Dopamine D2 and D3 Agonist Pramipexole May Enhance Cognitive Function in Bipolar I Disorder
Anil Malhotra from the Zucker Hillside Hospital found that pramipexole (Mirapex), a dopamine D2 and D3 agonist used in the treatment of Parkinson’s disease, improved measures of processing speed and working memory in euthymic bipolar patients (whose average age was 42) when compared with placebo in an adjunctive clinical trial.
Editor’s Note: Bipolar patients in a euthymic phase have consistently been shown to have some degree of cognitive dysfunction that is typically correlated with the number of prior depressive and/or manic episodes they have experienced. This is one of the first studies to directly target this cognitive dysfunction with a pharmacotherapeutic agent.
Pramipexole may be of additional value among depressed patients, because in two small, placebo-controlled studies, one led by Carlos Zarate at the National Institute of Mental Health and one led by Joseph F. Goldberg in New York, pramipexole has been shown to exert acute antidepressant effects in bipolar patients in the depressive phase of the illness. The new data from Malhotra raise the possibility that there could be a two-for-one benefit when pramipexole is used in the depressive phase of bipolar illness—improvement in both depression and cognition.
Other approaches to improving cognition in patients with bipolar disorder
There are other interventions that can improve cognitive function in bipolar patients. These include: optimizing pharmacotherapy in order to eliminate residual manic or depressive symptoms and achieve a complete remission; removing potentially sedating or cognition-impairing agents; adding folic acid, thereby reducing levels of homocysteine, which are directly correlated with degree of cognitive dysfunction in euthymic bipolar patients; using the indirect dopamine agonist bupropion (Wellbutrin), which has been shown to have some positive effect in those with ADHD; using modafanil (Provigil) to treat residual depressive symptoms and attention and concentration dysfunction; reserving use of psychomotor stimulants for later stages of the treatment algorithm, since these may be associated with the development of tolerance when used to treat residual depressive symptoms; and, finally, considering the use of anti-Alzheimer’s drugs such as the acetylcholinomimetic agents, including donezepil (Aricept) and the NMDA inhibitor memantine (Namenda).
Cognitive improvement can also occur with the dihydropyridine l-type calcium channel blocker nimodipine (Nimotop), which has been shown to increase somatostatin in cerebrospinal fluid. Somatostatin is often low in those with depression and Alzheimer’s disease. Now pramipexole is an option, particularly in instances of mild residual depression and/or an inability to tolerate the indirect dopamine agonist bupropion (Wellbutrin).
Since in multiple studies the degree of cognitive dysfunction has appeared to be related to the number of prior episodes, it is important to institute effective long-term preventive treatment as early in the course of bipolar disorder as possible in order to limit the number of manic and depressive episodes and thus prevent cognitive decline.
Preventive treatment with mood stabilizers not only helps patients avoid episode-related cognitive deficits directly, it also increases levels of brain-derived neurotrophic factor (BDNF). BDNF has neuroprotective effects and is necessary for learning and long-term memory. For example, animals whose brain BDNF was reduced 50% also lost their ability to perform easy tasks, such as learning to navigate a maze.
Since each episode of mania or depression is associated with decreases in BDNF, using agents that both prevent episodes (and thus prevent episode-related decreases in BDNF) and increase BDNF directly may be of particular clinical importance. Lithium, valproate, carbamazepine and lamotrigine all increase BDNF, and additionally several of these agents have been shown to increase the production of new neurons (neurogenesis) in the hippocampus as well. The atypical antipsychotic quetiapine also increases BDNF in the hippocampus and prevents stress from reducing BDNF, as do many other antidepressant modalities. Ziprasidone (Geodon) prevents stress from decreasing BDNF in the hippocampus, although the drug does not increase BDNF in the hippocampus.
It is noteworthy that in the ziprasidone studies, the typical antipsychotic haloperidol not only did not prevent stress-induced decreases in BDNF, but it actually exacerbated them.
The best defense against cognitive deficits may be lithium. Preliminary studies by Lars Kessing and colleagues suggest that long-term use of lithium may actually reduce the incidence of dementia in late life; the risk of late-life dementia also appears to be associated with an increasing number of prior depressive episodes. Lithium could thus reduce the risk of dementia by: 1) preventing episodes; 2) increasing BDNF, BCl-2, and neurogenesis; and 3) increasing hippocampal volume.