For many patients, the most painful part of bipolar disorder is the loss of control over their own mind.
SPECIAL REPORT: COGNITION
A single sentence in the landmark textbook Manic-Depressive Illness by Frederick Goodwin, MD, and Kay Jamison, PhD, overshadows much of the progress we have made in treating bipolar disorder: “Complete symptomatic remission does not ensure functional recovery.”1 In other words, we can treat the symptoms but that does not mean our patients will get their lives back. Strained marriages, checkered work histories, and lost friendships become the norm.
For these patients, it is not the depression or the mania but the cognitive symptoms of bipolar disorder that get in the way. Memory, attention, and higher-order constructs like judgment and social intuition are among the impairments that can persist after symptomatic remission, and they do so in about 30% to 60% of cases. Compared to mood symptoms, cognitive problems are more difficult to treat, but they can be helped.
The first step is recognition. Clinicians should ask questions such as: “Now that the depression and mania have gone away, do you feel like your mind is working fully, or are there still areas of life where you are not functioning all the way?” From there, assess occupational functioning (eg, finishing tasks, prioritizing, and time management) and household chores (eg, bills, shopping, cleaning, and basic hygiene). Also inquire about hobbies and recreation as well as family, relationship/sexual, and social life (eg, have they lost interest, has enjoyment faded, can they follow a plot of a movie, are there problems in relationships?).
Although subjective assessments are important and provide information about quality of life, objective testing can also help better understand cognitive issues. The trail-making test and the digit symbol substitution test are easy to administer and give meaningful results. They are now available through a free software package, THINC-it (available online at progress.im), that can be used to track progress.
Patient education is crucial; explain that it is common for these problems to continue even after the major episodes have resolved. Similarly, let them know that cognitive recovery is a slow process that requires their active involvement.It also helps for families to hear this message. Families need to allow opportunities for the patient to regain their skills in a judgment-free zone and accept the mistakes that come with these attempts. Too often those opportunities are blocked by criticism, blame, or family members who take over patients’ lives in a well-intentioned effort to prevent failure.
Patients often attribute cognitive problems to mood stabilizers. Although there is a grain of truth to this notion, the greater burden is from the episodes themselves. The strongest predictor of cognitive impairment is the number of past episodes, and episodes with long durations or psychotic features take a particular toll.2 Recovery, then, begins with prevention. Make sure patients understand this point by explaining that “each episode is like a small head injury, and the more episodes you have the worse these cognitive problems will get. Your brain needs time to heal, but it cannot do that if the episodes keep coming back.”
Next, set a reasonable goal in concrete terms. Engage patients by asking them “what would you most like to be able to do if these symptoms improved?” Cognitive remediation therapy improves functioning in bipolar disorder. Remarkably, it does so without bringing about meaningful improvements on objective tests of cognition. Instead, patients develop strategies to compensate for those deficits and implement their strategies in the real world. They learn to use calendars, to-do lists, reminders, and to break complex tasks into simpler steps.3 If rehabilitative therapists are not available, patients can borrow those techniques by setting goals and trouble-shooting their progress with the support of their clinician along the way (Table 1).
Few treatments have been studied for cognitive symptoms of bipolar disorder, and most of what we know is borrowed from related disorders like schizophrenia and age-related cognitive decline. The general approach is to support the health of the brain and body, with the idea that good cognition flows from well-functioning metabolic, cardiovascular, and circadian systems. The 3 interventions with the best evidence for cognition across various populations are aerobic exercise (45 minutes 3 to 5 times a week), diet (Mediterranean, Nordic, or Japanese style), and sleep.4
If exercise is too difficult, start with a walk in the woods. Compared to a similar walk in an urban or suburban environment, walking in the woods for 60 to 90 minutes improved cognition in small studies of depression, attention-deficit/hyperactivity disorder (ADHD), and healthy college students.5
To address dietary issues, start by introducing a few brain-friendly foods. Simple interventions like adding 1 to 2 daily servings of vegetables, nuts, or fruits (particularly blueberries) have improved cognition and mood in small controlled trials.6-8 With those in the mix, there is usually less room for the processed, fried, sugary, and fast foods that harm cognition.
Sleep consolidates memory and improves attention, processing speed, and creative problem solving. Unfortunately, sleep does not come easily to individuals with bipolar disorder, and trying to force it is counterproductive. Instead, patients should intervene at the points of the circadian cycle that are within their control (Table 2). In clinical studies, nocturnal darkness helped stabilize mania independent of sleep, and in animal studies it enhanced learning and memory.10-12
Cognitive exercises can help but they are less effective than the previous strategies. Puzzles and word games have mild benefits that do not clearly translate into functional change. Some of the best-studied games for mild cognitive impairment are dexterity and so-called “exergames,” such as Wii Bowling. These movement-oriented games further emphasize the importance of physical activity for cognitive health.13
Bipolar disorder is associated with several medical conditions that can impair cognition, such as obesity, diabetes, cardiovascular disease, and sleep apnea. In the case of diabetes, there is evidence that both metformin and liraglutide improve cognition in mood disorders.14,15 Herpes simplex virus-1 is associated with worse cognition in bipolar disorder. In a small randomized, double-blind, placebo- controlled trial, valacyclovir improved cognition in this population even in the absence of genital lesions.16
Among the mood stabilizers, lamotrigine has the most favorable cognitive profile. It improved cognition in large open-label studies and a post-hoc analysis of controlled trials.17-19 On the other hand, lamotrigine can cause word-finding problems, particularly in the elderly or when the dose goes above 150 mg/day.
