Mirapex (Pramipexole) is a drug that is approved by the FDA for the treatment of Parkinson’s disease and RLS (restless leg syndrome). Classified as a dopamine receptor agonist, pramipexole elicits partial or full agonism upon D3 receptors, D2 receptors (2L/2S), and D4 receptors. Interestingly, pramipexole also appears to modify mitochondrial function, and to a negligible extent, has an affinity for serotonin, noradrenaline, histamine, and acetylcholine receptor sites.
In addition to attenuating symptoms of Parkinson’s and RLS, preliminary evidence highlights the efficacy of Mirapex as a pharmacological intervention for major depressive disorder (MDD). Although it isn’t formally approved by the FDA for the treatment of depression, many psychiatrists routinely prescribe Mirapex as an off-label adjunct for individuals with refractory (treatment-resistant) depression. Its usage as an antidepressant is generally reserved for patients that fail to derive benefit from traditional options (SSRIs, SNRIs, atypicals, TCAs, MAOIs) and various medicinal permutations (e.g. California Rocket Fuel).
In select cases, Mirapex is also prescribed to bolster efficacy and/or combat side effects of a first-line serotonergic antidepressant such as weight gain and sexual dysfunction. Due to its hypothesized antidepressant efficacy, favorable side effect profile, and unique mechanism of action – many individuals with major depression are intrigued by the idea of trying Mirapex (pramipexole) to enhance their mood. In future years, it is possible that pramipexole will pass clinical trials (and receive FDA approval) for the treatment of depression.
How Mirapex May Target Depression (Mechanisms of Action)
It is understood that the bulk of therapeutic effects derived from Pramipexole usage stem from its ability to modulate dopaminergic signaling, particularly within the striatum. Evidence suggests that it stimulates D3 receptor sites, which in turn excites the direct striatopallidal pathway. It also stimulates D2 receptor sites to inhibit the indirect striatopallidal pathway. The simultaneous modulation of direct and indirect striatopallidal pathways has proven highly therapeutic for patients with Parkinson’s disease.
Some speculate that normalization of striatal dopaminergic activity may be one mechanism by which pramipexole directly treats depression. Certain neurophysiological footprints of depression are associated with dysfunctional signaling within in the striatum. Upon modulation of striatal signaling, this also affects the basal ganglia, as well as activation of other regions throughout the brain, which in turn may improve mood and/or reduce symptoms of depression (e.g. anhedonia).
In addition to normalization of dopaminergic signaling, perhaps directly agonizing D3 receptor sites provides most of the antidepressant effect. D3 receptor sites are abundant within the limbic regions and insufficient D3 stimulation is associated with depressed mood and anxiety. Moreover, the antidepressant effect ability of Pramipexole may be generated via multi-faceted mechanisms including: stimulation of dopamine receptors, modulation of dopaminergic signaling, alteration of other neurotransmitters, and possibly mitochondrial enhancement.
D3 receptor agonism: It is understood that Mirapex (pramipexole) acts as a D3 receptor agonist. In other words, it binds to D3 receptor sites to elicit a similar biological response to endogenous dopamine. This may be especially important for those with certain types of depression with suboptimal D3 receptor activation, particularly in the mesolimbic system.
There is mounting evidence to suggest that dopamine is linked to depression, particularly inadequate dopamine signaling. Individuals with reduced D3 receptors are more prone to depression and anxiety than those with sufficient D3 receptor densities. In addition, some individuals may have enough D3 receptors, but the receptors that they do have aren’t being adequately stimulated; the dopamine signaling is dysfunctional.
As a result of mesolimbic dopamine dysfunction, individuals may report depressive symptoms such as: anhedonia, lack of motivation, and psychomotor retardation (a hybrid of motor and cognitive deficits). Administration of pramipexole activates these receptors and may improve ability to feel pleasure, motivation, and psychomotor activation. It is also worth noting that many standard antidepressants (e.g. SSRIs) appear to increase BDNF levels.
An increase in BDNF tends to promote neurogenesis, but also regulates the expression of D3 receptors in certain areas of the brain. Of those who derive benefit from standard antidepressant interventions, perhaps the improved functionality of D3 receptors is an important mechanism. Without proper function of D3 receptors in the mesolimbic region, reward circuitry is erratic and individuals are prone to chronic stress and depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23872400
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25110304
D2 receptor agonism: Although Pramipexole has a higher affinity for D3 receptors than D2 receptors, it affects both to a significant extent. Some speculate that D2 receptor full agonism may facilitate an antidepressant effect in certain individuals. Other D2 agonists have been associated with antidepressant effects in animal models and among certain individuals with major depressive disorders.
Reports suggest that D2 receptor agonism, especially over a long-term, may normalize metabolic irregularities associated with depression. Chronic D2 stimulation provided by pramipexole may also facilitate hippocampal neurogenesis in humans; it appears to do so in animal models. In rodent models, pramipexole also appears to correct firing abnormalities of dopamine neurons by desensitizing D2 receptors in the ventral tegmental area (VTA) of the brain.
Additionally, desensitization of D2 receptors with chronic pramipexole administration may enhance 5-HT1A receptor function in the dorsal raphe. Enhancement of 5-HT1A receptor activity allows 5-HT neurons to fire at a supraphysiological rate. Increased firing rates of 5-HT neurons may contribute to a serotonergic antidepressant response, possibly via the prefrontal cortex and hippocampus.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/17426594/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15195095/
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18688211/
D4 receptor agonism: It is unknown as to whether D4 receptor agonism plays a role in Mirapex’s ability to improve mood. Although D3 receptor stimulation likely contributes to most of its antidepressant properties, it is necessary to consider that D4 receptor agonism may make a modest contribution to its mood enhancing properties. Studies of D4 receptor agonists suggest that they may enhance novelty seeking and alter duration of REM (rapid-eye movement) sleep.
