During the last few decades, there has been growing interest in identifying and treating cognitive impairment in bipolar disorder, especially as it persists in remission periods. In this analysis, Brisa Solé, PhD, from the University of Barcelona in Spain, and colleagues reviewed existing treatment approaches and provide recommendations for further research. Their analysis was published in the International Journal of Neuropsychopharmacology.
Treatments and Prevention Strategies
Many different drugs have been examined for potential benefits to neurocognitive impairment in bipolar disorder, including cholinesterase inhibitors, glutamate receptor antagonists, glucocorticoid receptor antagonists, dopaminergic agonists, intranasal insulin, some antioxidants, erythropoietin, and more.
“Unfortunately, there is no well-established pharmacological treatment for cognitive impairment, since studies have yielded mixed results with no convincing effects,” the researchers noted.
“Among all the components tested, very few of them have demonstrated positive effects on cognition.”
Below are some of the drugs examined for their effects on neurocognitive impairment in bipolar disorder:
- Mifepristone, a corticosteroid receptor antagonist: There is preliminary evidence of improved spatial working memory in depressed patients with bipolar disorder.2,3
- Pramipexole, a dopaminergic agonist: This drug might have a beneficial effect on processing speed and working memory, but the effect was only observed in euthymic patients with bipolar I disorder in a post hoc analysis of an 8-week, double-blind, placebo-controlled trial.4
- Intranasal insulin: This treatment showed an effect in executive function in euthymic patients, but showed no effect on primary cognition outcomes or other secondary outcomes.5
- Extract of Withania somnifera, an herbal medicine with antioxidant and neuroprotective effects: Euthymic and subsyndromal patients with bipolar disorder showed a better performance in auditory-verbal working memory.6
- Erythropoietin: Although no effect was seen in verbal memory, improvements were seen in sustained attention, working memory, executive function, and recognition of facial expression in euthymic patients.7
- Galantamine, a cholinesterase inhibitor: Some studies have reported a potential benefit in verbal memory, even in patients receiving electroconvulsive therapy.8,9,10,11
- N-acetyl cysteine: Results from large clinical trials found no benefit in cognitive functioning.12,13 However, in another study, patients with bipolar disorder were grouped with patients with schizophrenia, and those treated with N-acetyl cysteine for 6 months were found to have enhanced working memory performance.14
Previous research on cognitive remediation in schizophrenia has provided some guides for cognitive remediation in bipolar disorder. However, very few studies have focused exclusively on patients with bipolar disorder, and many were conducted with mixed affective disorder participants and were not rigorously controlled.
“Therefore, it is necessary to adjust or develop new interventions specifically addressed to the characteristics of the latter group,” the researchers wrote.
Some nonpharmacological approaches include:
- Functional remediation: an intervention aimed at restoring psychosocial functioning in bipolar patients. “In 21 weekly sessions, functional remediation provides several neurocognitive strategies and techniques for daily life to tackle the main neurocognitive deficits associated with [bipolar disorder] (e.g. attention, memory, and executive functions),” the researchers wrote.
- Several studies have found functional remediation to be effective at improving psychosocial outcome, including interpersonal and occupational functioning. One study found this to be effective in patients with bipolar II disorder and in cognitively impaired patients, and other studies found the intervention to have been effective at 1 year.14,15,16,17
- A study of briefer functional remediation treatment also found improvement in patients with bipolar I disorder; however, another study found that 12 weeks of functional remediation was not effective in patients with bipolar I disorder, with the authors suggesting that a longer, more intensive intervention might be necessary.18,19
- “Due to the fast advance in information and communication technology issues, one challenge in cognitive remediation is to implement computerized neurocognitive treatments in an effective manner. This kind of intervention delivery makes easier the accessibility to patients engaged in working life as well as to younger users who are familiar with new technologies,” the researchers noted.
- Strategies to enhance social cognition: an intervention intended to improve emotion perception, attributional style, and theory of mind. Results from 1 study showed that “[it] was found to be effective at improving…social cognition domains but not social functioning.”20
- Mindfulness-based interventions: Some studies have seen success in mindfulness-based interventions at reducing anxiety and depression, or as an adjunct to medication.18,21,22
- Transcranial magnetic stimulation and deep transcranial magnetic stimulation: Although some studies have shown these treatments to improve working memory, psychomotor speed, and visuospatial memory, other results have contradicted these findings.23,24,25
- “Therefore, studies with brain stimulation techniques are still rare in BD, and more studies will be required to assess the magnitude of effects compared with placebo and the durability of them,” the researchers wrote. “Even so, these extant studies raise several methodological considerations to keep in mind for further studies in order to achieve a potential cognitive enhancement…. Therefore, as noted, interventions focused on the enhancement of cognition and psychosocial functioning in bipolar patients are still in the early stages, and further research is needed to find the key components of cognitive and/or functional remediation.”
