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The unintended negative consequences of the coronavirus disease 2019 (COVID-19) pandemic continues to be a problem. Reduced social interaction and closure of public places, along with increased home confinement, has led to a sharp decrease in physical activity, a steady increase in food intake, and a 

 Stress has similarly impacted sleep, unhealthy eating, and even increased consumption of alcohol.

Public health and economic crises have been associated with serious, long-lasting negative impact on individual and population-based mental health outcomes. Indeed, a recent meta-analysis found higher rates of 

, depression, posttraumatic stress disorder, psychological distress, and stress during the COVID-19 pandemic.

 To further complicate matters, individuals are less likely to seek non-emergent health care, including care for mental disorders, during the pandemic.

Related health consequences of obesity such as hypertension and diabetes mellitus are a major source of morbidity.

 Stress, fatigue, physical inactivity, and a sedentary lifestyle can advance obesity and, subsequently contribute to a number of mental health disorders.

 Depression and obesity share a bidirectional relationship, where the presence of one disease increases the risk for developing the other (

 Increased carbohydrate consumption, a risk factor for obesity, is common in patients with depression. The presence of obesity often has a chronic course of illness and can result in poor treatment response in depression.

 are predominantly treated with antidepressants as a first-line treatment option, with 79% of primary care physicians prescribing antidepressants to these patients.

 Recent studies have shown that antidepressant medications can contribute to weight gain through various mechanisms, including increased food consumption and abnormal metabolic processes.

 Reductions in depressive symptoms and antidepressant usage may coincide with weight loss (as seen with bariatric surgery patients), and this underscores the importance of monitoring the increasing rates of obesity.

For the last 2 decades, depressive disorders have consistently ranked amongst the top 5 illnesses for years of life lived with a disability.

 Cognitive deficits is a core symptom of depression, and it often persist between affective episodes and beyond the remission of mood symptoms.

 Executive functioning, attention, memory, and learning can be affected.

 Obesity also contributes to impairments in cognition; individuals with obesity exhibit significantly impaired cognitive functioning and structural changes in brain regions associated with executive functioning.

 Moreover, in individuals with obesity, cognitive impairments 

 lower weight loss success, poor treatment adherence, and decreased physical functioning.

Individuals with a longer duration of illness and a higher frequency of depressive episodes are more likely to experience cognitive impairments. Persistent cognitive impairment contributes to consequences in occupational and social domains.

 In particular, evidence from adults with mood disorders implicates cognitive impairment as a mediator of workplace function and attendance, as well as patient-reported outcomes (eg, quality of life).

 Approximately 15% of patients with major depressive disorder attribute their unemployment to cognitive symptoms. Unfortunately, few treatments, including psychotropic medications, have proven effective in improving cognitive function in adults with mood disorders, especially in cases of treatment resistance.

Patients with comorbid depression and obesity often demonstrate higher levels of baseline inflammation, which is characterized by a higher level of inflammatory cytokines (a type of signaling molecule that promotes inflammation). Likewise, obesity involves a pro-inflammatory state. Conversely, findings have shown improved cognition is linked to a reduction in inflammation.

 Indeed, in a meta-analysis evaluating inflammation and treatment response, researchers found increased levels of inflammatory cytokines in patients with depression. In cases that successfully responded to treatment, the levels of inflammatory cytokines were decreased.

There are several proposed mechanisms that may mediate the relationship between chronic stress, inflammation, and mood disorders. Stressful experiences have been shown to increase production of cortisol. Glucocorticoids increase activities of the sympathetic system, such as heart rate and blood pressure, to reduce the stress response. However, if this system is dysregulated, chronic stress and cortisol production can lead to the desensitization of the glucocorticoid receptors. It can be conjectured that the dysregulation of the inflammatory pathway is also worsened by the presence of insulin resistance and increase in adipocytes. The bidirectional relationship between the 2 illnesses and the co-occurrence of an inflammatory state underscores the involvement of inflammation in the pathophysiology of depression and obesity.

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects. For more severe cases of depression, 

 in conjunction with other treatments (ie, pharmacological).