Whether the D4 receptor agonism provided by pramipexole is sufficient as to modify novelty seeking propensities and/or affect REM sleep isn’t fully elucidated. For this reason, it cannot be confirmed that agonism of the D4 receptor contributes to mood enhancement of pramipexole. That said, some studies of other D4 agonists demonstrate their ability to alter brain waves – particularly theta waves and gamma waves which could affect mood.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/25985889
- Source: http://www.ncbi.nlm.nih.gov/pubmed/16815751
Ways Mirapex (Pramipexole) May Alleviate Depression
There are many ways by which Mirapex may improve depressive symptoms among those with major depression. The mechanisms of D3, D2, and D4 receptor agonism appear to elicit a variety of neurological changes which may yield therapeutic mood enhancement in select individuals. Below are some ways by which Mirapex may improve the mood of an individual with depression.
- Antioxidant effects: Dopamine agonists such as pramipexole appear to exhibit antioxidant properties. Research suggests that administration of pramipexole increases cellular concentrations of glutathione (GSH), thereby reducing reactive oxygen species (ROS). Among certain individuals with depression and chronic stress, high levels of ROS may interfere with healthy neurotransmission and regional functions. A reduction in oxidative stress following administration of pramipexole may help with mood. (Source: http://www.ncbi.nlm.nih.gov/pubmed/11129106).
- Cortical plasticity: Individuals diagnosed with major depression often exhibit poor cortical plasticity, making it difficult to modify circuitry to escape the depression. It is known that antidepressant drugs enhance cortical plasticity, perhaps an important mechanism by which they improve a user’s mood. Studies have shown that pramipexole is capable of restoring cortical plasticity with chronic treatment, possibly helping some patients with abnormal circuitry recover from depression. (Source: http://www.ncbi.nlm.nih.gov/pubmed/19117337/).
- Hippocampal neurogenesis: Evidence from rodent studies suggests that pramipexole increases survival rates of hippocampal neurons. Administration of pramipexole for one month appeared to permanently enhance density of neurons within the hippocampus even after treatment was discontinued. Since many antidepressants appear to spur generation of new neurons in the hippocampus, perhaps this is an important antidepressant mechanism of pramipexole. (Source: http://www.ncbi.nlm.nih.gov/pubmed/19619535).
- Neuronal firing rates: Ongoing administration of pramipexole appears to increase firing of DA and 5-HT neurons. Increased firing of dopamine neurons is thought to enhance function within the prefrontal cortex. Enhancement of prefrontal functioning may improve depressive symptoms in certain individuals. Additionally, increased firing of 5-HT neurons is thought to enhance hippocampal functioning, which may also contribute to an antidepressant effect.
- Neuroprotective effects: Another mechanism by which pramipexole may treat depressive symptoms is via neuroprotective effects. It appears to prevent programmed neuronal death (apoptosis), reduce oxidative stress, decrease excitotoxicity, and upregulate neurotrophic factors. Studies have documented its ability to inhibit beta-amyloid neurotoxicity and increase survival of dopamine neurons exposed to glutamate. It prevents mitochondrial damage as caused by free radicals and decreases mitochondrial inflammation. Its efficacy as a neuroprotective agent appears to be indirectly induced by activation of D3 and D2 receptors. (Source: http://www.ncbi.nlm.nih.gov/pubmed/26801190).
- Neurotransmission: Pramipexole principally affects activation of dopamine receptors, but is also thought to slightly tweak the neurotransmission of serotonin, norepinephrine, histamine, and acetylcholine. Although its effect upon other neurotransmitters is weak, the cumulative tweak of all these neurochemicals may improve depressive symptoms. Examples of sites affected by pramipexole include: 5-HT1A, 5-HT2B, 5-HT1D, and Alpha-2 adrenergic receptors.
- Regional metabolism: Studies have shown that compared to a placebo, pramipexole significantly modifies regional metabolism. Administration of pramipexole seems to alter metabolism in regions such as the: bilateral orbitofrontal cortex, left ventrolateral prefrontal cortex, and right anteromedial prefrontal cortex. Researchers believe that pramipexole-induced metabolic changes may play a role in its distinct antidepressant effects (differing from SSRIs). (Source: http://www.ncbi.nlm.nih.gov/pubmed/21029512).
- REM modulation: There are clear associations between REM (rapid-eye movement) sleep dysregulation and depression. Researchers speculate that REM dysregulation among those with depression may be a result of genetic, epigenetic, or allostatic load associated with chronic stress. Evidence suggests that pramipexole affects the density of REM sleep, likely via modulation of dopaminergic signaling. Perhaps altered REM sleep may contribute to an antidepressant response in certain individuals.
- Reward-processing circuitry: Another mechanism by which pramipexole may treat depressive symptoms is by enhancing connectivity of reward circuitry. Specifically, it appears to upregulate activation of the nucleus accumbens (NAcc) and bolster communication between the nucleus accumbens and the anterior insula. Communication between the nucleus accumbens and anterior insula may be compromised in certain types of depression, and when normalized, mood improves. (Source: http://www.ncbi.nlm.nih.gov/pubmed/21484950).
- Striatal signaling: Pramipexole enhances signaling in the basal ganglia, perhaps most substantially within the striatum. Striatal function is necessary for responding to positive emotional stimuli and positive feedback signals during cognitive tasks, but is compromised among many individuals with depression. Administration of pramipexole normalizes suboptimal striatal signaling and rodent studies suggest it upregulates density of D3 and D2 striatal receptors.
Benefits of Mirapex for Depression (Possibilities)
It is understood that Mirapex (pramipexole) elicits significantly different pharmacological effects than standard antidepressant treatments. As a dopamine receptor agonist, it may target certain aspects of depression that traditional treatments fail to address. Below is a synopsis of possible benefits associated with using Mirapex as an antidepressant.
