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All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to review the pathophysiology of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (ANMDARE).

1. Understand the pathophysiology of ANMDARE to the cellular level.

2. Recognize the various tools used to diagnose ANMDARE as well as the specific findings seen.

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals seeking to improve the care of patients with mental health disorders.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and 

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

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Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune condition caused by reversible internalization of the NMDA receptor as the result of autoantibodies produced via an immunologic trigger.

 The condition was first described in the literature in 2005 by Vitaliani and colleagues,

 with a description of the autoantibodies coming just 2 years later by Dalmau et al.

 Since its discovery, it has become the most common autoimmune encephalitis.

Epidemiologically, a vast age range (2 months to 85 years) of affected patients has been documented, with a mean age of onset of around 21 years. There is an increased prevalence among younger women than men (4:1); this sex discrepancy appears to even out after age 45 years.

 It is frequently described as a paraneoplastic condition due to its popular association with ovarian teratomas; however, this is not always the case, as viral causes have been documented, as well as undetermined causes. This article reviews the most up-to-date literature regarding the pathophysiology of 

 and provides a brief overview of the clinical features, diagnostic imaging findings, and treatments.

The first described cases of ANMDARE involved 4 women diagnosed with comorbid ovarian teratomas and identified a distinguishable pattern of symptoms. The clinical features of ANMDARE can therefore be described as progressive through 3 stages (

This first stage presents with flu-like symptoms, such as headache, fatigue, and low-grade fever.

The prominent positive and negative symptoms indistinguishable from those seen in schizophrenia (eg, hallucinations, delusions, disorganized behavior, and paranoia) are associated with the second stage.

 In this third stage, there are more neurological symptoms, such as focal or generalized seizures, dyskinesias, and autonomic instability. Other neuropsychiatric symptoms include agitation, irritability, catatonia, 

 Some patients experience residual neurologic sequelae posttreatment that may last months to years.

These stages represent the most common progression, but other variations are seen. Below are cases discussed in the literature that exemplify this variety, followed by the pathophysiology as we understand it today and a brief overview of laboratory findings, imaging, and treatment.

A 27-year-old woman with no significant psychiatric or systemic medical history presents to the emergency department with a 15-day history of disorganized thoughts, hypochondriacal delusions, auditory hallucinations, insomnia, and short-term memory loss. History of present illness does not reveal headache, fever, seizures, dyskinesia, or autonomic instability. Mental status examination exhibits disorientation to time, abstract thinking deficits, poor attention, speech latency, verbal perseveration, and auditory hallucinations. Initial laboratory studies and imaging are normal; she is admitted to an inpatient psychiatric unit for management of 

While on the psychiatric unit, the patient displays food refusal, decreased speech, and alternating periods of hypo- and hyperkinetic movement. The initial medication regimen consists of aripiprazole, titrated to 30 mg/day and lorazepam 3 mg/day. Although she shows improvement in her psychotic and behavioral symptoms, her short-term memory symptoms worsen, leading to further neurological work-up.

Brain MRI shows diffuse sulcal enlargement of the cerebellar vermis. Electroencephalography (EEG) shows independent bilateral temporal slow activity without an extreme delta brush pattern. Complete blood analysis is unremarkable. Urine toxicology is negative.

Given the atypical presentation, anti-NMDA receptor antibodies are checked in serum and cerebrospinal fluid (CSF); results of both analyses are positive. All other autoimmune antibodies are negative. CSF also shows mild lymphocytic pleocytosis with lymphocyte predominance. Endovaginal ultrasound shows a mass in her right ovary, which is subsequently diagnosed as an ovarian teratoma.

Further treatment consists of intravenous (IV) immunoglobulin 0.4 mg/kg/d and methylprednisolone 1 g/d for 5 days, which are successful in improving her episodic and visual memory, verbal fluency, and attention as well as in decreasing her psychotic symptoms. Repeated brain MRI and EEG show no specific findings. She is discharged on aripiprazole 30 mg/d, prednisolone 60 mg/d, and monthly IV immunoglobulin 0.4 mg/kg/d for 5 days. Both psychiatric and neurological follow-up reveal marked improvement in all symptoms.

