<p>Persons with intellectual and developmental disabilities (including autism spectrum disorder) may engage in challenging behavior, which is often treated using psychopharmacological and/or applied behavior analytic interventions. Presently, aripiprazole and risperidone are the only medications approved by the U.S. Food and Drug Administration for the treatment of agitation and irritability in autistic patients. As such, psychotropic medications prevalence research suggests many drugs are being used off-label. Given the diverse profiles across this clinical population, single-case experimental designs (SCED) may be helpful in monitoring and reporting the behavioral effects of psychotropic medications. This systematic literature review examined peer-reviewed articles that used SCED to monitor the behavioral effects of psychotropic medications across medication adjustments. Of the sixty-nine articles published between 2000 and 2024, 53% of cases did not have a concurrent mental health diagnosis. Mean participant age was 25 years (range, 3-79), while antipsychotics were prescribed most often (47%). We uncovered several medication adjustment patterns, including prescribers selecting medication augmentation (adding a new medication) first across 70% of cases, followed by maximization (adjusting the dose of an existing medication) as the first prescription change (23%), and finally medication withdrawal (4%). Effect size estimates indicated overall medication adjustments appeared to have small to negligible effects on challenging behavior (0.01). In isolation, medication augmentation coincided with a mean effect size of 0.34 (moderate). These findings, and others, underscore a need for more research and collaboration between prescribing professionals and behavioral specialists to better understand and manage the use of psychotropic medications in this clinical population.</p>