Residents' Voices

Autism, pain, and the NMDA receptor

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Implications of NMDA receptor antagonism

The use of ketamine as an NMDA receptor antagonist for treating depression and other psychiatric illnesses has gained momentum. Esketamine, the S-enantiomer of racemic ketamine, is now available as an FDA-approved intranasal formulation for treatment-resistant depression. Ketamine stops afferent nociception to the brain and is used as an analgesic (at low concentrations) and anesthetic (at high concentrations).1

Dextromethorphan is abused as a recreational drug because at high doses it works similarly to both ketamine and phencyclidine. Individuals who abuse DXM can develop psychosis, motor/cognitive impairment, agitation, fevers, hypertension, tachycardia, and death.2 In patients with ASD, researchers have identified genetic variations of NMDA receptors that are linked to dysfunction of these receptors.3 In animal models, as well as in humans, researchers have found that suppression or excitation of the NMDA receptor can ameliorate ASD symptoms, including social withdrawal and repetitive behaviors.3

Many individuals with ASD suffer from sensory abnormalities, including a reduced sensitivity to pain or a crippling sensitivity to various stimuli. Patients with ASD may have difficulty describing these abnormalities, and as a result, they may be misdiagnosed. One case report described a 15-year-old girl diagnosed with social anxiety and chronic generalized pain when in social situations.4 Pediatric rheumatologists had diagnosed her with “amplified pain syndrome.” When she presented to a mental health clinic for a neurodevelopmental evaluation, she explained to clinicians how she simply “did not ‘get’ people; they are just empty shells” and subsequently was given a diagnosis of ASD.4

In psychiatric patients who have comorbid substance use disorders, it is vital for clinicians to not only detect the presence of substance misuse, but also to understand what drives the patient toward abuse. Ms. G’s case, with its combination of substance abuse and ASD, illustrates the importance of listening to our patients for more precise diagnostic formulations, which then shape our treatment recommendations.


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