A 23-year-old woman with no psychiatric or general medical history experiences a seizure at home lasting approximately 10 minutes, followed by several minor focal seizures with mouth twitching. She then develops mood instability, increased irritability, and periods of unprovoked and inappropriate laughing and crying. She is admitted to an inpatient psychiatric unit for management. Brain MRI shows T2 and diffusion-weighted imaging–hyperintense (DWI-hyperintense) lesions of the right temporal lobe. The initial treatment regimen consists of valproic acid 500 mg twice daily and 

During her admission, she develops a fever of 37.8 °C and a tonic-clonic seizure despite treatment with 

. At the time of the seizure, vital signs are stable, and she is responsive; however, she is disoriented to time and place. Neurological examination reveals decreased muscle tone in her upper and lower limbs with normal strength. She is transferred to a general hospital for further management. Lumbar puncture is performed, showing herpes simplex virus-1 (HSV-1) polymerase chain reaction immunoglobulin M (IgM) and IgG positivity. Anti-NMDA receptor antibody IgG testing is positive in both serum and CSF. Glutamic acid decarboxylase (GAD) antibodies are positive in serum. Contrast enhanced MRI reveals T2, fluid-attenuated inversion recovery (FLAIR) imaging, and DWI-hyperintense lesions in the right temporal lobe. EEG shows diffuse slow waves in the right temporal lobe. Pelvic ultrasound is negative.

Treatment consists of acyclovir 10 mg/kg IV every 8 hours, methylprednisolone 1000 mg/d IV, and valproic acid 500 mg every 8 hours. Symptoms remain uncontrolled after 7 days, so IV immunoglobulin 0.4 mg/kg/d is added to her regimen. After a second round of IV immunoglobulin therapy, her physical and cognitive symptoms sufficiently improve and she is discharged. Follow-up MRI shows resolution of hyperintense lesions.

NMDA-glutamate receptors are ionotropic receptors that regulate multiple neuropsychiatric functions, including learning, memory, and neuroplasticity.

 They are complexes made up of 4 subunits—2 GluN1 subunits and 2 GluN2 subunits—each with similar structures. These subunits serve as the target for the autoantibodies produced in ANMDARE (

The NMDA receptor is an ionotropic glutamate receptor that regulates multiple neurologic functions. It is a heterodimer consisting of 2 NR1 subunits that bind to glycine and 2 NR2 subunits that bind to glutamate.

 These subunits serve as the target for anti-NMDA receptor antibodies. Binding of each subunit’s respective ligand activates the receptor and opens the ion channel, which is highly permeable to calcium, and allows the receptor to exert its effects.

ANMDARE is ultimately caused by autoantibodies that stimulate reversible internalization of the NMDA receptor. This internalization creates a state of NMDA hypofunctionality, which is described in the NMDA hypothesis of psychosis.

 It also is the likely cause of the prominent positive and negative psychotic symptoms. It is most widely accepted that the specific site of autoantibody action is at the GluN1 subunit. These autoantibodies cause crosslinking of the NMDA receptors, altering their ability to interact appropriately, which leads to their internalization and trafficking through endosomes and lysosomes.

Production of these autoantibodies can largely be divided into 3 categories: paraneoplastic processes, viral infections, and unknown. The most common paraneoplastic trigger is ovarian teratomas.

 It is hypothesized that neuronal tissue expressing the NMDA receptor is contained within some teratomas. These tumor cells undergo apoptosis and release antigen to antigen-presenting cells (APCs), which engulf free antigen and present it to regional lymph nodes. Because antigens are typically intracellular in tumor cells and cannot be easily accessed by APCs, it is suspected the cytotoxic T cells play a role. Herpes simplex virus (HSV) is the most common viral trigger.

 It is thought that the inflammatory process of the encephalitis causes neuronal degeneration and formation of inflammatory infiltrates, leading to antigen uptake by APCs or direct delivery to local lymph nodes.

Regardless of the initial immunologic trigger, the downstream effect is the production of memory B cells, activation of naïve B cells via CD4-positive cells, and anti-NMDA receptor antibody-producing plasma cells, which pave the way for NMDA receptor disruption, destabilization, and internalization.

 Once naïve B cells are produced and activated, they enter the central nervous system (CNS) and undergo restimulation due to the high prevalence of NMDA receptors in the brain. This results in the production of plasma cells specific to the NMDA receptor.