- Apathy reversal: Many people diagnosed with depression struggle with apathy, characterized as a lack of interest and concern for everyday living. Apathy if commonly associated with dopamine dysfunction and/or poor dopamine signaling. It is commonly observed among those who abuse psychostimulants (e.g. methamphetamine) due to a downregulation of dopaminergic processes. Since Mirapex acts as a D3 receptor agonist, it enhances dopaminergic signaling and may sufficiently attenuate apathy-related symptoms of depression. Though pramipexole may not entirely eradicate apathy, it may significantly decrease it.
- Anhedonia reduction: One method by which Mirapex appears to treat depressive disorders is by decreasing anhedonia. Anhedonia is thought to result from suboptimal stimulation of mesolimbic D3 receptors and striatal dysfunction. Mirapex administration may bolster D3 receptor stimulation in the mesolimbic region and/or correct striatal abnormalities, each of which may improve reward processing and decrease anhedonic tone. (Source: http://www.ncbi.nlm.nih.gov/pubmed/22420038).
- Adjunctive option: In many cases, Mirapex is prescribed as an antidepressant augmentation strategy or as an “add-on” medication to bolster the efficacy of a first-line antidepressant treatment. Since Mirapex primarily affects the dopamine system and traditional antidepressants target the serotonin system, it can often be used safely along with an SSRI or SNRI. Adding Mirapex to an already-prescribed medication allows psychiatrists to target multiple neurotransmitter systems simultaneously. Furthermore, it may decrease unwanted side effects associated with serotonergic antidepressants (e.g. sexual dysfunction).
- Alternative option: Certain individuals that are diagnosed with refractory depression derive no therapeutic benefit from traditional treatments. They may end up testing seemingly every SSRI, SNRI, TCA, MAOI – and fail to respond. Lack of response may be related to the fact that most traditional interventions target serotonergic and/or noradrenergic processes and fail to address dopamine. Mirapex should be considered an evidence-based “off-label” alternative for those who don’t derive benefit from standard options.
- Cognitive enhancement: There is evidence to suggest that pramipexole (Mirapex) enhances cognitive function among individuals with Parkinson’s disease, bipolar disorder, and restless leg syndrome. Although it hasn’t been investigated extensively among those with depression, it could be speculated to enhance various cognitive faculties. While not everyone taking Mirapex for depression is likely to note enhancement of cognition, a subset of patients may experience marked improvements.
- Cost: Mirapex has been on the market since 1997 and is now available as genetic “pramipexole.” A 30-count of pramipexole tablets can be purchased for around $10 and a 90-count can be attained for under $20. Since many new antidepressants are expensive (especially for those with poor insurance), an added benefit for users of Mirapex is its low cost.
- Efficacy: Despite the fact that Mirapex isn’t approved by the FDA for depression, numerous studies highlight its efficacy. Most professionals can agree upon the fact that the literature suggests it is likely to provide therapeutic benefit as an antidepressant. Perhaps it’s just a matter of time before pramipexole is shuttled through clinical trials and marketed as an antidepressant agent.
- Long-term tolerability: Some studies suggest that when administered to over a 30-month term, Mirapex is well-tolerated with few side effects. Over 80% of long-term (30-month) Mirapex users experienced zero side effects associated with treatment. Others noted that side effects were mild. While this long-term research was carried out among patients with RLS, similar tolerability could be hypothesized for those with depression. (Source: http://www.ncbi.nlm.nih.gov/pubmed/17116213).
- Parkinson’s disease: Individuals diagnosed with major depression and concurrent Parkinson’s disease (or vice-versa) may stand to derive the most benefit from Mirapex. The drug is approved to correct signaling within the basal ganglia of Parkinson’s patients, thereby normalizing or ameliorating motor abnormalities. If you’ve been diagnosed with Parkinson’s disease, you may find that Mirapex improves both motor function and mood.
- Psychomotor performance: A common symptom of severe depression is psychomotor retardation, characterized by slowing of thought, decreased arousal, and decreased physical movement. Those with psychomotor retardation may find it challenging to get out of bed, take a shower, brush their teeth, etc. Mirapex appears to improve symptoms of psychomotor retardation, likely through dopamine receptor stimulation.
- Motivation boost: Among Parkinson’s patients taking Mirapex, significant increases in motivation are often reported. A meta-analysis of 7 randomized controlled trials suggests that the drug significantly improves motivational deficits associated with Parkinson’s. Although it is unclear as to whether Mirapex improves motivation among those with depression, a logical speculation is that it could.
- Restless leg syndrome (RLS): A subset of individuals diagnosed with major depression also have restless leg syndrome (RLS). Since Mirapex is clinically approved for the treatment of RLS, and evidence suggests it also acts as an antidepressant, those with both conditions may improve symptoms of each condition with just one pill. This could be advantageous over using a specific antidepressant along with another medication for RLS.
- Reward deficiencies: Diagnoses of depression are sometimes associated with deficiencies in reward-processing areas of the brain. Deficient reward processing may cause individuals with depression to avoid situations that non-depressed individuals would perceive as rewarding and/or pleasurable. Pramipexole may correct deficient reward processing by boosting signaling between the nucleus accumbens and anterior insula. For this reason, pramipexole could be speculated to provide benefit to those with reward deficiency disorders.
- Side effects: Some may find Mirapex side effects preferable over those associated with serotonergic antidepressants. Serotonergic antidepressants are associated with common side effects of weight gain, sexual dysfunction, and emotional “numbing.” Unwanted weight-related and sexual side effects may be less common with Mirapex due to the fact that it acts primarily upon dopamine.
