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

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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. Copyright \ua9 2013 by Pacini Editore S.p.A

Antidepressants have complex associations with longitudinal depressive burden in bipolar disorder

Aims: Antidepressants are common in bipolar disorder (BD), but controversial due to questionable efficacy/tolerability. We assessed baseline antidepressant use/depression associations in BD. Methods: Stanford BD Clinic outpatients, enrolled during 2000\u20132011, assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, were monitored up to two years with the STEP-BD Clinical Monitoring Form while receiving naturalistic expert treatment. Prevalence/correlates of baseline antidepressant use in recovered (euthymic 658 weeks)/depressed patients were assessed. Kaplan\u2013Meier survival analyses assessed times to depressive recurrence/recovery in patients with/without baseline antidepressant use, and Cox Proportional Hazard regression analyses assessed covariate effects. Results: Baseline antidepressant use was significantly (albeit without Bonferroni multiple comparison correction) less among 105 recovered (31.4%) versus 153 depressed (44.4%) patients, and among recovered patients (again without Bonferroni correction), associated with Caucasian race, earlier onset, worse Clinical Global Impression scores, and hastened depressive recurrence (only if mood elevation episodes were not censored), driven by lifetime anxiety disorder, and more (even with Bonferroni correction) bipolar II disorder, lifetime anxiety and eating disorders, and core psychotropics. Baseline antidepressant use among depressed patients was associated with significantly (again without Bonferroni correction) older age, female gender, and more (even with Bonferroni correction) anxiolytics/hypnotics, complex pharmacotherapy, and core psychotropics, but no other unfavorable illness characteristic/current mood symptom, and not time to depressive recovery. Limitations: Tertiary BD clinic referral sample receiving open naturalistic expert treatment. Analyses without/with Bonferroni correction. Conclusions: Additional research is required to assess the complex associations between baseline antidepressant use and longitudinal depressive burden in BD

Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management

Use of adjunctive stimulants in adult bipolar depression

Bipolar depression represents a high priority research field, due to its pervasiveness, and high economic and personal (suicidality, impaired function, quality of life) costs, and the limited evidence base to inform therapeutics. Mood stabilizers and second-generation antipsychotics for bipolar depression are commonly only partially effective, and their side-effects may overlap with depressive symptoms such as hypersomnia, daytime drowsiness, fatigue, psychomotor retardation, and weight gain. Moreover, the use of antidepressants in bipolar depression is controversial due to concerns regarding the risks of inefficacy or switching to mood elevation. Stimulants and related compounds such as modafinil and armodafinil have on occasion been used as adjuncts in bipolar depressed patients with encouraging results, but their use is limited by the paucity of systematic evidence of efficacy and safety. The present review aims to provide an updated perspective on the use of stimulants and stimulant-like medications in adult bipolar depression, considering not only recent randomized controlled trials, but also open naturalistic studies, in order to clarify the strengths and limitations of using these agents

Treatment of bipolar disorder : Review of evidence regarding quetiapine and lithium

Background Lithium, the prototypical mood stabilizer, and quetiapine, a second-generation antipsychotic, are widely used acute and maintenance pharmacotherapies for bipolar disorder. The Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study was the first comparative effectiveness assessment of lithium versus quetiapine (in combination with adjunctive personalized treatment), and found no overall significant differences in efficacy and safety/tolerability outcomes between lithium and quetiapine. Completion of Bipolar CHOICE offers a timely opportunity to review the evidence regarding lithium and quetiapine for bipolar disorder. Methods Controlled clinical trials and real-world observational studies that included quetiapine and lithium as monotherapy or as combination therapy were identified by literature search. Selected studies were reviewed in detail. Results Review of the available trials suggested comparable efficacy of quetiapine and lithium in acute mania, and possibly greater efficacy for quetiapine compared with lithium in acute bipolar depression and in prevention of recurrent (particularly depressive) episodes. Combination therapy including quetiapine and lithium was generally more effective than either agent alone in acute mania and bipolar maintenance, although adding lithium to quetiapine did not increase efficacy in acute bipolar depression. Safety data for quetiapine and lithium were consistent with the established profiles of the two treatments. Limitations Limitations include those of the available efficacy and effectiveness trial data. Conclusions Quetiapine and lithium have overlapping but distinctive roles in different phases of bipolar disorder, and further studies of these agents (particularly in combination with one another) are warranted