 Exercise may also help improve cognition in individuals with depression. In a study investigating the dose-dependent effects of 

 on cognition in patients with depression, high-intensity exercise was associated with improvements in executive function and working memory tasks. Meanwhile, other cognitive domains, such as attention, visual memory, and spatial planning, improved regardless of dose.

 Therefore, it is importan that adequate social and physical activities are integrated into treatment plans to promote well-being.

is a researcher at the Canadian Rapid Treatment Center of Excellence and the Institute of Medical Science at the University of Toronto. 

is a professor of psychiatry and pharmacology at the University of Toronto, and Head of the Mood Disorders Psychopharmacology Unit for the University Health Network, Toronto, Canada.

Effect of obesity and body mass index on coronavirus disease 2019 severity: A systematic review and meta‐analysis

2 .Xiong J, Lipsitz O, Nasri F, et al. Impact of COVID-19 pandemic on mental health in the general population: A systematic review.

3. Alosco ML, Spitznagel MB, Strain G, et al. Improved serum leptin and ghrelin following bariatric surgery predict better postoperative cognitive function.

4. Sarris J, O’Neil A, Coulson, et al. Lifestyle medicine for depression.

5. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies.

Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices.

7. Gill H, Gill B, El-Halabi S, et al. Antidepressant Medications and Weight Change: A Narrative Review. (Silver Spring)

8. Collaborators G 2016 ORF, GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of disease and injury in 2016 arising from occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016.

9. McIntyre RS, Lee Y. Cognition in major depressive disorder: a “Systemically Important Functional Index” (SIFI).

10. Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR. Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

11. Spitznagel MB, Garcia S, Miller LA, et al. Cognitive function predicts weight loss after bariatric surgery.

12. Rasmussen LJH, Caspi A, Ambler A, et al. 

Association of Neurocognitive and Physical Function With Gait Speed in Midlife

13. Baune BT, Air T. Clinical, Functional, and Biological Correlates of Cognitive Dimensions in Major Depressive Disorder – Rationale, Design, and Characteristics of the Cognitive Function and Mood Study (CoFaM-Study).

14. McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: response to remission to functional recovery.

15. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane Vives A, Cleare AJ. Inflammation and clinical response to treatment in depression: A meta-analysis. 

16. Schuch FB, Vancampfort D, Richards J, et al. 

Exercise as a treatment for depression: A meta-analysis adjusting for publication bias

17. Greer TL, Grannemann BD, Chansard M, et al. Dose-dependent changes in cognitive function with exercise augmentation for major depression : results from the TREAD study. 

Evidence suggests that physical activity aids in alleviating mild to moderate symptoms of depression in patients and may promote clinically significant antidepressant effects.

A Recipe for Homemade Obesity: The Association Between Depression, Obesity, and Cognitive Deficits

A single sentence in the landmark textbook 

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.”

 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.

 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 

 of cognitive impairment is the number of past episodes, and episodes with long durations or psychotic features take a particular toll.

 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.

 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 (

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 

 for cognition across various populations are aerobic exercise (45 minutes 3 to 5 times a week), diet (Mediterranean, Nordic, or Japanese style), and sleep.

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.

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.

 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 (

). In clinical studies, nocturnal darkness helped stabilize mania independent of sleep, and in animal studies it enhanced learning and memory.

 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 

 the importance of physical activity for cognitive health.

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.

 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.

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.

 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 

 dementia in the lower dose range (serum levels of 0.25 to 0.5 mEq/L).

 On the other hand, small impairments in short-term memory and creativity were attributable to lithium in a meta-analysis of clinical data.

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.

 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 

 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.

Valproate and carbamazepine are associated with deficits of attention, short-term memory, learning, and motor speed.

 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.

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.

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.

 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 

 in other populations and have positive effects in bipolar depression.

A positive finding comes from an extract of the ashwagandha plant. This extract improved memory, reaction time, and social 

 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).

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 

 that went viral, explained these deficits were a threat to her identity.

