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 and there is evidence that activation of the maternal immune system during pregnancy—whether by infection, chronic inflammation, or autoimmune disease—is associated with increased risk of neurodevelopmental disorders in the 

 In the case of the latter, maternal autoantibodies may cross the placenta and alter fetal development through epigenetic changes, brain microglial cell activation, and modulation of 

 Previous studies have focused on the association between maternal autoimmune disease and autism spectrum disorders, whereas attention-deficit/hyperactivity disorder (ADHD) has been less studied. Only 1 previous study examined the association between any maternal autoimmune disease and ADHD risk in 

Nielsen and colleagues aimed to investigate the association between any (and specific) maternal autoimmune disease and ADHD in children, and to incorporate those results into 

a systematic review and meta-analysis on this topic

 Using the New South Wales (NSW) Perinatal Data Collection, they identified all women with full-term, singleton live births from July 2000 to December 2010. Birth data were linked to all hospital admissions for both mother and child, and pharmaceutical data from the child for treatment of ADHD through registers. A child was considered to have ADHD if they had a stimulant prescription for ADHD and/or a hospital diagnosis of ADHD. Children linked to a first ADHD event before age 3 were excluded. Children were followed to death or at the end of follow-up in December 2014.

Maternal autoimmune disease was determined based on the mother’s hospitalization records. Children whose mother had at least 1 hospitalization for autoimmune disease were considered exposed. Exposed and nonexposed mothers were propensity matched based on age, country of birth, socioeconomic status, place of residency, parity, smoking during pregnancy, and mental health diagnosis. Cox proportional hazard models were used to examine the association of maternal autoimmune disease and ADHD, adjusting for child sex. Analyses were performed for any maternal autoimmune disease and individual conditions with at least 15 cases of ADHD among exposed children.

The authors also performed a systematic search of MEDLINE, Embase, and Web of Science to identify studies on the association between maternal autoimmune disease and ADHD. Included studies were assessed for study quality using the Newcastle-Ottawa Quality Assessment Scale. Meta-analyses of any (and specific) maternal autoimmune disease with ADHD in the offspring were performed by calculating random-effects pooled hazard ratios (HRs) and inverse-variance weighting.

In the NSW Perinatal Data Collection, 831,718 mothers and children were including and 12,767 (1.5%) exposed to maternal autoimmune disease. Propensity score matching including a cohort of 12,610 exposed children and 50,440 controls. During follow-up, 1094 male (3.4%) and 332 female (1.1%) children were diagnosed with ADHD. After adjustment, any maternal autoimmune disease (HR = 1.30), type 1 diabetes mellitus (HR = 2.23), psoriasis (HR = 1.66), and rheumatic fever or carditis (HR = 1.75) were associated with increased risk of ADHD, and this association was not moderate by child sex. When considering mothers diagnosed before or within 180 days of birth (N = 9700), any maternal autoimmune disease (HR = 1.28) and type 1 diabetes mellitus (HR = 1.95) remained significantly associated with ADHD.

Five studies, including the present cohort, were included in the meta-analysis. Two studies estimated the association with any maternal autoimmune disease, and 11 specific conditions were investigated in 2 or more individual studies. In the meta-analyses, any maternal autoimmune disease (HR = 1.20), type 1 diabetes mellitus (HR = 1.53), hyperthyroidism (HR = 1.15), and psoriasis (HR = 1.31), were all associated with increased risk of ADHD.

The authors found an association between any maternal autoimmune disease, type 1 diabetes mellitus, and psoriasis in both the present study and meta-analysis, and an association with hyperthyroidism in the meta-analysis. They noted significant heterogeneity in findings across individual studies, and that non-immune factors such as glycemic control (in type 1 diabetes) and endocrine aspects of hyperthyroidism may also contribute to associations with ADHD.

Strengths of the present study include the hybrid design, including a large population-based cohort and meta-analysis. Limitations include the lack of outpatient/primary care records for identifying maternal autoimmune disease, absence of data on the clinical status of the mother’s autoimmune disease and associated medications, and absence of data on nonstimulant ADHD medications and severity of ADHD.

Maternal autoimmune disease is associated with increased risk of ADHD in offspring, adding evidence that adverse maternal immune function during pregnancy may alter fetal neurodevelopment. Children of affected mothers may benefit from additional follow-up and support for developmental issues.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. 

