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Pramipexole has moved up the in our algorithm for treatment resistant depression. Today, learn how to use this dopamine agonist.
Publication Date: 03/02/2026
Duration: 19 minutes, 24 seconds
Transcript:
KELLIE NEWSOME: Treatment-resistant depression. Today, learn how to use this dopamine agonist. 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 psychiatry NP and a dedicated reader of every issue.
CHRIS AIKEN: I've spent the past year gathering every controlled trial I can find on treatment-resistant depression, and when I stepped back to look at the pile, I saw a concerning pattern. It was an inverted pyramid. The treatments that are popular at the top are the least likely to work, while the ones that have the strongest effects fall to the bottom and are very rarely used. When antidepressants don't work, people switch classes, raise the dose, or add in other antidepressants or stimulants, benzos, lamotrigine, or buspirone. If they are following practice guidelines, they'll probably augment with an antipsychotic, but those medications only work for a few months in what is usually a chronic disorder. The industry has tried to get approval for antipsychotics as long-term maintenance agents in depression, but they failed in three out of four large industry-sponsored trials that tested them for just six months, which the industry defines as long-term. By contrast, lithium worked long-term in a meta-analysis of 21 controlled trials that lasted an average of two years in unipolar, not bipolar, but unipolar depression, and psychotherapy has better long-term results than antidepressants in depression.
KELLIE NEWSOME: But how often do you see a patient with treatment-resistant depression who has tried TMS? In recent trials, TMS was more effective than pharmacologic augmentation. And how often have they tried accelerated or SAINT TMS, an accelerated 5-day protocol that brings up to 90% to full remission? How often do we see lithium, thyroid, pramipexole, MAOIs, celecoxib, light therapy, or ECT on their list of past trials?
CHRIS AIKEN: Not that often. Treatments that don't work are so common that I had to add two chapters at the end of this book on how to de-prescribe them. It's made me think that it's not the patients who are treatment resistant, but our profession that is resistant to changing what we're doing. Here's how I'd like to see practice change after writing this book. First, let's focus on treatments with long-term benefits. Sure, there's a role for rapid action, like keeping people out of the hospital in acute suicidality, but what's a two-week difference in onset in a lifelong illness? Next, let's use more neuromodulation, more lifestyle, and more psychotherapy strategies, and less irrational polypharmacy. Specifically, let's stop wasting time with medication maneuvers that do not work, like high-dose antidepressants, endless antidepressant switches, or augmenting with medications that failed to beat placebo, even in trials designed by those positioned to profit from their sale. And let's stop treating depression like a single SSRI-responsive entity and start personalizing the treatment. Common subtypes that benefit from a personalized approach include bipolar disorder, mixed features, vascular inflammation, seasonal and postpartum depression, as well as people with a complex trauma history or comorbidities. We can also personalize by addressing common deficits in depression, like deficiencies of iron, folate, probiotics, Vitamin D, omega-3, and light, as we do with a light box in seasonal affective disorder.
KELLIE NEWSOME: The research community is catching on to some of those ideas. Last year, researchers from Spain published the DEPRE-5 trial. They various pharmacologic augmentation strategies, kind of like a new version of the STAR*D trial. All of the strategies worked equally well – adding lithium, or a tricyclic, or psychotherapy – which didn’t surprise us – but what is new is they used “raising the dose” as the placebo group, convinced by earlier trials that it wouldn’t work. And it didn’t, so you can cross that one off your list – raising fluoxetine from 20 mg to 40 mg is not likely to get anyone better, at least not with treatment-resistant depression. In 2024, another group, from the Netherlands, launched a randomized trial that was designed to challenge the Dutch Treatment guidelines for depression, which give little attention to TMS. They randomized 89 patients with treatment-resistant depression to either follow the Dutch guidelines or go straight to TMS after two failed trials. The guidelines recommend switching to a tricyclic or augmenting with lithium or an antipsychotic at that step, but the trial arrived at a different conclusion: TMS worked better, with a large effect size of 0.77. That finding was replicated by a larger trial comparing TMS to aripiprazole augmentation.
