Pramipexole in Treatment-Resistant Depression – Mechanism of Action and Prescribing Strategies

Posted on:February 17, 2020

Last Updated: May 28, 2023

Time to read: 9 minutes

The National Institute of Mental Health-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) showed that approximately 30% of MDD patients exhibit a failed response to antidepressants or psychotherapy. [Rush et al. 2006]

The STAR*D trial is the largest real-world psychiatric clinical trial ever conducted and was designed to analyse the acute and long-term effect of sequential antidepressant treatment.
The response rate to standard antidepressant treatments is very poor, with only 10% of community-based patients exhibiting a 1-year response. [Dunner et al 2006]
TRD is the failure of 2 adequate dose-duration antidepressants from different classes and psychotherapeutic treatments either in combination or succession in the current episode. [Conway et al. 2017]

Although primary care physicians tend to follow antidepressant treatment guidelines, TRD is frequently undetected in the community with some patients undergoing up to eight antidepressant trials. In the STAR*D trial, it was shown that acute remission rates decreased from 37% to 31% to 14% with each adequate dose duration treatment. [Rush et al. 2006]

Learn More: RANZCP Guidelines for Depression

Primary care providers also find it difficult to distinguish unipolar depression from bipolar depression. [Hirschfield et al. 2005; Olfson et al. 2005]

The prevalence of bipolar disorder is relatively high in primary care settings and most patients are not engaged in specialist mental health care despite the clinical complexity and risk of self-harm. [Wang et al. 2005]

Accurate recognition of BD takes on average of 6–8 years between onset and diagnosis. [Wang et al. 2005]
The most common misdiagnosis is unipolar depression, with the real risk of antidepressant treatment worsening the disorder. [Hirschfeld et al 2003]
Practice guidelines state that antidepressant monotherapy increases the risk of inducing a manic episode. [Pacchiarotti et al. 2013]

Learn More: Is it Unipolar or Bipolar Disorder?

Based on the time during which patients are symptomatic of depression, bipolar disorder is often conceptualised as a predominantly depressive disorder. As such, it is critically important to re-evaluate TRD patients for a history of manic or hypomanic episodes to determine whether there is a bipolar diathesis.

TREATMENT REFRACTORY DEPRESSION

Guidelines show that for non-response, switching medication to one that has demonstrated superiority (e.g., duloxetine, escitalopram, sertraline, or venlafaxine XR) or prescribing adjunctive therapy (e.g., aripiprazole, olanzapine, risperidone, or lithium) are first-line approaches.

Most patients will initiate treatment in primary care and are likely to be prescribed sequential first-line antidepressant treatment trials that ultimately fail.
Once a patient is referred to a psychiatrist, there are only a few treatments for TRD, such as combination therapy with the atypical antipsychotics, lithium, ECT, or TMS.

However, there are newer approaches on the horizon, such as ketamine and related agents [Kishimoto et al. 2016], the repurposing of anti-inflammatory drugs [Kohler et al. 2014; Na et al. 2014], and dopamine receptor agonism. [Hori and Kunugi 2013]

The putative role of dopamine is linked to the consistent observation of reduced homovanillic acid (dopamine metabolite) in depressed patients. [Reddy et al. 1992]

DOPAMINE AND PRAMIPEXOLE

One of the major predictors of a poor response to antidepressant treatment and the development of TRD is anhedonia.

Anhedonia is an interest-activity symptom dimension that has been associated with dopamine dysfunction in the basal ganglia and impaired cortical-striatal reward circuitry. [Felger and Miller 2012]

Patients with treatment-resistant depression have deficits in interest, motivation, and hedonic capacity.

These symptoms are often associated with poor outcomes with antidepressants that selectively target the norepinephrine and serotonin systems. This same symptom constellation is thought to be most highly dependent on an intact dopamine system.

Evidence suggests a potential role for inflammation in mediating the development of resistance to antidepressants and stimulants, specifically when fatigue and anhedonia persist.

Patients with Parkinson’s disease commonly exhibit depression and anhedonia; however, L-Dopa shows little efficacy against these symptoms. [Loas et al. 2012]

However, a more recent study showed L-dopa reversed the effects of inflammation on the brain’s functional connectivity in reward circuitry and anhedonia in depressed individuals with higher C-reactive protein (CRP) > 2mg/L.

This improvement in reward circuitry in depressed individuals with higher CRP also correlated with reduced symptoms of anhedonia after levodopa.[Bekhbat, 2022]

MECHANISM OF ACTION OF PRAMIPEXOLE

Pramipexole is a selective agonist of the D2 family of receptors with significantly higher (7-10 times) greater affinity to the D3 receptor. [Eisenreich W et al., 2010]

D3 receptors are situated mainly in the mesolimbic system and at lower levels in the striatal areas.

Low doses of pramipexole activate mostly D3 presynaptic autoreceptors, and only a higher dose activates the postsynaptic receptors.

In normal dopaminergic systems, pramipexole acts on presynaptic D2 and D3 dopamine autoreceptors and suppresses the synthesis and synaptic release of dopamine.