2. Knuesel I, Chicha L, Britschgi M, et al. Maternal immune activation and abnormal brain development across CNS disorders. 

3. Estes ML, McAllister AK. Maternal immune activation: Implications for neuropsychiatric disorders. 

4. Gumusoglu SB, Stevens HE. Maternal inflammation and neurodevelopmental programming: a review of preclinical outcomes and implications for translational psychiatry. 

5. Nielsen PR, Benros ME, Dalsgaard S. Associations between autoimmune diseases and attention-deficit/hyperactivity disorder: a nationwide study. 

6. Nielsen TC, Nassar N, Shand AW, et al. Association of maternal autoimmune disease with attention-deficit/hyperactivity disorder in children. 

Activation of the maternal immune system during pregnancy is associated with increased risk of neurodevelopmental disorders in children. A recent review and meta-analysis examine the link in ADHD.

Maternal Autoimmune Disease and ADHD Risk in Children

MDD is a highly prevalent mental health condition. There is evidence that, in China, co-occurring somatic symptoms, including headache and stomachache might contribute to misdiagnosis of depression and delayed 

 Previous studies of somatic symptoms in MDD have yielded conflicting or inconclusive results, although there is some evidence for increased gastrointestinal 

 Given growing evidence for the microbiota-gut-brain axis in depressive disorders, GI symptoms might be a marker for 

Huang and colleagues estimated the frequency and clinical correlates of GI symptoms during depressive episodes in a large, nationwide sample of patients with 

 They hypothesized that the presence of GI symptoms would be associated with comorbidity in MDD, including insomnia, hopelessness, anxiety, and suicidal ideation. Study participants were from the National Survey on Symptomatology of Depression (NSSD) in China, which included inpatient and outpatient participants 18 years or older with a current DSM-IV episode of MDD.

Exclusion criteria were a lifetime diagnosis of bipolar or psychotic disorder, imminent risk of suicide or homicide, received electroconvulsive therapy within the past month, current pregnancy or breastfeeding, and substance use disorder over the past year. Patients were interviewed by trained psychiatrists on a broad range of symptoms, including depression and somatic symptoms, over the previous 2 weeks. Sociodemographic and clinical characteristics between patients with different severity of GI symptoms were performed with 1-way analysis of variance. Multiple linear regression analysis was used to analyze associations between GI symptoms and psychopathology, adjusting for potential confounding factors.

A total of 3256 patients (mean age 41, 40% male) were included in the analyses. Of those, 1750 patients (71%) had GI symptoms, with a frequency of several days/week for 38%, more than half of days for 23%, and almost daily for 10%. Patients with more GI symptoms had a significantly increased prevalence of anxiety; insomnia; poor concentration; limb and body pain; hopelessness; anger and irritability; and feelings of failure. In linear regression, suicidal ideation, anxiety, insomnia, anger, feelings of failure, and body pain were independently and significantly associated with GI symptoms in patients with MDD (

The authors concluded that more than 70% of patients with MDD reported GI symptoms during depressive episodes. Strengths of the study include the large, nationwide sample. Limitations include the cross-sectional nature of the study design, unmeasured and residual confounding factors, as well as the absence of data on specific GI symptoms. These findings are germane to investigations of the microbiota-gut-brain axis in depressive disorders.

“Mr S” is a 26-year-old Caucasian male with a history of recurrent major depressive disorder (MDD) and anxiety disorder. The onset of his depressive illness began when he was 19 years old. For the past 2 to 3 months during an exacerbation of his depression, he reports significant nausea and vomiting on a daily basis, particularly in the morning, which was not attributable to increased anxiety. Mr S reports that his gastrointestinal (GI) symptoms did not respond to treatment with either H-2 blockers or a proton-pump inhibitor. Subsequently, his antidepressant was changed to a different selective serotonin reuptake inhibitor, and a low-dose long-acting benzodiazepine was also added for anxiety. Over the next month, he reported significant improvement in not only mood and anxiety, but also nausea and vomiting, such that he was able to return to full-time employment.

Gastrointestinal symptoms are common in the clinical presentation of MDD. GI symptoms may be associated with the onset and clinical severity of depression, which could be a potential ancillary indicator in the management of MDD.

 is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

1. Smith K. Mental health: a world of depression. 

2. Harshaw C. Interoceptive dysfunction: toward an integrated framework for understanding somatic and affective disturbance in depression. 