Research suggests that it is primarily these antibodies produced by plasma cells already in the CNS that contribute most to development of disease compared with systemic antibodies.

 The site of recognition for the autoantibodies is on the GluN1 subunit of the receptor. The autoantibodies disrupt the stability of the receptor, particularly by interfering with the interaction between the NMDA receptor and EphB2, a protein that functions in a supportive and stabilization role to the NMDA receptor. It is specifically the disrupted interaction between EphB2 and NMDA that leads to displacement and internalization.

 Further characterization regarding the mechanism of internalization has not yet been clearly described. Recent studies have begun to explore the possible role of scaffolding and stabilizing proteins in this process, the most notable of which is PDS-95 due to its role in anchoring the NMDA receptor to the cell membrane.

Regarding the progressive stages of ANMDARE, what is known of the current pathophysiology can be correlated to the progression of clinical presentation. The prodromal phase of flu-like illness may be attributed to increased proinflammatory cytokines seen in patients with ANMDARE, such as increased serum IL-2 levels and increased CSF IL-6 and CXCL13 levels.

 The psychotic symptoms seen in the second stage appear to be most likely related to NMDA hypofunctionality resulting from growing numbers of anti-NMDA antibodies and internalization of the synaptic NMDA receptors.

In later stages of ANMDARE, neurologic symptoms, such as 

, are the hallmark. Research suggests that during the molecular stages before NMDA receptor internalization, anti-NMDA receptor antibodies act briefly as agonists to NMDA receptors, which lowers the seizure threshold.

 This is an important detail regarding pathophysiology, because it reveals that NMDA hypofunctionality does not completely explain the core symptoms. Other NMDA hyperfunctional symptoms include 

 and dystonia; the same mechanism of brief NMDA receptor agonist activity is theorized to be responsible for these symptoms.

 Finally, many patients with ANMDARE suffer severe cognitive symptoms, which—like the psychotic symptoms—can be explained by NMDA hypofunctionality.

 Decreased NMDA receptor function leads to decreased neuronal activity in the dorsolateral prefrontal cortex, which is required for working memory, cognitive flexibility, and executive planning.

ANMDARE can be diagnosed with the use of laboratory tests (both serum and CSF antibodies), imaging (ie, MRI and 18-fluorodeoxyglucose–positron emission testing (FDG-PET), EEG, and the following ancillary tests.

 The most common autoantibody detected and implicated in the diagnosis of ANMDARE is anti-NMDA receptor. Antibody studies should include CSF analysis.

 Serum analysis for antibodies can be performed, but they are not completely reliable on their own due to false-negative or false-positive diagnosis. Studies have shown that serum analysis is less consistent and has even shown positive results in patients without ANMDARE.

 Specifically in cases of ANMDARE caused by HSV encephalitis, other antibodies have been seen alongside NMDA receptor antibodies, such as GABA

 receptor and dopamine 2 receptor antibodies.

 CSF findings are abnormal in most patients with ANMDARE (80%), mostly in those with late-phase disease. Findings include lymphocytic pleocytosis, normal or mildly increased protein levels, and CSF-specific oligoclonal bands. Depending on the course of treatment, antibodies may be seen only in CSF. The CSF titers may be predictive of prognosis and response to treatment.

 MRI findings are normal in 50% of patients with ANMDARE (

 When findings are present, they are mostly seen on T2 or FLAIR and show signal hyperintensity in the cerebellar or cerebral cortex, hippocampi, basal ganglia, brainstem, frontobasal and insular regions, and sometimes the spinal cord.

 These findings are mostly mild/transient and occasionally show contrast enhancement.

18F-FDG-PET/CT scan could be helpful in the diagnosis of ANMDARE in patients with normal MRI findings (

 In a small (n=5) series of cases published by Solnes et al, patients with ANMDARE who demonstrated normal MRI results were all noted to have abnormal 18F-FDG-PET/CT scan results (

 Findings included lobar hypometabolism in a wedge-shaped pattern mostly found in the parietal lobe, followed by the occipital and temporal lobes.

 One study found frontotemporal hypoperfusion and brain atrophy.

 Other imaging modalities, such as MR spectroscopy and 9mTc-d,l-hexamethyl-propyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) show transient cortical and subcortical changes.