Lithium has cognitive risks and benefits. Although most mood stabilizers have neuroprotective effects, the ones seen with lithium are broader, and there is evidence from 5 controlled trials that lithium prevents dementia in the lower dose range (serum levels of 0.25 to 0.5 mEq/L).20,21 On the other hand, small impairments in short-term memory and creativity were attributable to lithium in a meta-analysis of clinical data.22
Well-designed trials of lithium’s cognitive effects are few, but 1 study looked at cognitive outcomes in 61 patients who were randomized to either lithium or quetiapine after a first-episode mania.23 After a year, those on lithium had greater verbal fluency than those on quetiapine. To test this in practice, ask the patient to name as many unique words as possible that start with the letter “P” in 1 minute.
Although some studies have found that atypical antipsychotics impair cognition, 1 small but well-designed trial tells a different tale for lurasidone. This study included patients with bipolar disorder who were euthymic but experiencing cognitive problems. The participants were randomized to either open-label lurasidone (average dose 48 mg/day) or treatment as usual. After 6 weeks, the lurasidone-treated patients performed significantly better on a battery of cognitive tests compared to the treatment-as-usual group, with a large effect size of 0.8.24
Valproate and carbamazepine are associated with deficits of attention, short-term memory, learning, and motor speed.25 There is no evidence that cognition improves on these 2 anticonvulsants. Furthermore, their cognitive profile was worse than that of lithium or lamotrigine in a naturalistic study.26
Overall, mood stabilizers cause small but real cognitive impairments. Lamotrigine, lithium, and lurasidone may improve cognition in some ways and worsen it in others. These responses differ by patient, and the best way to manage them is to fine-tune the dose and change the mood stabilizer when necessary.
Is it ADHD?
Patients with mood disorders often think that their cognitive problems are due to ADHD. About 15% of individuals with bipolar disorder have comorbid ADHD. However, if the symptoms began in adulthood and worsened with the mood episodes, it is unlikely that ADHD is the problem. In practice, this is difficult to tease apart, but some signs may lead the way. ADHD tends to make patients more hyped-up, with restless energy and prominent distractibility. The speech of patients with ADHD is marked by a frenetic, choppy rhythm, and they change topics frequently (even when not hypomanic). In comparison, the cognitive deficits of bipolar disorder have a slower feel and resemble age-related cognitive decline. Words do not come easily, and sentences are short. Forgetfulness, inertia, and indecision predominate.
In my experience, stimulants have calming effects on patients with ADHD because they treat the hyperactivity. In contrast, patients with bipolar disorder are more likely to feel energized on stimulants. At best, stimulants improve cognitive symptoms associated with bipolar disorder for 6 to 12 months and then tolerance sets in. At worst, they cause mania, mixed states, and psychosis. When genuine ADHD and bipolar disorder coexist, modafinil, armodafinil, clonidine, and guanfacine are safer alternatives. Atomoxetine, which resembles a noradrenergic antidepressant, is not a good alternative.
Besides the previously discussed mood stabilizers, there are few controlled pharmacotherapy trials for the cognitive symptoms of bipolar disorder. Treatments for dementia have failed (donepezil and galantamine), as have pramipexole, n-acetylcysteine, and methylene blue. Although modafinil and armodafinil have not been tested for cognitive symptoms of bipolar disorder, these agents improve cognition in other populations and have positive effects in bipolar depression.27
A positive finding comes from an extract of the ashwagandha plant. This extract improved memory, reaction time, and social cognition in a randomized placebo-controlled trial of patients with bipolar disorder who were euthymic but had cognitive problems (n = 53; effect sizes, 0.26 to 0.62). Unfortunately, this trial has not been replicated, but it is backed by bench studies that found ashwagandha had neuroprotective effects on the hippocampus. The extract is readily available in products with “Sensoril” on the label (target dose, 500 mg/d; starting dose, 250 mg/d for the first week).28
Conclusions: saving the self
Bipolar disorder is defined by its symptoms, but it is the impairment that makes it an illness. Its symptoms, after all, are also part of normal life: elation, sadness, irritability, fatigue, and elevated energy. For many patients, the most painful part of bipolar disorder is the loss of control over their own mind. Most would rather lose control of their right arm than the things that define their selfhood: how they act, what they say, and what they think and feel.
Cognitive symptoms extend that loss of control beyond the episodes of mania and depression. Linda Logan, a talented woman who wrote about her struggles with bipolar disorder in a New York Times article that went viral, explained these deficits were a threat to her identity.29 Even after her mood was stabilized, she “lost my sense of competence ... Word retrieval was difficult and slow ... Clarity of thought, memory, and concentration had all left me. I was slowly fading away.” Logan’s advice to psychiatrists was to “ask about what parts of the self have vanished.”
Start there. Go where the pain is.
Dr Aiken is the mood disorders section editor for Psychiatric TimesTM, the editor in chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much.
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29. Logan L. The problem with how we treat bipolar disorder. New York Times Magazine. April 26, 2013.❒