Preventing Cognitive Impairment With Multiple Strategies
It is important that clinicians prevent cognitive impairment with multiple strategies. For example, because cognitive impairment seems to be present from the first manic episode, interventions are needed in the early stages to avoid affective recurrences and to reverse neurocognitive deficits.16 “After achieving the remission of an acute episode, it will be necessary to use an effective pharmacotherapy for relapse prevention, implement psychoeducation programs to avoid multiple episodes, and promote healthy habits,” the researchers wrote.
Another step to treating cognitive impairment in bipolar disorder is to identify and treat subclinical symptoms and comorbidities, including substance use disorder, anxiety, attention deficit hyperactivity disorder, and obesity.
“Neurocognitive impairment needs to be considered a therapeutic clinical target in order to improve both psychosocial functioning and quality of life of patients with [bipolar disorder],” the researchers wrote. “Available evidence underscores that cognitive dysfunction is a critical mediator of adverse psychosocial outcomes in [bipolar disorder] and a predictor of unfavorable employment outcomes.”
Despite increased research in the last decade, no robust evidence of interventions for cognitive impairment in bipolar disorder is currently available. Further research is needed to draw any firm conclusions.
Disclosures: Dr Martinez-Aran has served as speaker or advisor for the following companies: Bristol-Myers Squibb, Otsuka, Lundbeck and Pfizer. Dr Vieta has received grants, CME-related honoraria, or consulting fees from AB-Biotics, Actavis, Alexza, Almirall, Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo Pharma, Eli Lilly, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Pierre-Fabre, Qualigen, Roche, Sanofi-Aventis, Schering-Plough, Servier, Shire, Solvay, Sunovion, Takeda, Teléfónica, Teva, the Spanish Ministry of Science and Innovation, the Brain and Behaviour Foundation, the Seventh European Framework Programme, the Stanley Medical Research Institute, United Biosource Corporation, and Wyeth. Dr Carvalho received speaker honoraria from Abbott, GlaxoSmithKline, Lundbeck, Pfizer, and Ache.
- Solé B, Jiménez E, Torrent C, et al. Cognitive impairment in bipolar disorder: treatment and prevention strategies [published online May 11, 2017]. Int J Neuropsychopharmacol. doi: 10.1093/ijnp/pyx032
- Young AH, Gallagher P, Watson S, Del-Estal D, Owen BM, Ferrier IN. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology. 2004;29:1538-1545. doi: 10.1038/sj.npp.1300471
- Watson S, Gallagher P, Porter RJ, Smith MS, Herron LJ, Bulmer S; North-East Mood Disorders Clinical Research Group, Young AH, Ferrier IN. A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol Psychiatry. 2012;72:943-949. doi: 10.1016/j.biopsych.2012.05.029
- Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK. Placebo-controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting cognitive dysfunction. J Clin Psychiatry. 2012;73:103-112. doi: 10.4088/JCP.11m07299
- McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Vaccarino A, Macqueen G, Lewis GF, Kennedy SH. A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord. 2012;14:697-706. doi: 10.1111/bdi.12006
- Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013;74:1076-1083. doi: 10.4088/JCP.13m08413
- Miskowiak KW, Ehrenreich H, Christensen EM, Kessing LV, Vinberg M. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry. 2014;75:1347-1355. doi: 10.4088/JCP.13m08839
- Matthews JD, Blais M, Park L, Welch C, Baity M, Murakami J, Sklarsky K, Homberger C, Fava M. The impact of galantamine on cognition and mood during electroconvulsive therapy: a pilot study. J Psychiatr Res. 2008;42:526-531. doi: 10.1016/j.jpsychires.2007.06.002
- Ghaemi SN, Gilmer WS, Dunn RT, Hanlon RE, Kemp DE, Bauer AD, Chriki L, Filkowski MM, Harvey PD. A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder. J Clin Psychopharmacol. 2009;29:291-295. doi: 10.1097/JCP.0b013e3181a497d7
- Iosifescu DV, Moore CM, Deckersbach T, et al. Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study. CNS Neurosci Ther. 2009;15:309-319. doi: 10.1111/j.1755-5949.2009.00090.x
- Matthews JD, Siefert CJ, Blais MA, Park LT, Siefert CJ, Welch CA, Dubois CM, van Nieuwenhuizen AO, Rooney KO, Seabrook RC, Durham LE, Adams HC, Fava M. A double-blind, placebo-controlled study of the impact of galantamine on anterograde memory impairment during electroconvulsive therapy. J ECT. 2013;29:170-178. doi: 10.1097/YCT.0b013e31828b3523
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- Berk M, Dean OM, Cotton SM, et al. Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial. BMC Med. 2012;10:91. doi: 10.1186/1741-7015-10-91
- Rapado-Castro M, Dodd S, Bush AI, et al. Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med. 2017;47:866-876. doi: 10.1017/S0033291716002932
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