 EEG findings are usually abnormal. The most common finding is nonspecific, slow, disorganized activity, sometimes with electrographic seizures.

 When patients present with catatonia, they show slow, continuous rhythmic activity in the delta-theta range.

 Nonepileptiform seizures may occur and, hence, video EEG may become increasingly important.

 ANMDARE often occurs as a paraneoplastic syndrome, most commonly in the presence of an ovarian teratoma. Very rarely, patients may be diagnosed with a different tumor type, such as Hodgkin lymphoma or neuroblastoma.

Important tests for ovarian teratomas include pelvic CT scans, MRI, and pelvic and transvaginal ultrasound. Tumor markers include β-human chorionic gonadotropin, AFP, CA-125, and testosterone. If an oophorectomy is performed, the resected ovaries can show presence of NMDA receptors.16

Other etiologies (aside from tumors) can include infections. Studies have shown positive mycoplasma antibodies, herpes zoster infection, diphtheria, pertussis, tetanus vaccination, and H1N1 vaccination.

 Some patients had associated microdeletion of the short arm of chromosome 6 (which included the HLA cluster) antithyroid peroxidase and antinuclear antibodies.

Despite the amount of research into ANMDARE, a definitive pathophysiologic mechanism has yet to be determined. Most studies investigating the mechanism have pinpointed the most likely pathway as NMDA receptor internalization as the result of autoantibodies, but further details regarding the process of internalization remain unclear. ANMDARE should always be kept in the differential when considering a first episode of psychosis or exploring specific anatomic causes of psychiatric symptoms. Significantly, ANMDARE provides a concrete clinical example of a pathophysiological mechanism first described only 17 years ago that is responsible for the onset of sudden psychotic symptoms.

When correctly diagnosed and treated with immunoglobulin and corticosteroids, ANMDARE resolves and these patients generally rapidly improve. As we continue to understand the complexities of the brain, and as further research reveals more information, it is likely that additional unique pathophysiology will be discovered as etiologic for psychosis, mania, and other psychiatric symptoms. These potential findings may provide pathways for the development of novel treatments to reduce, or even eliminate, these symptoms.

 The authors wish to acknowledge James A. Bourgeois, OD, MD, for offering suggestions and editing this paper.

Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mechanisms, treatment, prognosis.

2. Vitaliani R, Mason W, Ances B, et al. 

Paraneoplastic encephalitis, psychiatric symptoms and hypoventilation in ovarian teratoma.

Limbic encephalitis: the new cell membrane antigens and proposal of clinical-immunological classification with therapeutic implications.

Anti-N-methyl d-aspartate receptor encephalitis and electroconvulsive therapy: literature review and future directions.

5. Dalmau J, Armangué T, Planagumà J, et al. 

An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.

6. Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J. 

Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis.

A clinical approach to diagnosis of autoimmune encephalitis.

8. Câmara-Pestana P, Magalhães AD, Mendes T, et al. 

Anti-NMDA receptor encephalitis associated with an ovarian teratoma presenting as first-episode psychosis: a case report.

HSV encephalitis triggered anti-NMDAR encephalitis: a case report.

10. Amedonu E, Brenker C, Barman S, et al. 

An assay to determine mechanisms of rapid autoantibody-induced neurotransmitter receptor endocytosis and vesicular trafficking in autoimmune encephalitis.

11. Tüzün E, Zhou L, Baehring J, et al. 

Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma.

NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: the 2016 Cotzias Lecture.

Distinct intrathecal interleukin-17/interleukin-6 activation in anti-N-methyl-D-aspartate receptor encephalitis.

NMDA receptor internalization by antibodies: a reversible mechanism underlying psychosis?

15. Lynch DR, Rattelle A, Dong YN, et al. 

Anti-NMDA receptor encephalitis: clinical features and basic mechanisms.

16. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. 

Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.

17. Solnes LB, Jones KM, Rowe SP, et al. 

Diagnostic value of 18F-FDG PET/CT versus MRI in the setting of antibody-specific autoimmune encephalitis.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.

Reversible brain atrophy in anti-NMDA receptor encephalitis: a long-term observational study.

20. Dalmau J, Gleichman AJ, Hughes EG, et al. 

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.

21. Lebas A, Husson B, Didelot A, Honnorat J, Tardieu M. 

Expanding spectrum of encephalitis with NMDA receptor antibodies in young children.

