data. Lithium does, but most antipsychotics failed to make any difference in depression when they were tested against placebo for more than 3 months. So let’s get to it. Difficult to Treat Depression is available in paperback and as an audiobook, and we’re going to play the pramipexole chapter from that audio, right after the CME quiz. Earn CME through the link in the show notes.
CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.
KELLIE NEWSOME: And I'm Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
CHRIS AIKEN: In 2003, I opened a psychotherapy practice in Western North Carolina. I didn't set out to focus on treatment-resistant depression, but the problem came to my door in patient after patient, as it does for many in our field. In most towns, people get their first line psychiatric treatment, the SSRI, from primary care and only come to us if that doesn't work; and for a lot of people, it doesn't work. Somewhere between 30 and 60% of patients do not reach full recovery after two or more antidepressant trials. That 30 to 60% range comes from different interpretations of the STAR*D trial. The fact that it is such a wide range tells us something important. Defining meaningful recovery is not an exact science; these patients with treatment-resistant depression are really a varied bunch. They include older adults with vascular disease, patients with bipolar features, inflammation, insulin resistance, dysthymic temperament, childhood trauma, and chronic stress. And I learned pretty quickly in the 2000s that the algorithms we had to treat them, raise the antidepressant, switch the class, add bupropion, buspirone, or a stimulant, were not meeting their needs. This wasn't like antibiotic resistance, where they just need IV vancomycin or some other magic bullet. These depressions I was seeing were complex and needed an approach from many angles: lifestyle, nutrition, sleep, medication, psychotherapy, and sometimes neuromodulation.
KELLIE NEWSOME: The STAR*D trial has a step by step algorithm for treatment-resistant depression that reflects how psychiatry was practiced in the 1990’s. The problem is, most of the steps in that algorithm have failed in large, randomized controlled trials. John Rush, who lead the STAR*D trial, has since turned away from that approach. He proposed a new title to replace treatment-resistant depression: Difficult to Treat Depression. And that is the title Dr. Aiken took for his new book, which we’re going to read an excerpt from today. The book covers psychotherapy, lifestyle, neuromodulation, and CAM approaches like light therapy, omega-3, and probiotics, and medications: lithium, antipsychotics, thyroid, as well as novel agents that have new support from randomized controlled trials: Amantadine, minocycline, celecoxib, d-cycloserine, and pramipexole.
CHRIS AIKEN: In the past two decades, I've tried just about everything with a randomized trial in treatment-resistant depression, and pramipexole has been one of the most useful, but as I set out to write this book on difficult-to-treat depression, I hesitated. My own experience might be biased here. Pramipexole works in both unipolar and bipolar depression, and I'm a bipolar specialist. Pramipexole works better in depressed patients with high inflammation, and my practice borders on the region of the US with the highest rates of inflammatory conditions like obesity, metabolic syndrome, and vascular disease near the Appalachian Mountains. So I had reason to doubt that my own experience with this dopamine agonist would translate to the rest of the country. But as I finished the book, a new trial came out from England that forced me to bump pramipexole up from third line to second line for treatment-resistant depression.
KELLIE NEWSOME: The study was unlike any other we had seen in treatment-resistant depression. 70% of the trials that supposedly look at treatment-resistance enroll patients after just one antidepressant failure, not the two failures the definition requires. This study got it right, with an average of 3.5 antidepressant failures, and 21% had failed augmentation trials as well. It was also large, enrolling 150 patients. Dr. Aiken found that many popular strategies for treatment resistance worked in small or uncontrolled trials, but then failed to make a difference in large, placebo-controlled trials, strategies like augmenting with mirtazapine, bupropion, buspirone, or stimulants. Finally, this study tested the drug against placebo for a full year, and it held up for the entire year with a large effect size. Very few augmentation strategies have that long-term data. Lithium does, but most antipsychotics failed to make any difference in depression when they were tested against placebo for more than 3 months. So let’s get to it. Difficult to Treat Depression is available in paperback and as an audiobook, and we’re going to play the pramipexole chapter from that audio, right after the CME quiz. Earn CME through the link in the show notes.