3. Bruce-Keller AJ, Salbaum JM, Berthoud HR. Harnessing gut microbes for mental health: getting from here to there. 

4. Guo F, Cai J, Jia Y, et al. Symptom continuum reported by affective disorder patients through a structure-validated questionnaire. 

A study estimates the frequency and clinical correlates of GI symptoms during depressive episodes in a large, nationwide sample of patients with MDD in China.

Gastrointestinal Symptoms During Depressive Episodes

General medical illness can contribute to affective disorders in elderly patients. Treating the medical illness is an integral part in treating depression in these patients.


5 Medical Comorbidities Linked to Depression in Older Patients

Between mid-February and mid-March 2020, the number of sleep prescriptions in the United States rose by 14.8%. The increase may be due to the pandemic, says Manoj Malhotra, MD. Based on his experience, he says “the current environment, with myriads of shifts in our day-to-day lives, is a perfect storm for sleep challenges.”

In this Mental Health Minute, Malhotra explains how to distinguish between a general lack of sleep and chronic insomnia, and how to treat the latter.

 is vice president, United States medical affairs for the neurology business group at Eisai.

Have you seen more patients with sleep problems during the pandemic? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

Key considerations for healthcare providers seeking to manage their patients’ insomnia.  

The COVID-19 Pandemic Is a Perfect Storm for Sleep Challenges

In approximately half of patients with Huntington disease, symptoms of depression, irritability/aggression, executive dysfunction, psychosis, cognitive decline, and dementia present long before progressive motor symptoms. 

8 Neuropsychiatric Symptoms and Treatments of Huntington Disease

Body dysmorphic disorder (BDD) is a mental health disorder in which you cannot stop thinking about perceived defects or flaws in your appearance, flaws that are often minor or even invisible to others. This condition currently affects around 2-3% of the general population.

, we speak to Katharine Phillips, MD, about how her pioneering research on BDD, she books on the topic, and options for treatment.

is currently professor of psychiatry, DeWitt Wallace Senior Scholar, and Residency Research Director for the Department of Psychiatry at Weill Cornell Medicine. She is also an attending psychiatrist at New York-Presbyterian Hospital and adjunct professor of Psychiatry and Human Behavior at the Alpert Medical School of Brown University.

Millions of Americans have a skewed view of their own bodies, leading to serious depression and suicidality.  

Body Dysmorphic Disorder: Widespread and Potentially Deadly

Maybe I have heightened interest in blindness as a conversion symptom because I can sympathize with it. Sudden blindness happened to me during a diagnostic attempt to figure out the precise location of my brain bleed, and it left me with permanent right hemianopsia. I know that terrible moment: everything seems to be working fine—and then it is not.

Here is what being treated for sudden blindness was like for me, an experience that many patients with conversion symptoms might share. For 24 hours little flashlights appear as if by magic. Whoever is shining them seems to think that perhaps this time the result will be different than when the last individual shined a light in your eye. Everyone from the nursing aid to the senior neurologist sternly directs you to tell them how many fingers they are holding up. This continues long past the point when you are more than convinced that you cannot see fingers at all. Eventually they give up on finger counting and leave you to settle into the world that you can no longer see.

By the next day your newly discovered blindness is condensed down in their minds to an incidental mention in the morning report. Should you recover from the stroke, as I did, and be assertive enough to get a full copy of your hospital record, you may find that on the morning of the fateful event, the clinical statement is “patient complaining that he cannot see on the right side.” 

 is such a convenient word for the clinician, whose procedure has just rendered the patient with half a field of vision for the rest of his life. 

 suggests that it is really a small thing that the annoying patient is making into some big deal.

So I know the routine of the probing flashlights, and the insistent fingers, and the report that you are complaining. It makes me feel connected with the folks brought to the emergency department (ED) with sudden-onset blindness. Of course, possibilities such as stroke, or tumor, or multiple sclerosis must be ruled out, and flashlights have their role in the diagnostic. But when all those mechanical reasons for malfunction have been ruled out, we sometimes hear that there is no cause found, so it must be conversion disorder.