22. Zandi MS, Irani SR, Follows G, et al. 

Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma.

23. Gable MS, Gavali S, Radner A, et al. 

Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis.

24. Baltagi SA, Shoykhet M, Felmet K, et al. 

Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic.

Anti-NMDA receptor encephalitis after TdaP-IPV booster vaccination: cause or coincidence?

26. Florance NR, Davis RL, Lam C, et al. 

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

In this CME, review the pathophysiology of anti-N-methyl-D-aspartate receptor encephalitis. 

Exploring a Medical Mimic: Anti-NMDA Receptor Encephalitis Pathophysiology

According to the Physicians Foundation’s 2022 Survey of America’s Physicians, 8 in 10 physicians believe the United States cannot improve health outcomes or reduce health care costs without addressing social factors that affect patient health. Furthermore, although they are interested in addressing social drivers of health (SDOH) for patients, 61% of the 1502 surveyed physicians said they do not have the time or ability to do so effectively. The February 2022 survey examined the current impact of SDOH on physician practice, physician well-being, and their patients, as well as possible solutions needed to address the social factors.

“Over the course of the COVID-19 pandemic, there is no question that physicians and patients have all been impacted, some worse than others. Part of what drives the scale of that impact is SDOH,” Physicians Foundation CEO Robert Seligson said in a news release. “The desire from physicians to properly address the SDOH is there. We need take the initiative to make changes, like screening patients to identify social needs and creating financial incentives to support physicians in addressing their patients’ unique needs.”

Also known as social determinants of health, SDOH include factors such socioeconomic status, education, neighborhood and physical environment, employment, nutrition and food security, health care access, and social support networks.

The survey highlighted the resulting frustration of not being able to address SDOH for their patients. “[It] isn’t for lack of trying or effort—physicians face many barriers when addressing SDOH,” the Physicians Foundation report said. For instance, along with limited time, 84% of physicians said they have an insufficient workforce to navigate patients to community SDOH resources. Similarly, although there are some helpful resources to navigate SDOH factors, 77% of physicians reported community resources were not available, inadequate, or difficult to access, and 77% said there is inadequate information on how to access community resources.

The impact of SDOH challenges is very real, and not just for patients. More than half the physicians reported the challenges cause them stress on a daily or weekly basis. They cited factors such as existing payer reporting requirements taking time away from discussing patients SDOH (63%) and lack of reimbursement for screening or addressing SDOH (57%).

To make addressing SDOH easier for clinicians, the survey identified multiple policy steps that could improve patient health outcomes while ensuring high-quality, cost-efficient care. The top strategies were reimbursing physician-directed efforts to address SDOH (86%), incentivizing payers to invest in availability and quality of community resources to address patients’ SDOH (84%), and providing greater flexibility for Medicare Advantage to reimburse for addressing SDOH (81%).

“In 2021, The Physicians Foundation submitted the first-ever SDOH measures to Centers for Medicare and Medicaid Services (CMS), which are currently under consideration to be included in federal payment programs,” Seligson said in the news release. “If adopted, these measures might potentially impact reimbursements for physicians, as well as address SDOH in how our country pays for and delivers care to improve patient health.” ❒

8 in 10 physicians believe the United States cannot improve health outcomes or reduce health care costs without addressing social factors that affect patient health. 

Physicians Point to SDOH as Area of Improvement for Health Care

Apetamin is a syrup consisting of L-lysine, cyproheptadine, and B vitamins (thiamine, pyridoxine, nicotinamide, and dexpanthenol) that is produced by Indian pharmaceutical company TIL Healthcare Pvt Ltd.

 Cyproheptadine is available by prescription only in the United States,

 but Apetamin syrup is being sold illegally on social media platforms and other online sources as an unregulated weight-gain supplement.

 It has gained media attention in recent years, with social media influencers promoting it as a supplement for body enhancement, promising an hourglass figure that UK National Health Service (NHS) officials have described as “unobtainable and biologically unsafe.”

The misuse of cyproheptadine as a figure enhancer is occurring on an international scale. A 2019 case report from India describes a man who gained 15 kg of weight during a 1-year period while taking a “gym-tonic” pill composed of cyproheptadine and dexamethasone that was illicitly prescribed by his gym instructor for weight-gain purposes.