- Sleep enhancement: Preliminary evidence indicates that Mirapex alters sleep architecture and may modulate REM (rapid-eye movement). Depression is associated with dysregulation of REM, including things like: shorter REM latency, increased REM duration, and increased REM density. The possible modulation of REM and/or sleep architecture provided by Mirapex may be one way in which it decreases depression, and simultaneously helps you get a better night’s sleep.
Drawbacks of Mirapex for Depression (Possibilities)
Mirapex is far from a utopian wonder-drug and clearly has some drawbacks, especially when used as an antidepressant. Not only may users experience disconcerting side effects, but they may develop an impulse control disorder during treatment – possibly leading to excessive gambling, shopping, or risky sex. Additionally, the drug will clearly not work for all cases of depression (e.g. those with non-dopaminergic depressive footprints) and severity of discontinuation effects may rival serotonergic options.
- Impulse control disorder: A highly problematic adverse effect that occurs among 10% of Mirapex users is referred to as “ICD” or impulse control disorder. Mirapex is understood to enhance signaling between the nucleus accumbens and the anterior insula (increasing pleasure of possible rewards), but simultaneously interferes with signaling between the prefrontal cortex and nucleus accumbens (decreasing impulse control). As a result of these effects, some users of Mirapex may have difficulty resisting urges related to gambling, shopping, sex, or binge eating; gambling is most common.
- Ineffective: Clearly not all users of Mirapex will find it helpful for the treatment of major depression. Some users may have high hopes that Mirapex will alleviate depressive symptoms only to be disappointed that it didn’t yield benefit. Others may find that after a month or two of Mirapex use, they feel even more depressed than they did before treatment.
- Side effects: Some Mirapex users will experience severe adverse reactions and/or intolerable side effects. Common Mirapex side effects include: nausea, tiredness, dizziness, headaches, insomnia, dry mouth, inability to concentrate, and somnolence. The drug may be problematic among those required to operated a motor vehicle and/or heavy machinery in that unpredictable “sleep attacks” may occur.
- Tolerance: While Mirapex may be effective over a short-term (e.g. under 1 year), continued long-term usage may result in tolerance. Once neurophysiological tolerance is established, a user may find that Mirapex “stops working” or is no longer providing adequate antidepressant benefit. Tolerance generally leads users to increase their dosages, but this may be problematic in that when doses are increased, side effects may increase in severity. Additionally, the drug is not guaranteed to continue working when the dosage is increased, possibly leaving some individuals to discontinue and face withdrawal symptoms.
- Withdrawal symptoms: Assuming you don’t end up taking Mirapex for life or find that it stops working, you’ll end up discontinuing. Upon discontinuation, you’re guaranteed to experience Mirapex withdrawal symptoms, many of which will be as severe as any other antidepressant. Mirapex discontinuation results in dopamine agonist withdrawal syndrome (DAWS), characterized by: agitation, anxiety, depression, excessive fatigue, panic attacks, and irritability. It may take some users months (or more) to recover from these discontinuation symptoms.
Mirapex (Pramipexole) For Depression (Review of Literature)
To determine whether Mirapex warrants legitimate consideration for usage as an antidepressant, it is necessary to examine scientific literature investigating its efficacy as an antidepressant. Some published studies documented its efficacy as a standalone antidepressant, while other investigate its efficacy when used as an adjunct (or “add on”) to a first-line antidepressant (e.g. SSRI). Included below is a synopsis of nearly every published study analyzing pramipexole’s therapeutic potential as an antidepressant.
2013: A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder.
A study conducted by Cusin et al. (2013) noted that up to 1/3rd of individuals diagnosed with major depressive disorder fail to achieve adequate symptomatic relief with standard pharmaceutical interventions. Although adjunct medications and/or combination treatments may provide benefit, they are also associated with safety concerns. Researchers hypothesized that pramipexole may be a safe, effective antidepressant adjunct among individuals with refractory depression.
They set-up a double-blinded, placebo-controlled, randomized study with a total of 60 outpatients (ages 18 to 75). All had been diagnosed with treatment-resistant, non-psychotic major depressive disorder based on DSM-IV diagnostic criteria. Of the 60 participants, 30 were assigned to receive pramipexole and 30 were assigned to the placebo for 8-weeks.
Following the 8-week term, depression severity was assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). Results suggested that pramipexole augmentation yielded significant therapeutic benefit in accordance with the MADRS and that it was well-tolerated among patients. Authors concluded that pramipexole is a safe and possibly effective adjunct for those with refractory depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23945458
2013: Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: a double-blind, randomized pilot study.
A study published in 2013 by Franco-Chaves et al. documented the efficacy of Mirapex (a dopamine receptor agonist) when combined with an SSRI for the treatment of depression. The impetus for the study was based on the fact that antidepressants affecting multiple monoaminergic systems are generally more efficacious than those targeting just one. Researchers therefore aimed to determine whether a drug affecting dopamine signaling and another affecting serotonin reuptake would yield greater benefit than either option as a standalone.
They organized a double-blind, randomized pilot study and recruited 39 patients that fit DSM-IV criteria for major depression. All patients had failed to derive benefit from standard first-line agents that altered a single neurotransmitter system. The 39 patients were then divided evenly into 3 groups, each of which received: Mirapex (0.375-2.25 mg/day), Lexapro (10 mg/day), or a combination of Mirapex plus Lexapro – for a total of 6 weeks.
Results (based on the Mongomery-Asberg Depression Rating Scale) indicated that depressive symptoms improved significantly among those receiving the Mirapex or Lexapro monotherapy. However, the group receiving Mirapex plus Lexapro failed to derive significant antidepressant benefit. Authors concluded that, contrary to speculation, combination of Mirapex plus an SSRI (Lexapro) may be less effective than either option utilized as a standalone monotherapy and that tolerability issues may arise with the combination.
