Augmentative dopaminergic interventions for treatment-resistant bipolar depression: a focus on dopamine agonists and stimulants

Interventi farmacologici dopaminergici in associazione per il trattamento della depressione bipolare farmaco-resistente: focus su dopamino-agonisti e stimolanti

B. Dell’Osso, L. Cremaschi, G. Spagnolin, T.A. Ketter1, A.C. Altamura

Department of Psychiatry, University of Milan, Fondazione IRCCS “Ca’ Granda”, Ospedale Maggiore Policlinico, Milan, Italy; 1 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA


Bipolar depression is the most difficult-to-treat phase of bipolar disorder, in relation to its significant disruption of every-day life functioning and high suicidality risk. Despite the availability of several treatment options, the management of bipolar depression is still particularly challenging, with limited approved therapies. Mood stabilizers and second-generation antipsychotics may not be as effective in ameliorating depressive compared to mood elevation symptoms, and entail substantial somatic tolerability limitations. In contrast, antidepressants are widely used off-label in bipolar depression (perhaps in part due to their better somatic tolerability), but such use is controversial, as they may be associated with a higher risk of manic/hypomanic switch and rapid cycling. Among pharmacological augmentation strategies, compounds with pro-dopaminergic activity such as stimulants and stimulant-like agents (e.g., methylphenidate, modafinil and armodafinil) and dopamine agonists (e.g., pramipexole and ropinirole), have shown potential antidepressant effects, even though their use in clinical practice is still limited by the paucity of systematic evidence of efficacy and safety. The present review sought to summarize available evidence about such augmentative dopaminergic interventions for treatment-resistant bipolar depression, considering results of recent randomized controlled trials, as well as open studies, systematic reviews and guidelines indications.


A systematic review of the literature was conducted. We first identified articles published in English and focused on the use of stimulants and dopamine agonists in bipolar disorder, using the keywords ‘stimulant’, ‘psychostimulant’, ‘amphetamine’, ‘methylphenidate’, ‘modafinil’, ‘armodafinil’, ‘pramipexole’, ‘ropinirole’, ‘dopamine agonists’, variably combined with ‘bipolar disorder’, ‘bipolar depression’, ‘major depression’ and ‘treatmentresistant depression’. A second search was conducted about safety and tolerability, combining the keywords ‘stimulant’, ‘psychostimulant’, ‘methylphenidate’, ‘modafinil’, ‘armodafinil’, ‘pramipexole’, ‘ropinirole’, ‘dopamine agonists’ with ‘tolerability’, ‘safety’, ‘side-effects’, ‘adverse events’, ‘discontinuation’, ‘drop out’, ‘mania’, ‘suicide’, ‘cycle acceleration’. Additionally, reference lists of retrieved articles and proceeding of recent scientific meetings were manually searched for relevant publications.


21 reports met the inclusion criteria and were herein reviewed in detail. 11 reports described of pramipexole in adult bipolar depression, including 2 double-blind RCTs targeting depressive symptoms, 1 double-blind RCT targeting cognitive dysfunction, and 8 open reports, and one report on the use of ropinirole in bipolar depression was identified. 10 reports focused on the use of adjunctive stimulant-like agents and stimulants, including 1 double- blind armodafinil RCTs, and 1 double-blind modafinil RCT targeting depressive symptoms, 4 open uncontrolled modafinil studies, and 4 open uncontrolled methylphenidate studies. With respect to the use of stimulants in adult bipolar depression, although systematic evidence is quite limited, available data seems to support their use in at least some bipolar depressed patients, especially when they show significant drowsiness or fatigue. In contrast, the use of the stimulant-like agents modafinil and armodafinil seems to be more robust, supported by 2 RCTs as well as 4 open reports.


Taken as a whole, findings from reviewed studies seem to suggest that pro-dopaminergic compounds agonists, such as pramipexole and stimulant-like agents, deserve consideration as potential adjunct therapeutic agents in adult bipolar depression, at least in specific subgroups of patients, although caution for supporting their use is still recommended. Future research and clinical trials on larger samples and greater follow-up periods are encouraged to extend available evidence and better clarify the potential role of these medications in bipolar depression.

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