 Another recent study, this one from the Democratic Republic of Congo, describes the “C4 Phenomenon”: In Kinshasa, cyproheptadine is sold as an appetite stimulant under the name C4 and promoted as a way to obtain a rounded physical appearance.

 More than two-thirds of the population surveyed reported using C4 over the past 6 months, with use found to be more common among women and those with lower educational levels.

 Almost half of users reported that it had been recommended to them by their friends, and more than 90% reported self-prescribing.

NHS leaders in the United Kingdom have urged social media platforms such as Instagram to shut down accounts promoting or selling Apetamin, given significant concerns about its potential physical and mental health effects, particularly on young women and girls, to whom such content is predominantly targeted.

Cyproheptadine is a first-generation antihistamine with antiserotonergic, anticholinergic, and sedative properties.

 It has been in medical use since the 1960s and is approved by the FDA for the treatment of various allergic conditions.

 In the 2000s, it was studied for its orexigenic effects in undernourished children, with variable results.

 It has been used as an off-label treatment for a wide range of psychiatric conditions, including serotonin syndrome, akathisia, and selective serotonin reuptake inhibitor–induced sexual dysfunction. It has also been investigated for possible use in the treatment of nightmares in posttraumatic stress disorder, insomnia secondary to stimulant use, behavioral control in autism spectrum disorders, and neuropsychiatric sequelae of efavirenz.

A retrospective review of the French Pharmacovigilance Database by Bertrand et al examined all reported adverse effects of cyproheptadine since its first distribution in France in 1985 and concluded that it can be considered a “safe” drug.

 During this 35-year period, a total of 93 adverse effects (AEs) were reported, which were primarily neurological and hepatic in nature, with drowsiness representing the most common AE; hepatotoxicity was found to be uncommon.

The suggested initial dosing for the treatment of FDA-indicated conditions compared with the manufacturer’s suggested daily dose of Apetamin is outlined in 

Keep in mind, however, that individuals using illicitly obtained Apetamin as a weight-gain supplement may not adhere to these dosing recommendations. One case report from 2020 describes a woman who reported drinking Apetamin syrup directly from the bottle—to maximize its reported figure-enhancing effects; after 6 weeks of daily use, she developed autoimmune hepatitis.

Additionally, given that the illicit sale of Apetamin on social media is inherently unregulated, buyers cannot be certain that the product they are receiving is consistent with the formula reported by the manufacturer or that the product has not been adulterated with other substances. Consumption of unknown quantities of Apetamin presents the risk of unintentional cyproheptadine overdose. The maximum daily dose of cyproheptadine by age is outlined in 

In overdose, cyproheptadine may cause central nervous system depression and sedation, as well as anticholinergic syndrome, with symptoms such as dry mouth, dilated pupils, and flushing.

 A 2011 review of the characteristics of intentional cyproheptadine overdoses indicated that approximately 40% of cases were asymptomatic, whereas 17% developed anticholinergic delirium presenting as acute psychosis.

 The average dose ingested was lower for asymptomatic patients than for patients who developed delirium, at 49.

In addition, the weight gain associated with Apetamin use also presents a risk of developing obesity, which is in itself a risk factor for a range of health conditions including hypertension, type 2 diabetes mellitus, chronic kidney disease, and osteoarthritis.

Clinical Considerations for Psychiatric Providers

Given that Apetamin misuse is occurring on a global scale, it is important for psychiatric providers worldwide to be aware of the risks this agent presents so that they are prepared to appropriately counsel patients. As influencers on social media platforms appear to be predominantly targeting young women and girls in their promotion of Apetamin, awareness is particularly important for providers treating children and adolescents.

Although the study from Kinshasa suggests that potential risk factors for use include female gender and lower educational levels,

 further research is needed into what other factors may place someone at greater risk for use. Providers may wish to consider screening patients with a known history of eating disorders, body dysmorphic disorder, or other body image–related concerns—particularly patients who are known to use social media platforms. Providers may also simply consider including Apetamin in their routine questioning of young women about medication and herbal supplement use.