Conversion disorder is a diagnosis of elimination: when nothing can be identified by scan or blood work, the ED physician concludes that this is a rare case of conversion disorder. The DSM-5 named these experiences 

, which was meant to be less pejorative (not to mention less sexist) than the previous term 

 is from the Greek word for uterus). The word “conversion” is used to convey the sense that forbidden emotional conflicts are being converted to physical symptoms. This comes directly from Freudian explanations about how things work in the mind, and to my knowledge it is the only scrap of Freudian orthodoxy that remains in current psychiatric nomenclature. To me, the fact that DSM-5 is still using language derived from Freud suggests that there is little new thinking about how the brain produces the experience of blindness or, in other cases, paralysis, anesthesia, or seizures.

In a remarkable German study, researchers reported on a unique clinical situation, in which conversion disorder produced blindness in only 2 quarters of the visual field. The researchers were able to detect differences in the electrophysiological indices of visual processing, meaning that there were amplitude differences between the area of visual cortex where vision was occurring and the area of visual cortex where vision was not occurring. Psychodynamic therapy for this patient continued for a year and a half, augmented by a technique in which “a facilitator uses descriptive language intended to psychologically benefit mental imagery, often involving several or all senses, in the mind of the listener.”

The report specified that a great deal of effort went into helping the woman develop her own language to express feelings in a biographical framework. All of this therapy proceeded on the Freudian assumption that physical symptoms were expressions of emotion, but rather than experiencing forbidden emotions, the woman may simply have lacked the words to articulate and identify her own feelings. The woman regained her full field of vision, but the transition from being blind to experiencing full vision involved a period when she could see swirls, and then later periods when she could see clearly for brief periods of time. 

 reported that having achieved full visual field, a re-measurement of the electrophysiological indices found them to be equivalent in all 4 quadrants.

The article contains a graphic of the physiologic measurements of the evoked potential of the cortex response to the non-seeing eye area compared, to the same measurement normal vision area of the eye. There is a clear difference between the 2 traces, with the seeing portion of the eye producing a potential that is about double that which is measured from the non-seeing area. The publisher has not given permission to reproduce this remarkable figure, but 

it may be found online here (see figure 2).

This Schoenfield paper is amazing in several dimensions. Being able to measure electrophysiological activation deep in the visual cortex with such precision is a remarkable technological feat. Identifying a study participant who had blindness in just 2 of her 4 visual field quadrants was a statistical improbability. Even more remarkable (to this American practitioner) was the availability and funding of such high-quality multimodal therapy for a full year and a half.

Current medical education on conversion disorders suggests that the symptoms develop instantly and then resolve quickly, as soon as it is revealed to the patient that there is no medical justification for their symptom. The German article suggests otherwise, as this woman’s vision deteriorated in spite of good ophthalmologic care over a period of 4 years, and it recovered in gradual steps over a period of 18 months.

This study carries forward our understanding of the process and electrophysiological correlates of conversion blindness, but it does not offer any answers to questions such as: What is the body-mind alliance that institutes these changes? Why in this case was the symptom blindness and not muscle weakness or gastro-intestinal disturbance or migraines? Why opposite quadrants and not whole field vision? Even without giving answers to those questions, we are brought to consider that if the body-mind alliance is strong enough to cause this undesired change to happen, why would it not be strong enough in other circumstances to cause desired changes to happen?

Our training in allopathic skills does not carry us to any clear view, and so we tend to ignore the evidence. The body-mind alliance is there, in plain sight, waiting for us to recognize it and for us to use it as a healing tool.

is a community psychiatrist contracting telepsychiatry services to small community mental health centers in the rural area of his state. The author reports no conflicts of interest concerning the subject matter of this article.

1. Schoenfeld MA, Hassa T, Hopf J-M, et al. Neural correlates of hysterical blindness. 

A case in Germany overturns old ideas about conversion disorders. 

Hidden in Plain Sight

While psychotropic medications for schizophrenia, bipolar disorder, and other psychiatric disorders can cause weight gain, patients can take small steps to improve their health.

15 Steps to Helping Psychiatric Patients Achieve and Maintain a Healthy Weight

 for significant procognitive effects for antipsychotics and other pharmacologic approaches.

 Therefore, treatment of cognitive impairment in schizophrenia represents a tremendous area of unmet need.

 on the effects of exercise on brain structure and functional performance.

 found that aerobic exercise exerted a positive effect on global cognition and some, but not all, cognitive domains in patients with schizophrenia. Unfortunately, findings are limited by small samples, as well as variable types and intensity of exercise and study designs.