 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.”

is the mood disorders section editor for 

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 author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for

Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression

2. Burdick KE, Millett CE, Bonnín CDM, et al. 

The international consortium investigating neurocognition in bipolar disorder (ICONIC-BD)

3. Torrent C, Bonnin Cdel M, Martínez-Arán A, et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. 

4. Serra MC, Dondero KR, Larkins D, et al. 

Healthy lifestyle and cognition: Interaction between diet and physical activity

5. Berman MG, Kross E, Krpan KM, et al. Interacting with nature improves cognition and affect for individuals with depression. 

6. Travica N, D’Cunha NM, Naumovski N, et al. The effect of blueberry interventions on cognitive performance and mood: a systematic review of randomized controlled trials. 

7. Conner TS, Brookie KL, Carr AC, et al. Let them eat fruit! The effect of fruit and vegetable consumption on psychological well-being in young adults: a randomized controlled trial. 

8. Ren M, Zhang H, Qi J, et al. An almond-based low carbohydrate diet improves depression and glycometabolism in patients with type 2 diabetes through modulating gut microbiota and glp-1: a randomized controlled trial. 

9. Harvey AG, Soehner AM, Kaplan KA, et al. 

Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial

10. Bedrosian TA, Vaughn CA, Galan A, et al. Nocturnal light exposure impairs affective responses in a wavelength-dependent manner. 

11. Heo JY, Kim K, Fava M, et al. Effects of smartphone use with and without blue light at night in healthy adults: a randomized, double-blind, cross-over, placebo-controlled comparison. 

12. Henriksen TE, Skrede S, Fasmer OB, et al. Blue-blocking glasses as additive treatment for mania: a randomized placebo-controlled trial. 

13. Hill NT, Mowszowski L, Naismith SL, et al. 

Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis

14. Guo M, Mi J, Jiang QM, et al. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. 

15. Mansur RB, Ahmed J, Cha DS, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. 

16. Jancin B. Valacyclovir improves cognition in bipolar patients. 

17. Khan A, Ginsberg LD, Asnis GM, et al. Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder. 

18. Daban C, Martínez-Arán A, Torrent C, et al. Cognitive functioning in bipolar patients receiving lamotrigine: preliminary results. 

19. 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. 

20. Dell’Osso L, Del Grande C, Gesi C, et al. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. 

21. Forlenza OV, Radanovic M, Talib LL, Gattaz WF. 

Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomized clinical trial

22. Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. 

23. Daglas R, Cotton SM, Allott K, et al. A single-blind, randomized 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. 

24. Yatham LN, Mackala S, Basivireddy J, et al. 

Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomized, open-label, pilot study

25. Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. 

26. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. 

27. Nunez NA, Singh B, Romo-Nava F, et al. 

Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials

28. 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. 

The problem with how we treat bipolar disorder

For many patients, the most painful part of bipolar disorder is the loss of control over their own mind. 

Cognition, Bipolar Disorder, and the Self

As psychiatrists, we are constantly challenged by complex patients with a wide variety of clinical presentations. In fact, 2 patients with the same condition are never the same. Yet for all this diversity, there may be some common features. I propose that cognition is paramount in this respect.

 is a word that we use frequently, perhaps without pondering all that it entails. It is an important human attribute that has played a crucial part in our evolution. Yet the concept is so broad as to span many fields, from philosophy to psychology and the neurosciences. At the end of the day, we can all agree that cognition is essential for human fuctioning and flourishing.

Cognition involves many processes, both conscious and 

s. Different aspects include introspection, memory, learning, reasoning, perception, attention, problem solving, and the use of language. In some ways, this sounds so abstract that it is difficult to make practical sense of it. This is why I often reflect on my interactions with patients and what they have taught me.

On any given day, I see patients who are asymptomatic for their condition, yet they are certainly not enjoying a robust quality of life. For instance, one gentleman is without a doubt brilliant. He reads constantly and voraciously, and he can engage in a detailed discussion of various topics. After deciding that he wanted to read scripture in the original language, he learned several languages.

This patient is in remission from bipolar disorder. His scores are extremely low to nonexistent on the Patient Health Questionnaire (PHQ) 9, General Anxiety Disorder (GAD) 7, and Young Mania Rating Scale. Yet, he lacks significant organizational skills and has great difficulty in prioritizing tasks. This manifests in an extremely cluttered house, which is in shambles since his last manic episode approximately 2 years prior. Furthermore, this patient is obese and has increased inflammatory markers.

