SAFETY, TOLERABILITY, AND DRUG-DRUG INTERACTION CONCERNS IN POLYPHARMACOLOGY REGIMENS

Polypharmacy involving psychiatric medications continues to be common despite awareness that it may lead to increased incidence and/or severity of side effects or to potentially significant drug-drug interactions. This talk will draw attention to less obvious negative consequences of polypharmacy involving psychiatric medications. One scenario is where the effects of multiple medications add up, with potentially serious consequences. For example, clinically-significant anticholinergic side effects frequently occur due to a lack of recognition of the anticholinergic activity of psychiatric and nonpsychiatric medications that are not classified as anticholinergics (Al Rihani et al., 2021). Especially in older adults, this additive “anticholinergic burden” not infrequently leads to cognitive and functional impairment. Other examples of additive effects are falls and other accidents due to the additive effects of multiple medications on blood pressure and/or sedation. It is important to realize that the additive anticholinergic burden and sedative load are unintentional in most cases (Al Rihani et al., 2021). Therefore, it is essential that structured tools be used routinely to evaluate the risk of anticholinergic side effects, oversedation, and falls (Seppala et al., 2021; Al Rihani et al., 2021). Another scenario is where two or more medications are used together, and a side effect occurs if one of them is stopped abruptly. For example, stimulant and antipsychotic medications are often prescribed together for the management of ADHD with agitation or aggressive behavior (Scholle et al., 2018). If the stimulant is then stopped abruptly or is missed, acute dystonia has been reported to occur (Guler et al., 2015). Polypharmacy leading to an increased incidence of a side effect must also take into account the concomitant use of psychiatric and non-psychiatric medications. The example of additive effects of psychiatric medications that are antagonists at post-synaptic alpha-1 receptors (for example, clozapine, risperidone, trazodone) and antihypertensive medications is, or should be, well-known. However, an important but lesserknown example is the fairly common case of a serotonergic antidepressant and a thiazide diuretic being used together (Burroughs-Ray et al., 2025; Mago et al., 2008). On the other hand, using multiple medications together can sometimes reduce rather than increase the incidence and/or severity of certain side effects. For example: 1. The addition of aripiprazole to another antipsychotic like risperidone has been shown in multiple randomized controlled trials to reduce antipsychotic-induced hyperprolactinemia (Zheng et al., 2019). 2. In a randomized, placebo-controlled clinical trial, the addition of aripiprazole to a stable dose of clozapine was found to reduce body weight and dyslipidemia (Fleischhacker et al., 2010). 3. The combination of a stimulant and guanfacine may attenuate effects on heart rate, systolic BP, and the QTc interval (Sayer et al., 2016). Throughout the workshop, active engagement and interaction with the audience will be facilitated in several ways, including the following: 1. Before discussing each instance of additive effects, examples of medication lists will be shown, and the audience will be polled about what concerns they would have with that medication list. 2. The audience will be encouraged to share their experiences with each of the medication combinations discussed. 3. Findings regarding safety and tolerability concerns from the ASCP task force on polypharmacy will be shared with the audience to prompt interactive discussion and dialogue about optimal risk-benefit management strategies.

References

Al Rihani SB, Deodhar M, Darakjian LI, et al. Quantifying Anticholinergic Burden and Sedative Load in Older Adults with Polypharmacy: A Systematic Review of Risk Scales and Models. Drugs Aging. 2021;38(11):977-994. Zheng W, Cai DB, Yang XH, et al. Adjunctive aripiprazole for antipsychotic-related hyperprolactinaemia in patients with first-episode schizophrenia: a meta-analysis. Gen Psychiatr. 2019;32(5):e100091.