“Mrs Morris” is a 48-year-old Black woman with a history of chronic schizophrenia. During hospitalization for an episode of illness exacerbation, her antipsychotic medication was modified. Over the next 4 months, she gained approximately 50 lb. Mrs Morris declined to lower the dose of her antipsychotic or change medications because of her clinical improvement. She worried about risk of another illness relapse. However, she was receptive to the recommendation for increased physical activity for weight loss.

Mrs Morris started walking with a neighbor for about 30 minutes at a moderate pace at least 3 times per week. Over the next year, she lost 36 lb. Although there were no clinically appreciable changes in her cognitive function, she reported feeling better as a result of her exercise regimen.

 performed a 12-week randomized controlled trial of the effects of aerobic walking on cognitive function in patients with schizophrenia.

 The goal was to determine if the intensity of aerobic walking is associated with changes in cognition. Patients were randomized 1:1 based on age and sex to usual treatment with antipsychotics with or without aerobic walking. Inclusion criteria were 20 to 60 years, DSM-5 diagnosis of schizophrenia, stable antipsychotic dose for at least 1 month, Positive and Negative Syndrome Scale (PANSS) total score < 95, no history of major physical illness, and no physical disability that caused difficulty walking.

The program comprised 150 minutes/week of outdoor walking, typically divided over 3 to 5 sessions and each with a 5-minute warm-up, followed by a 5-minute cool-down. Transportation was provided to the exercise sessions as needed. Participants wore a Fitbit to monitor heart rate and exercise intensity and were supervised by research staff who provided guidance based on heart rate. The patients could rest if needed. Participants were stratified into high- and low-intensity groups based on the average in-session heart rate reserve. Cognition was evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS).

Data were analyzed using intention-to-treat and per-protocol analyses. Multivariate general linear model repeated measures were used to investigate the effects of time, group, and the time x group interaction on cognition, controlling for illness duration. The authors randomized 67 patients to treatment as usual (TAU, n = 34) or aerobic walking (n = 33) who completed the baseline assessment. Thirty-three patients in the TAU and 31 in the aerobic walking group completed the 12-week trial (

). At baseline, participants in the aerobic walking group scored approximately 0.5 standard deviations lower on 

 than the TAU group. The mean duration of aerobic walking was 129 minutes/week. Eleven patients achieved high-intensity walking and 22 maintained low-intensity. In the entire intent-to-treat sample, the authors found a trend for a group effect for greater improvement in verbal fluency in the aerobic walking group. They also found a significant group effect on attention and processing speed in high- versus low-intensity aerobic walking.

This was the first trial of the effects of aerobic walking and exercise intensity on 

in schizophrenia, according to the study authors. Most (> 90%) patients completed the trial with a mean of 3 days of exercise per week. The findings suggest that this intervention is feasible and acceptable to patients, and that supervision and transportation are associated with retention. Study limitations included the modest sample size (especially in the high-intensity group) and a relatively short study duration, as well as the inability for blinding to the intervention.

A supervised aerobic walking program involving moderate-intensity exercise is feasible and acceptable in patients with schizophrenia. Higher intensity aerobic exercise may have modest procognitive effects in these patients. Considering the other health benefits of aerobic walking, these programs can be useful for patients with schizophrenia.

is a professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain & Behavior Research Foundation, and the Stanley Medical Research Institute.

Pharmacological cognitive enhancement in schizophrenia

The magic of movement; the potential of exercise to improve cognition

Rosenbaum S, et al. Aerobic exercise improves cognitive functioning in people with schizophrenia: a systematic review and meta-analysis

Effects of aerobic walking on cognitive function in patients with schizophrenia: a randomized controlled trial

An earlier version of this article was published online as 

Exercise and Cognition in Schizophrenia: Is There a Link?

 This article appeared in the March 2021 print issue of 

Aerobic exercise has been found to exert a positive effect on global cognition and some, but not all, cognitive domains in patients with schizophrenia.

Is There a Link Between Exercise, Cognition, and Schizophrenia

FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY

Although vitamin deficiencies and their associated adverse effects are usually considered a public health problem in the developing world, they remain an important clinical consideration for select populations across the globe. In fact, there is concern that we may be confronted with increased negative consequences of poor nutrition due to decreased testing and screening and less education in our medical institutions about the importance of good nutrition to optimal health.