Another patient, a mechanical engineer who has been through extensive schooling and is given to preciseness, was seen by a neurologist who focuses on neurodegenerative disorders. His quantitative magnetic resonance imaging (MRI) showed no degeneration in his hippocampus. In addition, 

 showed no evidence of any memory disorder. He presented complaining of “adult-onset/attention deficit disorder.” Yet, on further exam, we realized his cognitive difficulties were due to depression.

Earlier I saw a woman who was morbidly obese. She very much wanted bariatric surgery and knee surgery for the immense pain. Her other physicians were in agreement with this plan. In the processes of her workup, she saw a sheet of labels with her name—the ones that are commonly used to identify information on documents or containers with biological specimens. The patient incorrectly deduced that each sticker was meant for a different test tube of blood. She thought the staff was going to draw at least 12 tubes; she began to think that she was going to be admitted against her will. It became clear that this patient was delusional; she was drawing incorrect cognitive conclusions that were negatively affecting her progress.

In addressing cognition, it is important to remember that psychotherapy, in addition to medications, can be an effective tool. Studies have demonstrated physical changes in the brain that occur as a result of effective psychotherapy. The work of 

, for instance, elucidated the synaptic changes related to memory and learning. (This won him, along with 2 others, the Nobel Prize for medicine in 2000.)

It is hard to overstate the importance of cognition in our day-to-day lives, especially as it relates to our work as psychiatrists. It is my hope that you will enjoy this 

 on cognition and that it serves as an appetizer to awaken a deeper hunger and curiosity.

is the medical director, Division of Neuropsychiatry, at Dent Neurologic Institute, and the medical director, Addiction Services, at Brylin Hospital in Buffalo, NY. The author(s) report no conflicts of interest concerning the subject matter of this article. ❒

In psychiatry, 2 patients with the same condition are never the same.

Diverse Patients, Common Ground

Tools for Assessing Cognition

There are a number of cognitive screening tools designed to help offer timely, quality care for the elderly and those struggling with cognitive loss and dementia. 


Which pharmacotherapeutic approach is most effective for cognitive enhancement? Test your knowledge with this quiz.

Mini Quiz: Cognitive Enhancers

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

“Ms Zorn” was a 45-year-old woman with no previous psychiatric history who presented with a 2-month period of “feeling like I am losing myself” and seeing “visually distorted faces.” Faces of people she was looking at would appear to be hideously elongated, with the facial components distorted, as if it was melting. Cars would also appear to be more round than usual.

She was admitted to an inpatient psychiatry unit for unspecified psychosis, but after 2 days she was transferred to a general medical unit for additional medical evaluation. She was started on 25-mg quetiapine bid, which was titrated to 200 mg bid. Lumbar puncture was completed to rule out central nervous system infection or autoimmune encephalopathy, with results pending at the time of transfer to an academic medical center for higher level of multispecialty care.

On interview, she said that she felt like she was “losing” herself and reported visual distortions of “faces melting.” Ms Zorn was able to recognize faces and colors. She reported photophobia. She had headaches, which were relieved with ketorolac. Her husband reported that she had new onset of episodes of shaking her arms in a circular motion. She would also walk around the room in circular patterns while saying to herself that she was “lost.”

Ms Zorn had decreased appetite, weight loss, and decreased sleep. She denied depressed mood, decreased energy, mania, trauma, or previous problems with memory. She denied auditory hallucinations and suicidal/homicidal ideation. She denied a family history of suicide and psychiatric illness. Developmental history was unremarkable. She had no history of substance abuse.

On mental status examination, she was awake, alert, oriented to person, time, place, and situation. She continued to experience visual distortions of “faces melting.” Ms Zorn’s thought process was linear and coherent. Affect was mildly anxiously perplexed, non-labile, and non-tearful. Speech was normal. Insight and judgment were marginal. Her Montreal Cognitive Assessment (MoCA) score was 10/30. Her decisional capacity was impaired, and the screening neurological examination was non-focal.