CHRIS AIKEN: I'm Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report.
KELLIE NEWSOME: And I'm Kellie Newsome, a psychiatry NP and a dedicated reader of every issue.
CHRIS AIKEN: I've spent the past year gathering every controlled trial I can find on treatment-resistant depression, and when I stepped back to look at the pile, I saw a concerning pattern. It was an inverted pyramid. The treatments that are popular at the top are the least likely to work, while the ones that have the strongest effects fall to the bottom and are very rarely used. When antidepressants don't work, people switch classes, raise the dose, or add in other antidepressants or stimulants, benzos, lamotrigine, or buspirone. If they are following practice guidelines, they'll probably augment with an antipsychotic, but those medications only work for a few months in what is usually a chronic disorder. The industry has tried to get approval for antipsychotics as long-term maintenance agents in depression, but they failed in three out of four large industry-sponsored trials that tested them for just six months, which the industry defines as long-term. By contrast, lithium worked long-term in a meta-analysis of 21 controlled trials that lasted an average of two years in unipolar, not bipolar, but unipolar depression, and psychotherapy has better long-term results than antidepressants in depression.
KELLIE NEWSOME: But how often do you see a patient with treatment-resistant depression who has tried TMS? In recent trials, TMS was more effective than pharmacologic augmentation. And how often have they tried accelerated or SAINT TMS, an accelerated 5-day protocol that brings up to 90% to full remission? How often do we see lithium, thyroid, pramipexole, MAOIs, celecoxib, light therapy, or ECT on their list of past trials?
CHRIS AIKEN: Not that often. Treatments that don't work are so common that I had to add two chapters at the end of this book on how to de-prescribe them. It's made me think that it's not the patients who are treatment resistant, but our profession that is resistant to changing what we're doing. Here's how I'd like to see practice change after writing this book. First, let's focus on treatments with long-term benefits. Sure, there's a role for rapid action, like keeping people out of the hospital in acute suicidality, but what's a two-week difference in onset in a lifelong illness? Next, let's use more neuromodulation, more lifestyle, and more psychotherapy strategies, and less irrational polypharmacy. Specifically, let's stop wasting time with medication maneuvers that do not work, like high-dose antidepressants, endless antidepressant switches, or augmenting with medications that failed to beat placebo, even in trials designed by those positioned to profit from their sale. And let's stop treating depression like a single SSRI-responsive entity and start personalizing the treatment. Common subtypes that benefit from a personalized approach include bipolar disorder, mixed features, vascular inflammation, seasonal and postpartum depression, as well as people with a complex trauma history or comorbidities. We can also personalize by addressing common deficits in depression, like deficiencies of iron, folate, probiotics, Vitamin D, omega-3, and light, as we do with a light box in seasonal affective disorder.
KELLIE NEWSOME: The research community is catching on to some of those ideas. Last year, researchers from Spain published the DEPRE-5 trial. They various pharmacologic augmentation strategies, kind of like a new version of the STAR*D trial. All of the strategies worked equally well – adding lithium, or a tricyclic, or psychotherapy – which didn’t surprise us – but what is new is they used “raising the dose” as the placebo group, convinced by earlier trials that it wouldn’t work. And it didn’t, so you can cross that one off your list – raising fluoxetine from 20 mg to 40 mg is not likely to get anyone better, at least not with treatment-resistant depression. In 2024, another group, from the Netherlands, launched a randomized trial that was designed to challenge the Dutch Treatment guidelines for depression, which give little attention to TMS. They randomized 89 patients with treatment-resistant depression to either follow the Dutch guidelines or go straight to TMS after two failed trials. The guidelines recommend switching to a tricyclic or augmenting with lithium or an antipsychotic at that step, but the trial arrived at a different conclusion: TMS worked better, with a large effect size of 0.77. That finding was replicated by a larger trial comparing TMS to aripiprazole augmentation.