1. Pramipexole is selective for which dopamine receptor?
A. D1
B. D2
C. D3
D. D4
CHRIS AIKEN: Pramipexole is a dopamine agonist that is highly selective for the D3 receptor. This receptor is involved in the antidepressant actions of aripiprazole, brexpiprazole, and cariprazine. Outside of those, D3 is rarely a target of psychopharmacology. In the pathophysiology of depression, however, D3 is a central player. D3 receptors are densely packed in the nucleus accumbens, the seat of motivation and reward. When these circuits are overactive, people seek out pleasure at any expense. When they are underactive, people have no motivation to do anything. They are tired, slowed down, and anhedonic. They give up easily (if they start at all), caught between the guilt of avoiding action and the drudgery of taking it on. This sounds very distressing, but "distress" is not the best choice of words for this apathetic state. Patients with anhedonia are less responsive to pleasure and pain. This numbing extends even to their experience of depression. They may tell you that everything is "OK" as their mood is worsening. They may run out of medication and neglect to call for a refill, instead waiting for their next appointment to raise the issue. Why does dopamine decline? Old age, inflammation, stimulant and cocaine misuse, and chronic stress are common causes. The key word there is chronic stress. Acute stress tends to raise dopamine, inspiring action and paradoxically improving depression. Under chronic stress, after about six months, dopamine declines and depression sets in. Evidence in Depression: This dopamine theory motivated clinical trials of pramipexole in depression. After its release for Parkinson's disease in 1997, researchers noticed improvements in mood as well as movement, something not seen with the dopamine precursor levodopa. In animal models, pramipexole reversed the passive, depressive state that sets in after chronic stress. In two small controlled studies, it treated bipolar depression better than a placebo with a large effect size (0.77-1.1). The manufacturer tested it as monotherapy in a phase II trial of major depression, where it surpassed placebo and equaled fluoxetine (Aiken CB, J Clin Psychiatry 2007;68(8):1230-1236). Psychiatrists encouraged the manufacturer to press on with phase III trials, but the impending generic release made it hard to justify the cost. Pramipexole was shelved for depression. It did earn FDA approval in restless leg syndrome (RLS), and improved mood in a large, placebo-controlled trial of patients with RLS and depressive symptoms (Montagna P et al, Sleep Med 2011;12(1):34-40). Putting aside the trials in Parkinson's disease and RLS, pramipexole's benefits in depression are supported by seven randomized controlled trials, two of which involved bipolar depression (Tundo A et al, Acta Psychiatr Scand 2019, 140(2):116-125). Pramipexole works as monotherapy and augmentation. Its benefits are large even in treatment-resistant cases (effect size 0.9). Most important, they are durable, with placebo-controlled trials showing sustained effects for up to a year (Browning M et al, Lancet Psych, June 29, 2025). Pramipexole is one of only a few pharmacologic options with evidence in patients with high degrees of treatment resistance, even if that evidence is only observational. It brought remission after failure of aripiprazole, ECT, and over six antidepressant trials (Tundo A et al, Biomedicines 2024;12(9):2064; Fawcett J et al, Am J Psychiatry. 2016;173(2):107-111). Unlike most therapies, its efficacy does not diminish as the degree of treatment resistance goes up, although patients with high degrees of resistance may require higher doses (eg, 2.5 mg instead of 1.5 mg) (Tundo A et al, Life (Basel) 2023, 13(4):1043). When to Consider Pramipexole: Pramipexole is appropriate for patients with treatment resistant depression and bipolar depression. Candidates who may particularly benefit include those with:
CHRIS AIKEN: Pramipexole is a dopamine agonist that is highly selective for the D3 receptor. This receptor is involved in the antidepressant actions of aripiprazole, brexpiprazole, and cariprazine. Outside of those, D3 is rarely a target of psychopharmacology. In the pathophysiology of depression, however, D3 is a central player. D3 receptors are densely packed in the nucleus accumbens, the seat of motivation and reward. When these circuits are overactive, people seek out pleasure at any expense. When they are underactive, people have no motivation to do anything. They are tired, slowed down, and anhedonic. They give up easily (if they start at all), caught between the guilt of avoiding action and the drudgery of taking it on. This sounds very distressing, but "distress" is not the best choice of words for this apathetic state. Patients with anhedonia are less responsive to pleasure and pain. This numbing extends even to their experience of depression. They may tell you that everything is "OK" as their mood is worsening. They may run out of medication and neglect to call for a refill, instead waiting for their next appointment to raise the issue. Why does dopamine decline? Old age, inflammation, stimulant and cocaine misuse, and chronic stress are common causes. The