It is necessary to mention that the study was small-scale (13 participants per group) and conducted over a short-term (6-weeks). That said, the study provides evidence to support the usage of Mirapex (pramipexole) as a standalone antidepressant. When administered as a standalone, it provided similar significant therapeutic relief to Lexapro.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23517885
2010: Long-term use of pramipexole in bipolar depression: a naturalistic retrospective chart review.
A report by El-Mallakh et al. (2010) documented the long-term use of pramipexole as an adjunct to mood stabilizers among 16 patients with bipolar disorder. The 16 patients were followed for over a 6-month term and researchers recorded their responses. Within 2 months of taking pramipexole, 50% of the patients (a total of 8) discontinued due to tolerability issues.
Among all 16 patients that used pramipexole, measures of depressed mood significantly improved after the first month of treatment. These mood improvements were noted as remaining significantly improved for a period of 36 weeks. Pramipexole appears to improve global function (GAF) and clinical global impressions (CGI) without any alterations in the emergence of mania.
This study provides evidence to support the antidepressant properties of pramipexole when administered as an adjunct in cases of bipolar disorder. Though tolerability issues surfaced in some participants, pramipexole did not increase risk of mania. Since it significantly decreased depressive symptoms, it may be a viable intervention for bipolar depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20425143
2010: Pramipexole for the treatment of depressive symptoms in patients with Parkinson’s disease: a randomized, double-blind, placebo-controlled trial.
Although it is understood that pramipexole can improve motor function among patients with Parkinson’s disease, it likely also attenuates Parkinson’s-induced depressive symptoms. A study conducted by Barone et al. (2010) assessed the efficacy of pramipexole as an antidepressant among individuals diagnosed with Parkinson’s. Researchers theorized that it may improve mood of Parkinson’s patients due to the fact that Parkinson’s-induced depression stems from dopaminergic dysfunction.
For the randomized, placebo-controlled, double-blinded study, researchers recruited 323 individuals – each of which were diagnosed with mild to moderate Parkinson’s disease. Of the 323 initial recruits, 296 were assigned at random to receive either pramipexole (0.125-1 mg, t.i.d.) or a placebo for a duration of 12 weeks. Prior to the study, depression severity was assessed with the Beck Depression Inventory (BDI).
Of the 296 participants, only 287 met criteria to be included in analysis of the results. Changes in BDI scores at the end of 12-weeks (compared to pre-treatment baseline) were used as the primary clinical endpoint. Results indicates that pramipexole significantly improved depressive symptoms among those with Parkinson’s disease compared to a placebo.
Researchers noted that the drug elicits a “direct antidepressant effect” among Parkinson’s patients. Incidence of adverse effects among the pramipexole group didn’t occur significantly more than those receiving the placebo. This large-scale trial confirms the efficacy of Mirapex as an antidepressant among individuals with Parkinson’s-induced depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20452823
2010: Effect of dopamine agonist pramipexole (mirapex) on tremor, affective disorders and quality of life in patients with Parkinson’s disease.
A Russian study conducted by Levin et al. (2010) assessed the effects of Mirapex on tremor, mood, and quality of life among those with Parkinson’s disease. The study took place over a 6-month term and included 98 patients (aged 42 to 75) that had been previously diagnosed with Parkinson’s disease. By the end of the 6-month term, researchers noted significant improvements in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) and Geriatric-Depression Scale (GDS-15).
Cumulative depressive symptoms had reportedly decreased by 56% (on average) as a result of pramipexole. In addition to reducing depressive symptoms, it improved overall quality of life among older adults and elderly patients. The drug was well-tolerated and appeared to provide a sustained therapeutic mood-boosting effect.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20436448
2008: Pain and depression in Parkinson’s disease: new therapeutic possibilities of pramipexole.
A study published by Letvinenko et al. (2008) sought to evaluate the effect of pramipexole administration for a 3-month term among patients with Parkinson’s disease. Researchers specifically aimed to understand whether pramipexole would improve symptoms of pain, but also documented its effect on mood. They recruited 78 patients, 30 of which were receiving pramipexole as an adjunct to L-DOPA and amantadine.
The intensity of pain as reported by patients often directly correlated with depression scores. Treatment with Mirapex not only reduced pain severity by 48.2%, but depression scores decreased after 12 weeks from “15.2” to “10.4” – a statistically significant amount. This provides evidence to suggest that pramipexole may target tremor, depression, and pain associated with Parkinson’s disease.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19008798
2008: Mirapex (pramipexole) in the treatment of non-motor disturbances in Parkinson’s disease.
A report by Nodel and Iakhno (2008) discusses the effect of Mirapex on non-motor disturbances in Parkinson’s disease. Specifically, it notes that Mirapex has been evaluated for anxiety, depression, cognitive, and sleep disorders – among 66 individuals diagnosed with Parkinson’s. Regardless of whether its used with L-DOPA (or other antiparkinson agents), it appears to effectively treat all aforestated non-motor disturbances – including depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18577955
2005: Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole.
An investigation conducted by Lemke et al. (2005) sought to understand whether administration of pramipexole (Mirapex) improved anhedonia, depression, and motor functioning among individuals with Parkinson’s disease. Authors assessed the frequency of anhedonia among 657 individuals diagnosed with Parkinson’s disease. They discovered that anhedonic tone was present in over 45% of patients and nearly 80% of depressed patients.
Patients with anhedonia exhibited more substantial deficits in motor skills and more severe depression compared to non-anhedonic patients. Upon administration of pramiprexole, anhedonia and overall depression significantly improved. This suggests that dopamine agonism provided by pramipexole is likely therapeutic for reversal of Parkinson’s-induced depression and anhedonia (as well as motor deficits).