CHRIS AIKEN: So in an evidence-based world, we'd go more quickly to TMS. When depression is severe, and antidepressants don't work, we'd use ECT for psychotic depression, which is about one in three cases that don't respond well to antidepressants. We'd use mood stabilizers for bipolar depression. About 50% of treatment-resistant cases have undetected bipolar. And we'd use lithium and psychotherapy for long-term prevention in patients with chronic or recurrent episodes of depression. Why doesn't this happen? Well, many of the treatments that work in treatment-resistant depression, or TRD, are off-label, not just in depression, but in psychiatry. It feels safer to add mirtazapine or bupropion. Maybe they failed in TRD, but at least they're approved in depression, and they don't come with major medical risks, or do they? You know, when depression is not treated, depression comes with a host of medical risks: higher rates of cancer, stroke, and metabolic disease. Depression takes years off a person's life from medical problems, not just suicide. So adding these seemingly benign treatments that don't work really does come with medical risks.
KELLIE NEWSOME: Let's get back to pramipexole, where we left off last week. Why is this one underused?
CHRIS AIKEN: Several mood experts have told me or written that they use it as a secret weapon: Joe Goldberg, Antonio Tundo, John Rush, and the late Jan Fawcett. Twenty years ago, Joe Goldberg met with the pharmaceutical company that made pramipexole to convince them to run large trials in depression, but the company declined because they were about to lose their patent on the drug, branded back then as Mirapex. And when there isn't industry funding, it takes a long time for trials to come out, if they do at all. Jan Fawcett published a series of patients who responded to pramipexole after failing over six antidepressant trials, including ECT. Antonio Tondo published a large trial where 70% to 80% of patients responded to pramipexole after failing to respond to aripiprazole. But it wasn't until last year that those uncontrolled observations were confirmed in a large placebo-controlled trial of pramipexole in treatment-resistant depression.
KELLIE NEWSOME: That aripiprazole study is interesting because aripiprazole and pramipexole share a common mechanism – dopamine D3 agonism.
CHRIS AIKEN: Yes, and they do share a common risk: hedonic dysregulation, which is Greek for too much pleasure. It's also called pathological gambling, although it can come out in other ways besides gambling. There is a risk of hedonic dysregulation with aripiprazole, as well as an FDA warning, as there is with cariprazine and brexpiprazole, which are D3 agonists. But we are more reluctant to take on that risk in a drug that hasn't been well studied in psychiatry, like used to be the case for pramipexole, and that's where this new trial from the UK comes in. They rigorously looked for hedonic dysregulation and found a low rate of 3%. Earlier depression trials found a much lower risk of 0%, but it wasn't clear that they rigorously looked for it. Now, by comparison, the rate of hedonic dysregulation with pramipexole is 10 times higher in Parkinson's disease, around 20% to 30%. So this is a rare example where psychiatric patients have a lower risk of psychiatric side effects on it than other patients. Why? We don't know, but it may be that psychiatric patients start out with a lower hedonic drive to begin with.
KELLIE NEWSOME: How high is the risk with aripiprazole?
CHRIS AIKEN: We don’t have good data on that, especially since a lot of the aripiprazole trials didn’t test for that or involved different populations like bipolar or schizophrenia, while pramipexole is often used in practice for restless legs or Parkinson’s. But if we forget that these are used in vastly different populations, two epidemiologic studies suggest the risk is about the same – one found a 3-fold increase in gambling with aripiprazole and pramipexole, and another found a 7-fold increase with both medications.
KELLIE NEWSOME: So the risk is similar, but with pramipexole, we’re not going to see weight gain, sexual dysfunction, diabetes, tardive dyskinesia, or the host of other warnings that weigh down antipsychotics. So, let’s get into the details of how to use it, with our audio chapter from Difficult to Treat Depression. But first, a preview of the CME quiz – earn CME through the link in the show notes.