key word there is chronic stress. Acute stress tends to raise dopamine, inspiring action and paradoxically improving depression. Under chronic stress, after about six months, dopamine declines and depression sets in. Evidence in Depression: This dopamine theory motivated clinical trials of pramipexole in depression. After its release for Parkinson's disease in 1997, researchers noticed improvements in mood as well as movement, something not seen with the dopamine precursor levodopa. In animal models, pramipexole reversed the passive, depressive state that sets in after chronic stress. In two small controlled studies, it treated bipolar depression better than a placebo with a large effect size (0.77-1.1). The manufacturer tested it as monotherapy in a phase II trial of major depression, where it surpassed placebo and equaled fluoxetine (Aiken CB, J Clin Psychiatry 2007;68(8):1230-1236). Psychiatrists encouraged the manufacturer to press on with phase III trials, but the impending generic release made it hard to justify the cost. Pramipexole was shelved for depression. It did earn FDA approval in restless leg syndrome (RLS), and improved mood in a large, placebo-controlled trial of patients with RLS and depressive symptoms (Montagna P et al, Sleep Med 2011;12(1):34-40). Putting aside the trials in Parkinson's disease and RLS, pramipexole's benefits in depression are supported by seven randomized controlled trials, two of which involved bipolar depression (Tundo A et al, Acta Psychiatr Scand 2019, 140(2):116-125). Pramipexole works as monotherapy and augmentation. Its benefits are large even in treatment-resistant cases (effect size 0.9). Most important, they are durable, with placebo-controlled trials showing sustained effects for up to a year (Browning M et al, Lancet Psych, June 29, 2025). Pramipexole is one of only a few pharmacologic options with evidence in patients with high degrees of treatment resistance, even if that evidence is only observational. It brought remission after failure of aripiprazole, ECT, and over six antidepressant trials (Tundo A et al, Biomedicines 2024;12(9):2064; Fawcett J et al, Am J Psychiatry. 2016;173(2):107-111). Unlike most therapies, its efficacy does not diminish as the degree of treatment resistance goes up, although patients with high degrees of resistance may require higher doses (eg, 2.5 mg instead of 1.5 mg) (Tundo A et al, Life (Basel) 2023, 13(4):1043). When to Consider Pramipexole: Pramipexole is appropriate for patients with treatment resistant depression and bipolar depression. Candidates who may particularly benefit include those with:
- Marked anhedonia, amotivation, and psychomotor slowing
- High levels of treatment resistance (multiple failed medication trials or ECT)
- Inflammatory markers or conditions
- Comorbid restless leg syndrome
- Soft signs of bipolarity
- Bipolar depression (used with a mood stabilizer)
Pramipexole has no known potential for addiction or misuse. Patients who are prone to psychosis or OCD may experience worsening of those symptoms on it and are less ideal candidates. Anecdotally, I have had the most success with Pramipexole among the second and third line options in this book. Mechanism of Action: Pramipexole is a selective agonist at the dopamine receptor that regulates hedonic drive (D3) in the nucleus accumbens. There are five dopamine receptors, and pramipexole’s affinity for D3 is 7-fold higher than the others, including D2, the receptor involved in psychosis. Pramipexole belongs to a newer class of dopamine agonists, the non-ergot alkaloids. This class represents a safety advantage over the ergot alkaloids, bromocriptine and cabergoline, which cause valvular heart disease at high rates (20-25%) (Andrejak M and Tribouilloy C, Arch Cardiovasc Dis 2013, 106(5):333-339). The newer dopamine agonists appear to be free of that risk, which is caused by activation of 5-HT2B serotonergic receptors in the heart. The other non-ergot alkaloids, ropinirole and rotigotine patch, lack placebo-controlled trials in depression, but did improve mood in observational studies and trials of Parkinson's disease. Compared to pramipexole, rotigotine is slightly more selective for D3, and ropinirole is less selective.
KELLIE NEWSOME: We’ll pick up next week with the nitty-gritty on how to use pramipexole. Difficult to Treat Depression is available in paperbackor audio. Here’s what Andrew Penn, professor at UC San Francisco, had to say: “Aiken proves himself to be the premier translator of clinical psychiatry research into pragmatic and clear clinical advice for psychiatric providers. I intend on making sure all of my PMHNP students leave training with a copy, knowing it will be well used in their practice for years to come."
KELLIE NEWSOME: We’ll pick up next week with the nitty-gritty on how to use pramipexole. Difficult to Treat Depression is available in paperbackor audio. Here’s what Andrew Penn, professor at UC San Francisco, had to say: “Aiken proves himself to be the premier translator of clinical psychiatry research into pragmatic and clear clinical advice for psychiatric providers. I intend on making sure all of my PMHNP students leave training with a copy, knowing it will be well used in their practice for years to come."
