The most troublesome statement in Goodwin and Jamison’s Manic-Depressive Illness may be this: “Complete symptomatic remission does not ensure functional recovery.”1 This is no small problem. For some 30% to 60% of patients with bipolar disorder, simply treating their mood symptoms is not enough to help them return to a full life.2
There’s a third pole that needs to be addressed for that to happen: cognitive symptoms. These often persist even when patients are euthymic, and they range from problems with memory and attention to more subtle deficits such as picking up on social cues and making wise decisions. The steps below, culled from clinical experience and a systematic literature review, should help you guide your patients toward a fuller recovery.
1. Educate. Patients usually become aware of cognitive problems as their mood starts to lift. Unless they are prepared for that disappointment, there is a risk they may blame their medications and stop treatment.
2. Adjust medications carefully. Cognitive side effects tend to be dose-dependent, so a careful dose reduction can often clarify whether a medication is contributing to the problem.
3. Choose mood stabilizers with a favorable cognitive profile. Lamotrigine stands out here. Although it can cause word-finding difficulties, lamotrigine improves multiple areas of cognition, according to large open-label studies and a post-hoc analysis of controlled trials.3-5
Two studies from 2016 place lithium’s cognitive profile in a more favorable light than its reputation would suggest. A review found no clear evidence of cognitive side effects from lithium,6 and a randomized trial showed that lithium improves verbal fluency (or at least doesn’t worsen it as much as quetiapine, which was the comparator arm in this study that followed 61 patients for a year after a manic episode).7
There are still a few cognitive pitfalls with lithium, including the fact that these optimistic results may not apply to all patients. Cognition may be impaired because of subclinical hypothyroidism in patients who take lithium,6 and optimizing thyroid-stimulating hormone levels can help (a good target is 2.4 microIU/mL).8 Lithium can also slow motor speed, and some patients interpret that slowing as a cognitive effect.6
Cognitive side effects tend to be worse for valproate, carbamazepine, and possibly the atypical antipsychotics, but all of these findings vary widely by study, by patient, and even by genetics.9 In practice, that means it can take a lot of custom tailoring to get it right. There will certainly be patients whose cognition is worse on lithium and better on valproate, though the research may favor lithium on average.
4. Lifestyle. In order of importance, I emphasize: sleep, exercise, and diet. A large body of research supports a role for each of these in cognition and mood, though specific studies in bipolar disorder are scarce.10 A good dose of exercise is 30 to 60 minutes of aerobics every other day.11 Lowering saturated fats and simple sugars is the most important dietary change. The MIND diet is a nice blend of several approaches that have research support for cognition (it stands for "Mediterranean-DASH Intervention for Neurodegenerative Delay").12 Foods rich in flavanols seem have cognitive benefits as well (eg, tea, berries, and dark chocolate).13
5. Therapy. Functional Remediation Therapy is a new approach in which patients practice exercises in a group setting to improve their cognitive and social skills. It appears better at restoring functioning than directly improving cognition—but then again, wasn’t that the goal we started out with here? Still, the effect sizes are small, and only 2 out of 3 trials were positive.2 Some of these groups used web-based trainings between sessions, and the programs they chose are available at: www.cognifit.com, www.rehacom.us, and www.brainhq.com.