Casimir Funk, PhD, discovered that key nutrients, which he termed 

, are essential to maintaining good health and that deficiencies in these key nutrients led to pathognomonic disease states. This realization was a result of observing birds that were fed a diet of polished rice and developed a diffuse polyneuritis (beriberi). The same birds were then fed a diet of brown rice, and their “nervous symptoms rapidly disappeared.”

 This experiment helped establish the importance of vital amines, later shortened to “vitamin.”

Vitamins can be broadly delineated into water-soluble and fat-soluble categories. Water-soluble 

 are typically absorbed very quickly via the gastrointestinal tract and widely distributed in various tissues throughout the body. However, because these vitamins are water soluble, they are not efficiently stored in tissues. Therefore, this class of vitamins requires regular consumption (either through diet or supplementation) to avoid deficiency. Conversely, fat-soluble vitamins are more easily stored, typically in adipose tissue; therefore, they require less frequent intake.

 Examples of water-soluble and fat-soluble vitamins can be found in 

, also known as folate or folic acid, is crucial for DNA synthesis and repair, as well as the metabolism of amino acids involved in methylation reactions.

, folate deficiency can lead to neural tube defects in the fetus.

 In adults, folate deficiency can result in multiple neuropsychiatric symptoms. These symptoms may include cognitive impairment, insomnia, psychosis, depression, peripheral sensory deficits, and weakness. These manifestations are very similar to those of vitamin B

 deficiency. In patients with depression, folate deficiency can contribute to severity and can impede depression treatment.

Folate, which is absorbed in the small intestine, is obtained via diet or supplementation. Select food sources of folate or folic acid can be found in 

 Most serum folate is found in its active form, methyltetrahydrofolate (methyl THF). Methyl THF undergoes a B

-dependent enzymatic reaction, donating its methyl group to form tetrahydrofolate, which, in turn, is later involved in DNA formation. Any disruption in this process can lead to a deficiency in folate and its associated manifestations.

Folate deficiency can manifest from several different causes. High anabolic states, such as pregnancy, can result in increased utilization and depletion of folate stores. Similarly, chronic alcohol abuse causes poor absorption, impaired metabolism, and increased destruction of folate. Even moderate amounts of alcohol (for instance, 8 oz of red wine or 2.7 oz of vodka per day for a 2-week period) have been shown to reduce folate levels in otherwise healthy men.

 Certain medications have been shown to contribute to folate deficiency. A summary of common medications as well as their mechanism of folate deficiency can be found in 

Patients who appear to be at highest risk for deficiency include individuals with 

; individuals who take the noted medications (

); patients who require increased intake of folate (eg, pregnancy, hemodialysis, chronic anemias); and those patients with poor absorption because of intestinal dysfunction from surgery or inflammatory bowel syndromes. Women of childbearing age are also considered to be at risk. According to the 

National Health and Nutrition Examination Survey

, nearly 20% of women aged 14 to 30 years have inadequate serum levels of folate. The survey also found that almost 25% of non-Hispanic Black women have insufficient intake of folate compared with 13% of non-Hispanic White women.

Screening and testing should occur in individuals who are at high risk, have evidence of a macrocytosis or hyper-segmented neutrophils, and have unexplained neuropsychiatric conditions (eg, weakness, ataxia, paresthesia, 

Folic acid supplementation is recommended for all individuals who are at high risk. Evidence suggests that pregnant women should take at least 600 μg of folic acid daily to prevent neural tube defects.

 Folic acid is also typically given to patients on methotrexate to reduce adverse effects, although the dose given varies among rheumatologists.

 Patients with chronic hemolytic states and renal dialysis are recommended to take 5 mg daily to weekly, depending on requirement.

In 2018, a systematic review of survey data examined global folate status in women of childbearing age. Despite methodological limitations such as nonuniform measurement techniques and/or cutoff values, Rogers et al

 determined that the prevalence of folate deficiency was more than 20% in lower income countries and less than 5% in higher income countries. In January 1998, the United States implemented a mandate to fortify grain products with folate in an effort to 

 the incidence of fetal neural tube defects.

 Since then, folate deficiency has become very rare in the United States, with a prevalence of less than 1%.

Patients exhibiting macrocytic anemia on initial complete blood count and peripheral blood smear should be evaluated for both folate and vitamin B

 deficiency because these 2 conditions often present simultaneously. The diagnosis of folate deficiency is usually made when serum levels are less than 2.0 mcg/L.