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15939976
2004: Pramipexole in treatment-resistant depression: an extended follow-up.
A study conducted by Cassano et al. (2004) documented the long-term safety and efficacy of pramipexole when used as an antidepressant adjunct for cases of refractory depression. The study incorporated 23 patients that had been diagnosed with treatment-resistant depressive episodes over the course of 16-weeks. It should be noted that 12 of the patients were diagnosed with unipolar depression, while 11 patients were diagnosed with bipolar depression.
In all cases, pramipexole (at doses of 0.375-1.5 mg/day) was administered as an adjunct to either an SSRI or TCA. Prior to administration of pramipexole, patients were assessed with various neuropsychiatric rating scales including the: MADRS, CGI-S, and LIFE. Within 22 weeks of pramipexole administration, over 60% of participants (14 patients) experienced remission of depressive symptoms.
Approximately 24 to 28 weeks after remission, 5 participants (35%) experienced a resurgence of depressive symptoms. Side effects appeared limited and pramipexole was considered tolerable over a long-term. Authors concluded that pramipexole augmentation appears safe and effective as a treatment for unremitting episodes of major depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15549689
2004: Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression.
A study conducted by Goldberg et al. (2004) expanded upon previous research suggested that pramipexole may be an effective intervention fro refractory bipolar depression. Researchers set up a double-blinded, placebo-controlled, randomized trial of pramipexole incorporating 22 individuals with bipolar depression (based on DSM-IV criteria). A total of 12 patients were assigned to receive flexible-dosed pramipexole (~1.7 mg/day), while 10 were assigned to receive a placebo – in addition to an already-prescribed mood stabilizer.
The study was carried out for a period of 6 weeks and assessed antidepressant efficacy of pramipexole with the Hamilton Depression Rating Scale (HAM-D) by comparing pre-treatment (baseline) to post-treatment scores. The Clinical Global Impressions (CGI) was implemented as a secondary measure to the HAM-D. A total of 10 patients receiving pramipexole and 6 receiving the placebo – finished the study.
A total of 8 patients receiving pramipexole experienced significant improvement on HAM-D scores compared to just 2 patients receiving the placebo. Secondary measures of the CGI indicated that severity of depression was significantly reduced among the pramipexole users compared to placebo users. Investigators concluded that pramipexole appears safe and effective as a treatment for bipolar depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/14992985
2003: Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study.
A study conducted in Russia by Rektorová et al. (2003) examined the effect of pramipexole and pergolide for the treatment of depression among individuals with Parkinson’s disease. The study was conducted over an 8-month term, was multicenter, and incorporated a randomized, open-label design. A total of 41 patients participated in the study, each of which was diagnosed with Parkinson’s disease and symptomatic mild to moderate depression.
All patients had been receiving L-DOPA therapy and were assigned to receive either: pramipexole or pergolide as an adjunct. Prior to the study, researchers assessed depressive severity with the Montgomery-Asberg Depression Rating Scale (MADRS) and allowed patients to report symptomatic severity with the Self-Rating Depression Scale by Zung. By the end of the 8-month term, Self-Rating Depression Scale scores had significantly decreased among all 41 patients – regardless of whether receiving pramipexole or pergolide.
Additionally, both medications appeared to significantly improve motor function among Parkinson’s patients. However, only the group receiving pramipexole experienced a significant reduction in depression when measured by the Montgomery-Asberg Depression Rating Scale. Authors concluded that pramipexole elicits a significant antidepressant effect among patients with Parkinson’s-induced depression, whereas the antidepressant efficacy of pergolide remains unclear.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12823492
2002: Pramipexole in treatment-resistant depression: a 16-week naturalistic study.
A study conducted by Lattanzi et al. (2002) aimed to elucidate the efficacy of pramipexole among in-patients with treatment-resistant major depressive episodes (based on DSM-IV diagnostic criteria). A total of 37 patients were recruited for the study – 16 with unipolar depression and 21 with bipolar depression. At the start of the study, all patients were already being treated with either an SSRI or TCA (tricyclic) antidepressant.
Pramipexole was administered to all patients at dosages ranging from 0.375 mg/day to 1.0 mg/day. Researchers assessed antidepressant efficacy of add-on pramipexole based on changes of scores on neuropsychiatric scales including: Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) scale. Tolerability was determined based on changes in the Dosage Record Treatment Emergent Symptom Scale (DOTES).
Researchers noted that 6 patients dropped out of the study within the first week, leaving only 31 patients to be included in the final analysis. Of the 31 patients included in the final analysis, just 19 followed through with the 16-week follow-up. It was mentioned that 10 patients ceased pramipexole usage as a result of intolerable adverse reactions.
Authors concluded that pramipexole as an adjunct to an SSRI or TCA appears effective and well-tolerated among individuals with refractory depressive episodes. However, their conclusion that the drug was “well-tolerated” may be unjustified; 10 patients discontinued due to pramipexole-induced side effects. That said, it appears to provide antidepressant benefit for a majority of individuals experiencing treatment-resistant depressive episodes.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12479663
2001: Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series.
A study by Perugi et al. (2001) investigated the usage of dopamine agonists (DAAs) as interventions for treatment-resistant bipolar depression. Authors cited previous evidence suggesting pramipexole (Mirapex) and ropinirole (Requip) appear to effectively treat major depression, however, efficacy as a treatment for bipolar depression hadn’t been investigated. For their study, 18 individuals diagnosed with Bipolar 2 (NOS) treatment-resistant depressive episodes were reviewed.
In all cases, patients had derived no benefit from traditional antidepressants and mood stabilizers after 8 weeks. Researchers added dopamine agonists Mirapex and Requip as adjuncts to already-administered antidepressants and mood stabilizers. Improvement in depression was assessed with the Clinical Global Impression (CGI) scale and adverse effects were documented throughout the trial.