1. How does pramipexole differ from traditional psychostimulants like methylphenidate and amphetamines?
A. It does not cause psychotic symptoms
B. It inhibits dopamine reuptake
C. It is sedating
D. It improves cognitive processing speed but not symptoms of ADHD
CHRIS AIKEN: Pramipexole should not be confused with other dopaminergic medications like methylphenidate and amphetamine. These block dopamine reuptake, making it available to act on the five dopamine receptors in various regions of the brain. These stimulants improve energy and cognition, while pramipexole causes fatigue and has no effect on cognition. Unlike pramipexole, the stimulants largely failed in trials of depression. At high doses, the excess dopamine they release causes inflammation in the brain. Pramipexole has the opposite effect. It is neuroprotective within the dopamine system and anti-inflammatory in the brain. Inflammation wears down dopamine transmission, reducing its synthesis, packaging, and release within the CNS. This suggests that pramipexole may treat inflammatory depression by restoring dopamine tone and decreasing neuroinflammation, a possibility suggested by one clinical study (Ventorp F et al., Psychiatr Res Clin Pract 2022, 30;4(2):42-47).
KELLIE NEWSOME: How to use pramipexole:
CHRIS AIKEN: Pramipexole should not be confused with other dopaminergic medications like methylphenidate and amphetamine. These block dopamine reuptake, making it available to act on the five dopamine receptors in various regions of the brain. These stimulants improve energy and cognition, while pramipexole causes fatigue and has no effect on cognition. Unlike pramipexole, the stimulants largely failed in trials of depression. At high doses, the excess dopamine they release causes inflammation in the brain. Pramipexole has the opposite effect. It is neuroprotective within the dopamine system and anti-inflammatory in the brain. Inflammation wears down dopamine transmission, reducing its synthesis, packaging, and release within the CNS. This suggests that pramipexole may treat inflammatory depression by restoring dopamine tone and decreasing neuroinflammation, a possibility suggested by one clinical study (Ventorp F et al., Psychiatr Res Clin Pract 2022, 30;4(2):42-47).
KELLIE NEWSOME: How to use pramipexole:
A slow titration is needed to prevent nausea and orthostasis. When introducing pramipexole:
- Start with 0.125–0.25 mg at bedtime.
- Raise by 0.25 mg every 3–7 days.
- Expect slight improvement (like 10-20% change) at 0.75 mg. From this dose, titrate faster if the medication is tolerable, raising to 1.0 mg for a week and then 1.5 mg.
- Most patients require between 1-2 mg, though patients with high levels of treatment resistance may require 2-5 mg/day.
- For nausea, consider ginger (1,000-2,000 mg q12 hr prn), (ondansetron (4 mg q12 hr prn) or a proton pump inhibitor (eg, pantoprazole 20-40 mg QD)
- Dose at bedtime to minimize daytime fatigue (rarely, patients find it activating and may prefer morning dosing)
Pramipexole works as both monotherapy and augmentation in unipolar depression, although in bipolar disorder, it should be used with a mood stabilizer. Response is typically seen within 4-6 weeks of reaching a therapeutic dose. Pramipexole is one of a few neuropsychiatric medications that is excreted unchanged by the kidneys (the others are lithium, paliperidone, gabapentin, pregabalin, acamprosate, and amantadine). It is free of pharmacokinetic drug interactions and does not undergo hepatic metabolism. Pramipexole is available as an extended-release version, but this has not been studied in psychiatric populations. The XR was developed for Parkinson's disease, where twice daily dosing is often necessary to maintain its motoric effects, but most psychiatric patients can be treated with a single dose at night.