 Measurement of serum homocysteine and methylmalonic acid (MMA) can also aid in differentiating between folate and B

 deficiencies. In folate deficiency, only serum homocysteine levels are elevated. In B

 deficiency, both homocysteine and MMA levels are elevated because B

 is involved in both homocysteine and MMA metabolism. Folate, on the other hand, has a role in only the homocysteine pathway

). Clinically elevated homocysteine can result in increased risk of thrombosis and its complications, such as myocardial infarction.

Oral replacement of folate is the recommended treatment. If the patient is unable to take oral medications, intravenous repletion is acceptable. The typical dose is dependent on the deficiency severity but ranges from 1 mg to 5 mg daily.

 Folate-deficient megaloblastic anemia due to dietary insufficiency or medications should be treated with 5 mg of folic acid daily for 4 months. Patients with malabsorptive states should be treated with up to 15 mg daily for 4 months.

s an associate clinical professor in the Department of Psychiatry at The University of North Texas Health Science Center at Fort Worth in Texas. 

 is a research coordinator in the Department of Behavioral Health Research at John Peter Smith Health Network in Fort Worth, Texas.

The authors report no conflicts of interest.

1. Adams KM, Kohlmeier M, Zeisel SH. Nutrition education in US medical schools: latest update of a national survey. Acad Med. 2010;85(9):1537-1542.

2. Piro A, Tagarelli G, Lagonia P, Tagarelli A, Quattrone A. Casimir Funk: his discovery of the vitamins and their deficiency disorders. Ann Nutr Metab. 2010;57(2):85-88.

3. Reinhard T. The Vitamin Sourcebook. NTC/Contemporary Publishing Group; 1998.

4. Chan YM, Bailey R, O’Connor DL. Folate. Adv Nutr. 2013;4(1):123-125.

5. Scott JM, Weir DG, Molloy A, McPartlin J, Daly L, Kirke P. Folic acid metabolism and mechanisms of neural tube defects. Ciba Found Symp. ١٩٩٤;١٨١:١٨٠-187; discussion 187-191.

6. Papakostas GI, Petersen T, Lebowitz BD, et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol. 2005;8(4):523-528.

7. US Department of Agriculture (USDA), Agricultural Research Service, Nutrient Data Laboratory. USDA National Nutrient Database for Standard Reference, Legacy. Updated April 2018. Accessed January 19, 2021. 

8. Greenberg JA, Bell SJ, Guan Y, Yu YH. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4(2):52-59.

9. Gibson A, Woodside JV, Young IS, et al. Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study. QJM. 2008;101(11):881-887.

10. Hesdorffer CS, Longo DL. Drug‐induced megaloblastic anemia. N Engl J Med. 2015;373(17):1649-1658.

11. Tinker SC, Cogswell ME, Devine O, Berry RJ. Folic acid intake among US women aged 15-44 years, National Health and Nutrition Examination Survey, 2003-2006. Am J Prev Med. 2010;38(5):534-542.

12. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academies Press; 1998.

13. Taylor PC, Balsa Criado A, Mongey AB, Avouac J, et al. How to get the most from methotrexate (MTX) treatment for your rheumatoid arthritis patient?-MTX in the treat-to-target strategy. J Clin Med. 2019;8(4):515.

14. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513.

15. Rogers LM, Cordero AM, Pfeiffer CM, et al. Global folate status in women of reproductive age: a systematic review with emphasis on methodological issues. Ann N Y Acad Sci. 2018;1431(1):35-57.

16. FDA. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register. August 5, 1996. 

https://www.federalregister.gov/documents/1996/08/05/96-19803/food-standards-amendment-of-standards-of-identity-for-enriched-grain-products-to-require-addition-of

17. Khan KM, Jialal I. Folic Acid Deficiency. StatPearls Publishing; 2020.

18. Vuckovic BA, Cabarkapa VS, Ilic TA, Salatic IR, et al. Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients. Croat Med J. 2013;54(5):480-488.

19. Lever EG, Elwes RD, Williams A, Reynolds EH. Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. J Neurol Neurosurg Psychiatry. 1986;49(10):1203-1207.❒

A myriad of neuropsychiatric symptoms result from folate deficiency, including cognitive impairment, insomnia, psychosis, depression, peripheral sensory deficits, and weakness. Treatment and prevention strategies are discussed. 

Psychosomatics