Results indicated that dopamine agonists were well-tolerated and didn’t appear to exhibit contraindications with already-administered medications. Of the 18 patients, a total of 8 derived clinically significant relief from depression based on change in CGI scores from baseline. Researchers concluded that both Mirapex and Requip may be therapeutically useful for the treatment of drug-resistant bipolar 2 depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/11518474
2000: Comparison of pramipexole, fluoxetine, and placebo in patients with major depression.
A relatively large-scale study conducted by Corrigan et al. (2000) compared the antidepressant efficacy of Mirapex (pramipexole), Prozac (fluoxetine), and a placebo – among individuals with major depression. Researchers organized a randomized, double-blinded, parallel group study among 174 individuals that had received diagnoses of major depression. The study began with all patients receiving a placebo for the first week.
For 8-weeks thereafter, patients were administered pramipexole at one of three doses (0.375 mg/day, 1.0 mg/day, or 5.0 mg/day) and were compared to a parallel-group of patients receiving fluoxetine 20 mg/day. Efficacy of these interventions were assessed based on changes in Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity (CGI-S) – at week 9.
Results documented that among patients receiving pramipexole 1.0 mg/day, clinically significant improvements in depression were observed based on the HAM-D, MADRS, and CGI-S by the end of 8 weeks. Furthermore, the group receiving pramipexole 5.0 mg/day appeared to derive the most substantial mood improvements by the end of 8 weeks. However, at the high dose of 5.0 mg/day, tolerability issues were more prominent (as evidenced by a heightened drop-out rate among those receiving this dose).
The individuals receiving fluoxetine 20 mg/day exhibited significant improvements at the end of 8 weeks based on the MADRS, but not the HAM-D nor CGI-S. Researchers concluded that pramipexole appears to alleviate depressive symptoms at 1.0 mg/day and more significantly as the dosage is increased to 5.0 mg/day. That said, greater tolerability issues seem to occur at the high-end of the daily dosing range.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10812530
2000: Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review.
A study conducted by Sporn et al. (2000) documented the efficacy and safety of pramipexole as an adjunct treatment in cases of refractory depression (unipolar and bipolar). Prior to pramipexole treatment, patients were taking antidepressants and/or mood stabilizers without satisfactory symptomatic relief. This investigation assessed the efficacy of pramipexole among 32 patients in a naturalistic setting.
Efficacy of pramipexole as an adjunct was determined based upon change in Clinical Global Impressions (CGI) scores from baseline. The average dose of pramipexole administered was 0.70 mg/day for an average total duration of 24 weeks. Results indicated that 6 of 12 patients with refractory bipolar depression and 8 of 20 patients with unipolar depression – derived significant antidepressant benefit from pramipexole as an adjunct.
Of the 32 patients, 4 discontinued due to adverse reactions, while 8 discontinued due to lack of therapeutic effect. Authors concluded that pramipexole may be an effective, safe adjunct for the treatment of refractory unipolar and bipolar depression. That said, they noted that this was a small-scale, naturalistic pilot study and that further research is necessary to elucidate the antidepressant efficacy of pramipexole.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10984002
Limitations associated with research of Mirapex for Depression
There is considerable evidence to suggest that Mirapex is likely effective when used as a standalone antidepressant, as well as when used as an adjunct to a conventional antidepressant (e.g. SSRI). However, it is necessary to realize that there are some limitations associated with research of Mirapex as an antidepressant. Several notable limitations include: lack of large sample sizes, suboptimal trial designs, and unclear dosing guidelines.
- Adjunctive efficacy: Although many studies document the efficacy of Mirapex as an adjunctive agent to a first-line antidepressant, some investigations report poorer tolerability and efficacy compared to its standalone usage. Further research is necessary to determine whether Mirapex is legitimately effective as an adjunct. Additionally, researchers should attempt to elucidate whether adjunctive Mirapex is better tolerated and/or more effective with certain antidepressant classes (e.g. SSRIs) compared to others (e.g. TCAs). Thereafter, researchers may even want to investigate whether adjunct Mirapex is better tolerated and/or more effective when used with a specific agent (e.g. mirtazapine) compared to another (e.g. escitalopram).
- Depression specifics: Numerous studies have investigated the antidepressant potential of Mirapex, but not all studies incorporate the same subtypes of depression. Despite being documented as “effective” in many studies for depression, many of these studies are small-scale and focused solely on depression associated with Parkinson’s disease. It is important to understand whether Mirapex is effective for other depressive subtypes such as bipolar or unipolar depression, as well as refractory vs. non-refractory cases.
- Dosing guidelines: The guidelines for dosing of Mirapex among the clinically depressed are vague and may be subject to interindividual variation based on numerous factors including: body size, sensitivity, other medications (and their dosages), etc. That said, researchers haven’t pinpointed recommended dosages of Mirapex when used as an antidepressant adjunct compared to a standalone treatment. Some studies note that higher doses are more effective, but tolerability may be an issue for patients at high levels.
- Format: It is possible that one format of Mirapex may result in greater patient compliance and/or efficacy than another. Mirapex is manufactured in both immediate-release and extended-release tablets. Some speculate that the extended-release tablets may result in favorable compliance among patients, thereby keeping depression at bay better than t.i.d. dosing with immediate-release formats.
- Monotherapy: Many studies highlight the efficacy of pramipexole when used as an adjunct, but few intentionally investigate its efficacy as a monotherapy. While some studies note that it improves depressive symptoms among those with Parkinson’s disease as a monotherapy, most research involves administration of pramipexole along with either: an antidepressant (TCA or SSRI), mood stabilizer, or L-DOPA. Additional studies are necessary to evaluate the efficacy of pramipexole as a standalone antidepressant; preliminary evidence suggests it may be equally as therapeutic as FDA-approved SSRIs.