CHRIS AIKEN: Side effects:
CHRIS AIKEN: Side effects:
Tolerability
Pramipexole does not cause weight gain, sexual dysfunction, or cognitive impairment. The most common side effects are nausea and fatigue. At low doses (≤ 1.5 mg), these are not a major obstacle, but they cause more discontinuation in the higher dose range (2.5 mg). As a dopaminergic medication, various motoric side effects can occur on pramipexole, such as muscle twitching. These are rare, though I have seen them in older adults and patients with a history of cocaine or methamphetamine use disorder. Pramipexole does not cause tardive dyskinesia. When used in RLS, pramipexole can shift the restless symptoms from the nighttime to the morning (rebound) or cause them to start earlier in the afternoon (augmentation). These problems are worse with long-term use, affecting around one in ten patients after a year with restless leg syndrome. It is not known if rebound and augmentation occur in mood disorders.
Risks
Pramipexole's main risks are cardiac and neuropsychiatric. On the cardiac side, it can cause orthostasis and falls, a rare problem that is reduced by titrating slowly. Although it does not seem to cause valvular heart problems like the ergot alkaloids, it can cause edema, and there are a few case reports of congestive heart failure on the drug. Sudden sleep attacks have been reported on pramipexole in Parkinson's disease, including a risk of car accidents with them. Like other D3 agonists (eg, aripiprazole), pramipexole carries a warning of compulsive gambling. Neurologists call this hedonic homeostatic dysregulation, and the syndrome includes a broad spectrum of pleasure-seeking behaviors. Patients may overspend online, play video games excessively, or have uncomfortable urges to masturbate at work. The problem is more common in Parkinson’s disease (15%) than mood disorders (1-3%), possibly because depressed patients start out with a lower hedonic drive. Serious impulsivity is rare and improves with dose reduction. More often, patients report benign compulsivity on pramipexole, such as cleaning the garage or organizing their books alphabetically. Substance use disorders are not part of the syndrome, and neither are manic symptoms. In the bipolar trials, pramipexole did not cause mania (where it was used with a mood stabilizer). Pramipexole can cause psychotic symptoms by activating the D2 receptor. These are usually mild, such as seeing shadows or hearing sounds. These are rare (0.4%), but more common in the higher dose range (3-5 mg). In the cases I have seen, reality testing was intact, and the psychosis resolved with dose reduction or discontinuation. Sudden sleep attacks have been reported on pramipexole in Parkinson's disease, including while driving. There were early reports of melanoma on pramipexole, but those have since been linked to Parkinson's disease rather than the medication. The FDA removed warnings of melanoma from the prescribing information in 2018.
KELLIE NEWSOME: The bottom line. Pramipexole is a D3-selective dopamine agonist with large and durable benefits in unipolar and bipolar depression. It may be particularly beneficial in patients with anhedonia, inflammation, or high levels of treatment resistance. Pramipexole is well tolerated, with no weight gain, sexual dysfunction, or cognitive impairment, making it a valuable option for patients who have experienced side effects with other treatments. You’ve just heard a chapter excerpt from Difficult to Treat Depression, the full 2025 book is available in paperback or as an audiobook and includes chapters on psychotherapy, novel medications, neuromodulation, male and female hormones, deprescribing, and how to detect unique subtypes like bipolar, mixed, inflammatory, vascular, and psychotic depression.
KELLIE NEWSOME: The bottom line. Pramipexole is a D3-selective dopamine agonist with large and durable benefits in unipolar and bipolar depression. It may be particularly beneficial in patients with anhedonia, inflammation, or high levels of treatment resistance. Pramipexole is well tolerated, with no weight gain, sexual dysfunction, or cognitive impairment, making it a valuable option for patients who have experienced side effects with other treatments. You’ve just heard a chapter excerpt from Difficult to Treat Depression, the full 2025 book is available in paperback or as an audiobook and includes chapters on psychotherapy, novel medications, neuromodulation, male and female hormones, deprescribing, and how to detect unique subtypes like bipolar, mixed, inflammatory, vascular, and psychotic depression.
