Questions to Consider When Evaluating Adverse Effects of Psychotropic Medications

Joseph Goldberg, M.D.

With nearly one in five U.S. adults taking at least one psychiatric medicine—and just as many regularly taking five or more prescription drugs in total —assessing and managing the adverse effects of psychotropic drugs poses ever-increasing challenges (1).

Evaluating side effects can be particularly hard in mental health settings because psychiatric symptoms often color the presentation of possible side effects and vice-versa. High rates of medical and substance use comorbidity in people with serious psychiatric disorders can confuse even well-trained mental health professionals. It can be hard to differentiate among psychiatric symptoms, adverse drug effects, and unrelated medical comorbidities (such as distinguishing between a suspected “drug” rash and a case of shingles, or an iatrogenic tremor from an essential tremor).

The “Managing the Side Effects of Psychotropic Medications” symposium at APA’s 2016 Annual Meeting addressed general principles of assessing adverse drug effects and provided attendees with practical strategies for managing iatrogenic weight gain, sexual dysfunction, and cardiac safety risks. As noted in the symposium, clinicians must consider many interrelated factors when evaluating possible adverse drug effects. When evaluating the adverse effects of medication, consider the following questions:

• Are the side effects reported by the patient caused by a prescribed medication or the condition being treated? For example, management for insomnia may be different when it results from taking a selective serotonin reuptake inhibitor (SSRI) as opposed to being a residual symptom of depression. Insomnia caused by an SSRI may remit with adjunctive clonazepam (2) or a change in daily time of administration, while its persistence as a residual depressive symptom may signal the value of adding an evidence-based adjunct for depression, such as quetiapine or mirtazapine. Similarly, sexual dysfunction caused by an SSRI may improve by adding a phosphodiesterase inhibitor (3, 4) or bupropion (5), or switching to vortioxetine (6) or bupropion, whereas persistent loss of interest in sex due to depression may respond to more aggressive antidepressant therapy.

• Are the reported side effects the result of the patient’s heightened susceptibility to physical concerns? Such changes can arise from biological predispositions (e.g., slow metabolizer phenotypes), body dysmorphia, alexithymic traits (7), or tendencies to perceive bodily sensations as noxious and intense (“somatosensory amplification” [8]).

• Do suspected adverse effects involve contradictory physiological mechanisms (such as dry mouth with diarrhea) or temporal implausibilities (such as suspected drug hypersensitivity syndromes occurring years after starting an anticonvulsant)?

• How does the severity of the side effects (e.g., nausea and sexual dysfunction versus arrhythmias and serotonin syndrome) guide decisions about “watchful waiting” versus active interventions?

• Under what circumstances can you safely re-challenge someone with a drug after an adverse event? For example, lamotrigine can be reintroduced using a very slow dose titration after resolution of a benign skin rash (9), whereas re-challenge with clozapine after myocarditis is generally not recommended.

• How might your patient’s perception of adverse effects of medication affect treatment adherence? Often, managing adverse effects depends more on good doctor-patient communication and the quality of the therapeutic alliance than on simply stopping or avoiding a particular medication.

There has been remarkably little research on anticipating and counteracting psychotropic drug side effects. Little guidance exists for clinicians about when it is wisest to change medications versus pursue possible antidotes. Notably, in the case of metabolic dysregulation and iatrogenic weight gain, several pharmacogenetic markers have been preliminarily identified that may contribute to increased risk (or confer protection) (10, 11). Alongside clinical predictors of metabolic adverse effects (such as age [12], sex [13], and baseline body mass index [14]), and coupled with possible remedies for iatrogenic weight gain (such as metformin [15], topiramate [16], or naltrexone [17], among others), one could proactively navigate metabolic risks instead of simply avoiding higher liability drugs—especially when alternatives are few and benefits are substantial.

Comprehensive psychopharmacotherapy entails understanding all significant end-organ effects and interactions—both beneficial and undesirable—from a drug regimen. Optimal treatment blends pharmacodynamic awareness with appreciation for an individual patient’s unique clinical presentation, illness severity, medication expectations, and personal therapeutic goals. ■