Due to the atypical presentation of psychotic disorder, the full workup included a neurology consultation; brain MRI and lumbar puncture results were normal, except for autoimmune encephalitis results that were pending. Serum HIV, syphilis, vitamin B12, lead, rapid plasma regain (RPR), anti-nuclear antibody ammonia, and thyroid stimulating hormone (TSH) levels were normal; EEG was unremarkable. Pelvic ultrasound and CT were ordered to rule out ovarian teratoma. Quetiapine regimen was changed to 100 mg in the morning and 300 mg in the evening.

Ms Zorn was seen in follow-up on hospital day 2. Neurology had started her on 1-g methylprednisolone daily for a 5-day course for presumed 

. She was placed on a continuous EEG. On exam, she reported feeling better compared with the previous day. She no longer reported any distortions of faces or objects in the room, although she did report some “blue dots” in her field of view. She had 3 hours of sleep the previous night. Her husband noted that the she had decreased episodes of her aimless pattern of waving her arms in a circular motion. Her MoCA score was 14/30. Due to the significant improvement in her hallucinations following the first dose of methylprednisolone, the scheduled quetiapine was held.

When seen on hospital day 3, Ms Zorn said that she could fall asleep, but had trouble staying asleep. She had an episode where she got up and walked around the room purposelessly. Her MoCA score was 13/30 and decisional capacity was impaired. Quetiapine 50 mg post merdien (PM) was started to address poor sleep. On hospital day 4, she reported that her visual phenomena had returned, with her seeing “pixels” (flashing punctate lights) and “faces melting.” She had had difficulty sleeping. MoCA was 12/30 with continued limited insight, judgment, and 

. Quetiapine was increased to 100 mg pm and mirtazapine 7.5 mg pm was started to improve sleep.

On hospital day 5, her husband reported that she had had continued visual phenomena of pixels and faces melting. Ms Zorn was only able to sleep for 1.5 hours after receiving quetiapine and mirtazapine. On exam, she reported the visual hallucinations and had a MoCA score of 12/30. Continuous EEG was reported as normal and abdomen CT was negative for ovarian teratoma. To address continued 

and poor sleep, quetiapine was increased to 100 mg am and 300 mg pm. Mirtazapine was increased to 15 mg pm.

Ms Zorn was seen again on hospital day 6. She reported that she had been able to sleep for 8 hours. She denied any visual “melting” of faces but stated that the “world looked pixelated at times.” MoCA score was 14/30. Subsequently, when seen on hospital day 8, she stated that she was still seeing pixels in the periphery of her visual field. MoCA score improved to 17/30. Quetiapine was consolidated to 400 mg pm.

She was next seen on hospital day 10. The cerebrospinal (CSF) encephalopathy panel came back positive for anti-NMDA receptor antibody R1, confirming a diagnosis of anti-NMDA (N-methyl-D-aspartate)-receptor encephalopathy (ANMDARE). Neurology started plasmapheresis for 7 treatments, every other day. She had no hallucinations. She reported that she was getting “deep sleep.” MoCA score was 16/30. A quetiapine 50 mg am dose was added.

Plasmapheresis started on hospital day 11. The patient denied any visual distortions. She said that she felt significantly better than the previous week; MoCA score was 16/30. When next seen on hospital day 15, Ms Zorn reported sleeping from 11:00 pm to 5:30 am. She denied visual distortions. MoCA score had improved to 21/30; however, 

continued to be impaired. On hospital day 18, she was doing well. She had declined her scheduled quetiapine the previous day “to give it a try.” She no longer saw distorted faces. She had no gait disturbance. MoCA score improved further to 25/30. Given her improved mental status, the psychiatry team decided that she had recovered her decision-making capacity. Mirtaza-pine was decreased to 7.5 mg pm and quetiapine held.

Ms Zorn was seen for the last time on day 22 of hospital admission. After her final 

treatment, she continued to be free of psychotic symptoms. She stated that she was “doing better than last week,” and that she was “80% back to normal.” She was sleeping well and was increasingly physically active during the day. She was excited to return home; MoCA score was 22/30. Decisional capacity continued to be intact. Mirtazapine 7.5 mg bedtime was continued.