Effects on postsynaptic receptors are elicited only at higher dose levels and with substantially longer latencies than are needed for presynaptic autoreceptor stimulation.

However, in dopaminergic systems in which dopamine release is reduced, as a result of presynaptic neurone degeneration or increasing age, postsynaptic dopamine D2 and D3 receptors are more readily stimulated by pramipexole.

In Parkinson’s disease, pramipexole stimulates both D2 and D3 postsynaptic receptors in dopamine depleted circuits. Pramipexole may have neuroprotective and neurorestorative effects on dopamine function, especially in Parkinson’s disease. D3 stimulation also promotes reward activity.

In depression, the beneficial effects are likely to be due to pramipexole-induced stimulation of postsynaptic dopamine D2 receptors. This same effect in frontal cortical regions may reduce the negative symptoms of schizophrenia.

SIDE EFFECTS OF PRAMIPEXOLE

Common side effects

intolerance most commonly due to nausea
sleeplessness
sleepiness
dizziness
tremors
compulsive behaviours
sleep attacks.
increased anxiety
increased sexual arousal

Intolerance occurs early—within 3–10 days—and at low dosages (0.25–1.0 mg/day).

When side effects occur, lower to the last dosage where the side effect didn’t occur and attempt to increase the dose after 1-2 weeks.

HIGH DOSE PRAMIPEXOLE

Pramipexole was initially shown to be effective in non-treatment-resistant unipolar and bipolar depression with 1.0mg/day exhibiting the most favourable benefit to safety ratio. [Corrigan et al. 2000]

More recently, a randomised double trial reported a moderate reduction in depressive symptoms with 1.35 to 2 mg/day. [Cusin et al. 2013]

In 2016, a case series was published on the outcome of adjuvant pramipexole delivered at a high dose. [Fawcett et al. 2016]

Given the previously reported high rate of study attrition at 5 mg/day, the presence of side effects and measures of intolerance were important clinical outcomes. Meanwhile, efficacy was assessed by monitoring symptomatic response, remission, and nonresponse rates.

Of the 42 outpatients included in this study, 24 were diagnosed with MDD while 24 were diagnosed with bipolar depression with no evidence of psychotic depression.
All patients had TRD, which was defined as having failed to respond to a minimum of four adequate antidepressant trials. Eight patients had not responded to ECT.
Pramipexole dosage started at 0.25mg/day with increases to 5.0 mg/day feasible based on tolerance and whether remission had been achieved.

Results:

The mean (standard deviation) dosage for response or remission was 2.46 (1.1) mg/day.
Unipolar – Remission (45.8%), response (29.2%), non-response (4.2%), intolerant (12.5%)
Bipolar – Remission (50.0%), response (27.8%), non-response (5.6%), tolerant (16.7%)
Overall, 76.0% of patients exhibited a response, 47.6% of patients remitted, and only 19.0% of patients were unable to tolerate pramipexole’s side effects.
Patients that remitted were still in remittance 16 months after the trial had ended, which shows that long-term high-dose pramipexole has a persistent anti-depressive effect.
Of the 8 patients who failed ECT, four patients showed a response, while the other 4 patients entered remission.

Two patients who had bipolar II depression experienced hypersexuality, and one patient experienced a psychotic episode in the context of renal infection. This patient was successfully rechallenged with pramipexole during recurrence of depression at a dose of 1.0 mg/day with no recurrence of psychotic symptoms.

Evidence from real-world studies suggests that adding pramipexole to traditional ADs could be an effective treatment option for patients with TRD. Pramipexole augmentation appeared to be safe, with nausea and somnolence being the most frequent side effects. [Tundo et al, 2023]

PRACTICAL TIPS IN PRESCRIBING PRAMIPEXOLE

Slower titration rate in younger patients
Starting dose not more than 0.125–0.50 mg/day
Dose only once a day at bedtime, unless the patient has trouble with sleep (rare)
Therapeutic dose range, 1.0–5.0 mg/day
Common adverse events: nausea, sleepiness, dizziness, tremors, compulsive behaviours, sleep attacks
If nausea occurs, reduce the dosage, then increase after 1–2 weeks
Severe anhedonia, lack of motivation, inability to initiate behaviours, and unreactive mood are predictors of response
Expected benefit, occurs by 4 weeks at a maximally tolerated dose
Avoid abrupt discontinuation because of the risk of dopamine agonist withdrawal syndrome (1 in 7)

CONCLUSION

Adjunctive pramipexole at a dose higher than previously studied resulted in a clinically meaningful response in 76% of TRD patients. Enhancing tolerability requires careful and gradual titration to prevent side effects.

Pramipexole and potentially other dopamine agonists may be useful in the treatment of refractory depression.

Pramipexole currently does not have FDA or TGA approval in the US or Australia for the treatment of depression.

Pramipexole is available in generic and branded forms (Sifrol, Simipex and Simpral) in Australia. Extended-release versions are available. PI available here.