In addition to the risks described, psychiatric providers should also keep in mind that for patients who are prescribed monoamine oxidase inhibitors, cyproheptadine has the potential to prolong anticholinergic effects.

 is a resident physician in the Department of Psychiatry at Temple University Hospital in Philadelphia, Pennsylvania. 

 is an assistant professor of clinical psychiatry and behavioral science and director of the Psychiatry Residency Program in the Lewis Katz School of Medicine at Temple University in Philadelphia.

1. Appetite stimulants. TIL Healthcare. Accessed January 27, 2022. 

https://tilhealthcare.com/appetite-stimulant/

2. Cyproheptadine. Package insert. Teva Pharmaceuticals USA; 2009.

3. Murdoch C, Powis S, Wallace K. Letter to Instagram from Claire Murdoch regarding the drug Apetamin. UK National Health Service. May 3, 2021. Accessed January 27, 2022. 

https://www.england.nhs.uk/publication/letter-to-instagram-from-claire-murdoch-regard-the-drug-apetamin/

4. Bawaskar HS, Bawaskar PH, Bawaskar PH. 

5. Lulebo AM, Bavuidibo CD, Mafuta EM, et al. 

The misuse of cyproheptadine: a non-communicable disease risk behaviour in Kinshasa population, Democratic Republic of Congo

Safety of cyproheptadine, an orexigenic drug. analysis of the French National Pharmacovigilance Data-Base and systematic review

Cyproheptadine: a psychopharmacological treasure trove?

8. Garland V, Kumar A, Theisen B, Borum ML. 

Apetamin hepatotoxicity: potential consequences of purchasing a body enhancement drug off the internet

Review of the epidemiology and characteristics of intentional cyproheptadine overdose in Hong Kong

In overdose, cyproheptadine may cause central nervous system depression and sedation, as well as anticholinergic syndrome.

Under the Influence: Misuse of Apetamin, the Illicit Social Media Weight-Gain Drug

This article is dedicated to the memory of Sharland Trotter, EdD, whose wisdom, courage, and generosity gave life to this project.

What can we learn about practicing while dying from a therapist who is terminally ill? In this article, we examine this wisdom in an interview generously given by the brilliant therapist Sharland Trotter, EdD, 3 weeks before her untimely death. In the interview, Trotter shared her experiences and insights while treating patients for 3 years between her diagnosis with metastatic colon cancer in 1994 and her passing on Thanksgiving Day 1997.

The literature on this subject focuses primarily on the question of when and to what extent a therapist diagnosed with terminal illness should disclose this fact to their patients. Contrary to the majority view in the literature at the time of her death,

 but in accordance with emerging views that have gradually become widely accepted,

 Trotter adopted a policy of maximal disclosure consistent with the patients’ needs from the moment she was diagnosed. The broader clinical implications of Trotter’s insights are discussed.

Most articles about the therapist who is terminally ill are written from the patient’s perspective. The few articles written from the therapist’s perspective mostly focus on serious illness from which the therapist ultimately recovered, with Feinsilver

 being a notable exception. Articles written from the patient’s perspective primarily focus on the patient’s reaction to the therapist’s illness. Halpert

 focuses on the analyst’s denial of their own illness, which leads to denial by the patient. He states that patients use denial in response not only to their own guilt about their aggressive wishes toward the analyst, but also to their perception that the analyst cannot tolerate awareness of their illness. Meloche

 focuses on the ways the knowledge that the therapist is dying becomes therapeutically useful in completing unfinished past mourning with the dying therapist’s help. Clark

 focuses on the ways the therapist’s illness limits their ability to use the self as part of analysis. Auxéméry

 focuses on patients’ difficulty returning to treatment after the sudden death of their therapist. Rizq

When therapists are terminally ill, should they err on the side of self-disclosure or silence?

Psychosomatics

Exploring a Medical Mimic: Anti-NMDA Receptor Encephalitis Pathophysiology

Physicians Point to SDOH as Area of Improvement for Health Care

Under the Influence: Misuse of Apetamin, the Illicit Social Media Weight-Gain Drug

To Disclose or Not to Disclose? Lessons From a Dying Therapist

The Heart of Psychiatry

Psychosocial Insights: Exploring Issues in Heart Health

DTx Receives FDA’s Breakthrough Device Designation for Anxiety and Depression Symptoms Associated With Cancer

Delirium: Don’t Miss It

Lyme Disease in Psychiatry: Controversies, Chronic Symptoms, and Recent Developments

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