6. Augmentation. Ashwagandha is an Indian form of ginseng that has neuroprotective effects on the hippocampus. In patients with euthymic bipolar disorder, it improved memory, reaction time, and social cognition in a randomized, placebo-controlled trial (n = 53; effect sizes, 0.26-0.62). Look for products with the Sensoril formulation, as that was the type used in the study (target dose, 500 mg/d; starting dose, 250 mg/d for the first week).14
Two other agents that are helpful in bipolar depression, modafinil and omega-3 fatty acids, are worth considering. Their cognitive benefits are not known in bipolar disorder, but are well-documented in non-affective populations.10,15 I’ve seen good results with modafinil and armodafinil, and a trial is underway that will test whether that observation passes the muster of placebo-control.16
That reminds me: There’s a long list of treatments that generated initial hope but did not pan out in controlled trials. These include 3 that improve bipolar depression but not cognition (pramipexole, N-acetylcysteine, and methylene blue); and several Alzheimer agents (donepezil and galantamine, though galantamine did help memory during ECT). Future directions to look for include intranasal insulin, which is undergoing phase II trials for Alzheimer disease and has a positive study for cognition in bipolar,17 and erythropoietin, which has several positive studies but carries a thrombolytic risk.18
7. Pay attention to substance use. Cognition is worse in those with dual diagnosis,2 and in the case of cocaine there is a natural treatment that can improve mood, cognition, and sobriety. Citicoline is a neuroprotective agent with 2 positive controlled trials in bipolar with cocaine abuse, and another in unipolar and bipolar with methamphetamine use. It is well-tolerated and available through online retailers (target dose, 1000 mg/d, after starting at 500 mg/d for the first week).19
8. Test for herpes simplex virus-1 (HSV-1). Cognition is significantly worse in patients with bipolar disorder who are seropositive for this common virus, and antiviral therapy can help. Valacyclovir improved several cognitive measures in this population in a randomized, double-blind, placebo-controlled trial (n = 60; the study is in press but has been presented at meetings).20
That’s a start, but we clearly need more research in this area. It’s also a start for me. Jim Phelps, MD, who created this column a few years back, has generously invited me to join him in the adventure. We’ll be scouring the research to bring you new and forgotten findings in bipolar, and sharing our passion for the humanistic side of this all-too-human disorder. In an upcoming column, we’ll delve deeper into cognition with a how-to-guide on Functional Remediation Therapy.
Dr. Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, which he coauthored with Jim Phelps, MD.
1. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. Oxford, UK: Oxford University Press; 2007.
2. Vieta E, Torrent C, Martínez-Arán A. Functional Remediation for Bipolar Disorder. Cambridge, UK: Cambridge University Press; 2014.
3. Khan A, Ginsberg LD, Asnis GM, et al. Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder. J Clin Psychiatry. 2004;65:1483-1490.
4. Daban C, Martínez-Arán A, Torrent C, et al. Cognitive functioning in bipolar patients receiving lamotrigine: preliminary results. J Clin Psychopharmacol. 2006;26:178-181.
5. Kaye NS, Graham J, Roberts J, et al. Effect of open-label lamotrigine as monotherapy and adjunctive therapy on the self-assessed cognitive function scores of patients with bipolar I disorder. J Clin Psychopharmacol. 2007;27:387-391.
6. Paterson A, Parker G. Lithium and cognition in those with bipolar disorder. Int Clin Psychopharmacol. 2016 Oct 12. doi: 10.1097/YIC.0000000000000152.
7. Daglas R, Cotton SM, Allott K, et al. A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: a 12-month follow-up study. Eur Psychiatry. 2016;31:20-28.
8. Frye MA, Yatham L, Ketter TA, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand. 2009;120:10-13.
9. Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. Acta Psychiatr Scand. 2012;126:315-331.
10. Depp CA, Dev S, Eyler LT. Bipolar depression and cognitive impairment: shared mechanisms and new treatment avenues. Psychiatr Clin North Am. 2016;39:95-109.
11. Kelly ME, Loughrey D, Lawlor BA, et al. The impact of exercise on the cognitive functioning of healthy older adults: a systematic review and meta-analysis. Ageing Res Rev. 2014;16:12-31.
12. Morris MC, Tangney CC, Wang Y, et al. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11:1015-1022.
13. García-Blanco T, Dávalos A, Visioli F. Tea, cocoa, coffee, and affective disorders: vicious or virtuous cycle? J Affect Disord. 2016 Nov 25. doi: 10.1016/j.jad.2016.11.033.
14. Chengappa KN, Bowie CR, Schlicht PJ, et al. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry. 2013;74:1076-1083.
15. Solé B, Jiménez E, Martinez-Aran A, Vieta E. Cognition as a target in major depression: new developments. Eur Neuropsychopharmacol. 2015;25:231-247.
16. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT01965925. Updated December 30, 2016. Accessed January 2, 2016.
17. McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A. 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.
18. Miskowiak KW, Ehrenreich H, Christensen EM, et al. 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.
19. Wignall ND, Brown ES. Citicoline in addictive disorders: a review of the literature. Am J Drug Alcohol Abuse. 2014;40:262-268.
20. Jancin B. Valacyclovir improves cognition in bipolar patients. Clinical Psychiatry News. June 5, 2013.