As she was medically stable for discharge, she was referred for psychiatric follow-up near her home. She was advised that any future recurrence of psychosis should first be addressed as if it was a recurrence of delirium and/or ANMDARE.

ANMDARE is a relatively recently described illness that may present with psychiatric symptoms, neurologic symptoms, or both (either simultaneously or sequentially).

 While the exact mechanism remains obscure, antibodies to the NMDA receptor (on CSF and/or serum assay) is 

 Management includes empiric treatment of manifest symptoms and immunomodulation systemic therapies.

ANMDARE is important to the consultation-liaison psychiatrist for a number of reasons. First, its presentation lies in the “neuropsychiatric borderland” involving collaboration between psychiatry and neurology (as in other neuropsychiatric illnesses like Parkinson disease, Huntington disease, and multiple sclerosis). Second is its importance in the often hard-to-define syndrome of “atypical psychotic disorder.” In comparison to the classic presentation of schizophrenia, ANMDARE features a later age of onset, female predominance, visual hallucinations, relative lack of cognitive disorganization, and a lack of an extended prodromal period.

This case illustrates the atypical presentation of psychotic illness rather well. Ms Zorn was in her mid-40s, of high academic and professional achievement, adaptive social function; without a clear prodrome, she relatively promptly developed a psychotic picture with striking and disturbing visual hallucinatory phenomena. Clinical suspicion for ANMDARE was confirmed with reference laboratory (Mayo Clinic) results of + R1 antibody to NMDA receptor on CSF analysis. This was accomplished in the context of a thorough laboratory evaluation for other esoteric causes of atypical psychotic illness.

Empiric treatment of the psychiatric symptoms with mirtazapine and quetiapine, concurrent with 2 rounds of immunomodulation therapy, led to amelioration of symptoms and near complete cognitive recovery in a period of 2.5 weeks. Her cognitive status based on objective measure with the 

(MoCA) was initially in the moderate to severely impaired range.

 With comprehensive treatment, Ms Zorn’s cognitive status improved to a level of only mild impairment. Correspondingly, her decisional capacity improved from significantly impaired to largely intact over the same period.

Psychiatrists assessing and treating patients with atypical presentation of psychotic illness should actively consider a diagnosis of ANMDARE as explanatory.

 In female patients with suspicion of ANMDARE, pelvic ultrasonography and/or CT scan should be ordered to rule out commonly co-occurring ovarian teratoma.

 Patients with ANMDARE who are treated with high-dose intravenous corticosteroids should be monitored (and treated for) any corticosteroid-associated psychiatric adverse effects, which can overlap with the atypical psychotic symptoms at illness onset. Empiric treatment with psychopharmacology for psychotic and/or depressive symptoms should be pursued, although such medications may not be necessary indefinitely once definitive immunomodulation therapy is completed.

ANMDARE should be on the differential for atypical psychosis, with an expectation of a thorough search for laboratory and systemic clinical (especially neurologic) findings, empiric treatment of psychiatric symptoms, and reassessment of the patient as immunomodulation therapy is completed. Prospective study of ANMDARE illness cohorts are needed to quantify recurrence risk, need for ongoing intervention, and ultimate prognosis.

Consultation-liaison psychiatrists working in academic medical centers may be in a position to assist multispecialty teams in the identification, diagnosis, management, and ongoing follow-up of these patients. As with any illness that affects cognitive function, attention to and serial assessment of decisional capacity is a critical part of C-L psychiatry care, especially as pertains to patient consent for major immunomodulation therapies.

 is chair, Department of Psychiatry, Baylor Scott & White Health, Central Texas Division, and clinical professor for medical education, Texas A&M University Health Science Center, Temple, TX. 

is a medical student, Texas A&M University Health Science Center, Temple, TX. The authors report no conflicts of interest concerning the subject matter of this article.

1. Tuzun E, Zhou L, Baehring JM, et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. 

2. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. 

In comparison to the classic presentation of schizophrenia, ANMDARE features a later age of onset, female predominance, visual hallucinations, relative lack of cognitive disorganization, and a lack of an extended prodromal period.

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