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Antipsychotic (Non)selectivity: A Setup for Swallowing and Side‐Effects in Seriously Ill Elderly Adults

Swallowing is a highly coordinated, complex process that is critical to life. After initiation of swallowing, 30 pairs of muscles are coordinated to bring food and liquid boluses safely into the esophagus while avoiding the trachea. The process involves voluntary (ingestion, chewing, bolus transport) and involuntary (pharyngeal stage, respiratory pause, esophageal stage) components. Similar to most complex processes in the body, age (presbyphagia), disease, and medications affect swallowing function. The swallowing (food and liquid) process includes participation of a complex array of neurotransmitters, with glutamate and gamma-aminobutyric acid serving as the primary excitatory neurotransmitters. Dopamine, particularly the dopamine-1 receptor, plays an important role in neuromodulation. Muscarinic acetylcholine receptors participate in autonomic regulation and smooth muscle contraction. Thus, one must consider the role of the collection of complex neural pathways and transmitters in the context of medications and swallowing. Most antipsychotic medications have dopamine-2 receptor antagonist activity with variable selectivity. Table 1 identifies the dissociation coefficients of antipsychotic medications for neurotransmitter receptors using data from the Psychotropic Drug Screening Program. Low dissociation coefficients suggest a strong affinity for the drug-receptor complex, as highlighted by the dissociation coefficients for haloperidol and the dopamine-2 receptor. The affinity of antipsychotic medications for multiple neurotransmitter receptors affects their biological effect in a highly variable way, more than just dopamine-2 activity. Evidence continues to point to an association between antipsychotic medication and mortality, especially in vulnerable populations such as older adults and those with dementia. For example, a metaanalysis of randomized trials of antipsychotic medications in individuals with dementia found that antipsychotic use increased the risk of death. Subsequent analyses found that the risk of death was dose dependent and highest early in the prescription. Although death is a definitive outcome, the studies focusing on death have focused on cardiac death—to the neglect of swallowing function. Because aspiration is the leading cause of death in individuals with dementia, and antipsychotics can cause oropharyngeal dystonia, a potential connection between antipsychotics, aspiration, and dementia makes clinical sense. A study of antipsychotics and aspiration contributes to our understanding of the limits and dangers of antipsychotics. It statistically linked short courses of antipsychotics in hospitalized individuals to aspiration pneumonia. Traditional adjustment and propensity analysis support the conclusion of this risk. The attributable risk of antipsychotics for aspiration pneumonia increases with age and is greater in individuals with dementia and delirium. Because of the diverse receptor binding, widespread systemic effects, and lack of other medications, the relationship between aspiration and antipsychotics is less certain for some conditions. For example, the antiemetic effects of antipsychotics results in their use for symptom management of nausea associated with advanced disease and palliative and hospice care, yet a randomized, placebo-controlled trial of haloperidol and risperidone in individuals receiving palliative care found more extrapyramidal side effects, poorer symptom control, and greater mortality with antipsychotics. One of the previous studies did not include prochlorperazine, a high-potency antipsychotic with cross-affinity for the histamine-1 and serotonin-2 receptors, in its analysis. There is inherent difficulty in identifying the prescribing indication as an antipsychotic or anti-emetic. Subgroup analysis of prochloroperazine users could identify whether prochlorperazine may have a different benefit for antiemetic properties; its exclusion from the previous study warrants reconsideration. Thus, we remain on a centuries’-long pathway toward demonstrating that Paracelsus’ adage continues to be correct. In individuals with dementia, those receiving palliative care, and those who are acutely ill and hospitalized, antipsychotics, even at low dose, become poison.