Rare Genetic Variation and Psychosis: Treatment Considerations for Psychiatrists

Numerous genetic disorders confer significant risk for the development of psychosis. Contemporary reviews on this topic have typically focused on describing “red flag” features, outlining workup recommendations, and highlighting the importance of screening for comorbid medical issues. ¹ However, few if any articles have discussed the potential implications a genetic disorder diagnosis may have on antipsychotic selection. As such, this letter is intended to offer a practical framework for approaching the management of psychotic symptoms in individuals with rare genetic disorders. This is especially needed given the scarcity of formal treatment guidelines in this context. As genome/exome sequencing becomes more accessible at a reduced cost over the coming years, psychiatrists will presumably more frequently encounter patients with genetic disorder diagnoses, making this paper particularly timely. However, such testing is unlikely to become a routine part of clinical care for most individuals experiencing psychosis in the near term. While pharmacogenetic testing is more relevant to general psychiatric populations, numerous reviews on this topic exist and its utility is unrelated to whether a patient has a genetic disorder. Importantly, while this letter specifically focuses on psychotic illnesses, the overarching principles can be extrapolated to the management of other psychiatric populations.

Although psychiatrists may be hesitant to prescribe antipsychotics in this context due to a lack of familiarity with a given disorder, the general concerns regarding delaying initiating treatment (with respect to the potential for poorer outcomes) ² still apply. Rare genetic variation in and of itself does not contraindicate the use of antipsychotics, but many such conditions associated with psychosis also confer risk for neurodevelopmental abnormalities and various medical issues that may predispose to idiosyncratic side effects. As such, it is important to consider the physiological overlap between a given disorder's possible comorbidities and the varying side effect profiles of different antipsychotics when providing care to individuals with genetic conditions. Although this may seem intuitive, as being mindful of concurrent medical problems when prescribing psychotropics is standard of care, it deserves special consideration in this context given that: (1) psychiatrists are likely to be unfamiliar with many genetic disorders, and (2) an individual's medical comorbidities may not yet be manifest at the time of assessment, potentially causing them to be overlooked.

While the following examples are not meant to be exhaustive or prescriptive, they nonetheless illustrate the general thought process governing this approach. Considering that many genetic disorders can cause a wide constellation of medical problems, some suggestions may seem contradictory. In such cases clinical judgement is required to prioritize mitigating the most serious potential side effects (possibly at the expense of causing others) when selecting medications.

As many copy number variant (CNV) syndromes (e.g., 22q11.2 deletion syndrome) confer risk for not only schizophrenia but also the development of seizures and congenital cardiac defects, ¹ antipsychotics that are less prone to lowering seizure threshold (e.g., aripiprazole, risperidone) and causing adverse cardiac effects (e.g., aripiprazole, cariprazine, lurasidone) may be preferable. Increased vigilance with respect to monitoring for signs of seizure activity and cardiac dysfunction before and during antipsychotic initiation/titration is also recommended. The prophylactic use of an anticonvulsant should additionally be considered when pursuing a clozapine trial. ³ Similarly, given that Wilson disease and Prader-Willi syndrome are both associated with low bone mineral density/osteoporosis,^4,5 partial dopamine 2 receptor agonists (aripiprazole, brexpiprazole, cariprazine) rather than antagonists may be a safer choice for such individuals, given their comparative effects on prolactin. As Prader-Willi syndrome is also associated with increased appetite and obesity, ⁵ less metabolically problematic treatments should probably be favoured over quetiapine, olanzapine, and clozapine, all else being equal. Another example involves the potential for early-onset parkinsonism in both 22q11.2 deletion syndrome ⁶ and a variety of inborn errors of metabolism that can cause psychosis, ⁷ such that antipsychotics with a lower likelihood of causing extrapyramidal symptoms (quetiapine and clozapine) may be better tolerated if motor dysfunction is present. Consideration should also be given to avoiding the use of (predominantly) renally excreted (e.g., paliperidone) and/or potentially nephrotoxic (e.g., lithium) psychiatric medications in patients with (or at high risk of developing) compromised kidney function due to congenital renal defects. A variety of urogenital anomalies can be seen in various relevant genetic disorders, including numerous CNV syndromes (e.g., 22q11.2 deletion syndrome ⁶ ) and Kleefstra syndrome. ⁸ Conversely, renally excreted medications may be preferable for use in patients with hepatic impairment secondary to, for example, Niemann Pick C or Wilson disease.^4,9 Moreover, when hepatically metabolized compounds are required, dose modification and close monitoring for signs of toxicity is recommended. As a final example, given the significant risk of aspiration consequent to progressive swallowing difficulties in numerous lysosomal storage disorders (e.g., Niemann Pick C ⁹ ), such patients should be carefully monitored for the development of sialorrhea if clozapine is trialled, given that hypersalivation may compound the problem. Lastly, although not an antipsychotic, given its frequent use in schizophrenia/schizoaffective disorder, it is worth noting that valproate is contraindicated in certain inborn errors of metabolism that can cause psychosis, including urea cycle disorders, mitochondrial disorders, and acute intermittent porphyria, as outlined in the product's monograph.

While not comprehensive or representative of hard-and-fast guidelines, these examples highlight the need for psychiatrists to familiarize themselves with those genetic disorders that predispose to psychosis, when encountered clinically. Although expecting clinicians to perform exhaustive literature reviews for this purpose is unrealistic, numerous readily accessible, clinically oriented resources that summarize the most salient phenotypic features of various genetic disorders exist. A good starting point is the online, peer-reviewed, journal-style, point of care resource, GeneReviews^®, as referenced above (https://www.ncbi.nlm.nih.gov/books/NBK1116). OMIM is also a useful website that focuses on genotype-phenotype correlations by collating relevant information from published reports (https://www.omim.org). When in doubt, consultation with medical genetics should be sought. However, as providing advice on psychiatric treatment selection is outside geneticists’ scope of practice, psychiatrists may additionally want to confer with psychiatric colleagues who have experience in this area. In rare cases, there may also exist disorder-specific consultation services, including with respect to providing psychiatric care, such as the Phelan-McDermid Syndrome Neuropsychiatric Consultation Group (https://pmsf.org/neuropsychiatric-consultation-group).

In summary, although the recommendations herein do not represent consensus practice guidelines, when providing care for individuals with psychosis occurring on the background of rare genetic variation, psychiatrists should take the time to educate themselves accordingly to ensure the safe and rational prescribing of antipsychotic medications in this population.

Take Home Messages

A variety of rare genetic disorders confer significant risk for psychosis.

While rare genetic variation in and of itself does not contraindicate the use of antipsychotic medications, it is imperative that psychiatrists providing care for affected individuals become informed with respect to any potential medical comorbidities and make treatment decisions accordingly.