- Sample sizes: To truly understand whether Mirapex is an effective antidepressant, we’d need to recruit a large sample of individuals with depression for a trial. Larger samples give us a better idea of whether a particular drug is effective or ineffective. Many studies investigating the antidepressant efficacy of pramipexole among individuals without Parkinson’s disease have fewer than 35 participants. Although the data extracted from these studies could be accurate, it necessitates follow-up confirmation with larger samples.
- Study designs: Ideally, research of pramipexole as an antidepressant would incorporate double-blinded, placebo-controlled, randomized designs. Studies would all incorporate large sample sizes and take place over an extended duration. Unfortunately, it’s relatively difficult to fund such robustly designed studies, and for this reason, the robustness of study designs in pramipexole research (as an antidepressant) is lacking. This may lead researchers to question the legitimacy of preliminary findings.
- Tolerance investigation: Users of nearly any antidepressant can vouch for the fact that over time (e.g. years), the drug stops working or diminishes in efficacy. The reason it stops working is a result of neurophysiological tolerance. While some drugs (e.g. psychostimulants) are clearly associated with faster tolerance onset (e.g. SSRIs) than others, tolerance is inevitable. Researchers may want to investigate how long it takes an individual with non-Parkinson’s depression to become tolerant to Mirapex.
- Tolerability: Researchers report no significant issues with the tolerability of Mirapex, yet in many studies, a significant portion of participants “dropped out” or discontinued due to drug-related adverse effects. Though the drug is approved by the FDA for the attenuation of Parkinson’s symptoms and RLS, tolerability among those with depression should be separately assessed. Tolerability of Mirapex may warrant comparison to conventional antidepressant to determine whether it could (potentially) serve as a viable first-line atypical option.
Verdict: Mirapex (Pramipexole) Likely Effective for Depression
Evidence from the 12 aforementioned studies highlights notable therapeutic potential of Mirapex for the treatment of depression. There is perhaps most robust evidence to support usage of Mirapex as an antidepressant among individuals with Parkinson’s disease. The depression associated with Parkinson’s disease is thought to stem from deficient dopaminergic signaling in the striatal region of the basal ganglia.
Administration of Mirapex to Parkinson’s patients normalizes activation of hypofunctional dopamine receptors in the striatum, leading to improvements in motor function. What’s more is that correction of striatal dysfunction with Mirapex appears to significantly improve depressive symptoms such as anhedonia and psychomotor retardation among Parkinson’s patients. The drug is clearly an effective antidepressant for those diagnosed with Parkinson’s disease.
Due to several of the limitations (highlighted above), it is unclear as to whether Mirapex can be considered a clinically effective antidepressant. However, in nearly every study, it was found effective as either: an adjunct or standalone treatment for bipolar and/or unipolar depression – particularly cases in which the depression was unresponsive to first-line conventional treatments. Therefore, it is logical to conclude that Mirapex (pramipexole) should be considered among those for whom first-line options are ineffective and/or intolerable.
It may also be worth a shot if a patient’s depressive symptoms are suspected to stem from deficient dopaminergic (rather than serotonergic) signaling. Since the drug is also approved for the treatment of RLS, cases of comorbid depression (along with RLS) may want to test standalone treatment with Mirapex (as opposed to a combination of drugs which may lead to more side effects). The bottom line is that Mirapex can significantly treat depressive symptoms and there’s no published evidence to undermine its efficacy.
What dosage of Mirapex works best for depression?
The dosage of Mirapex that’s best for depression may depend entirely on the individual. Some individuals are more sensitive to medication than others, and thus may require a lower dose. That said, it also depends whether the individual with depression is using Mirapex as an adjunct or standalone treatment; higher dosages may be better tolerated among those taking it as a standalone compared to an adjunctive agent (along with an SSRI, TCA, or mood stabilizer).
Assuming you are suffering from unipolar major depression, optimal dosages have been suggested to range from 1.0 mg/day to 5.0 mg/day. Research indicates that individuals taking the highest possible dosages of Mirapex derived the most substantial antidepressant benefits compared to those taking lower dosages. There is no evidence that standalone Mirapex administered under 1.0 mg/day provides significant antidepressant benefit.
That said, when used as an adjunctive intervention, Mirapex is often most successful at a lower dosage of 0.375 mg/day to 1.0 mg/day. Most psychiatrists and psychopharmacologists will understand how to properly calibrate your dosage based upon other medications you’re taking and individual sensitivity. Although higher doses of Mirapex appear to provide more benefit, tolerability should be evaluated.
Have you tried Mirapex (Pramipexole) for depression?
If you’ve used Mirapex (pramipexole) for depression, share your experience in the comments section below. Mention whether you found it therapeutically effective, ineffective, or if it exacerbated your underlying depressive symptoms. To help others get a better understanding of your situation, share some details such as: whether you were taking it as a standalone or adjunct, your psychiatric diagnosis (e.g. refractory, unipolar depression), the dosage used (e.g. 1.0 mg/day), and format (standard or extended-release).
Among those that found Mirapex effective as an antidepressant, document the degree to which it improved your depressive symptoms (on a scale of 1 to 10). How long did it take for you to notice the therapeutic effects of Mirapex “kicking in?” Did it take several weeks after your first dose for your mood to lift? Or did you notice mood improvement within just a few days after your initial dose?
Understand that while Mirapex may be an effective antidepressant (as a standalone), it is still considered “off-label,” in that it is not formally approved by the FDA for the treatment of major depression. Also realize that many individuals experience unwanted side effects and have trouble tolerating Mirapex, especially at high doses. That said, it appears as though Mirapex is another reasonable option for those who fail to attain relief from conventional antidepressants.