Managing Side Effects Associated with Antipsychotics

Antipsychotics are associated with movement disorders as well as metabolic effects, including weight gain, altered glucose metabolism, and dyslipidemia. Andrew J. Cutler, MD, a clinical professor in the Department of Psychiatry at SUNY Upstate Medical, discussed neurobiological bases, differential diagnosis, and treatment options for a range of side effects associated with antipsychotics during a presentation at the Neuroscience Education Institute Max! Virtual Meeting.

First, he discussed antipsychotic-induced movement disorders, including akathisia, tardive dyskinesia, parkinsonian tremor, and acute dystonia. Patients often use terms such as “anxiety” or “itching” to describe akathisia, although these do not really capture the essence of the condition. An objective sign, he said, is disordered movement, which can deter patients from taking their antipsychotics. “It can really be an uncomfortable experience,” Dr. Cutler said.

Treatment strategies to address akathisia include dose reductions, change to lower-risk agents if feasible, and withdrawal akathisia. Allow at least six weeks before judging the effectiveness of dose reductions or medication switching, he said.

Drug-induced parkinsonism is the most common movement disorder induced by drugs that affect dopamine receptors. Women and older adults have a higher risk for this side effect. There are also genetic risk factors: Genes associated with GABA receptor-signaling pathway are involved in neuroleptic-induced tardive dyskinesia in patients with schizophrenia. Drug-induced parkinsonism is often more bilateral and symmetric parkinsonism. More prominent bradykinesia and rigidity can be seen with drug-induced parkinsonism; however, approximately 30% to 50% patients with drug-induced parkinsonism show asymmetric parkinsonism and tremor at rest. Patients experiencing drug-induced parkinsonism should stop taking the offending drug, lower the dose, or switch to atypical antipsychotics with a lower risk of extrapyramidal symptoms. 

Antipsychotic-induced metabolic disorders are another significant issue, according to Dr. Cutler. Weight change during antipsychotic use is common, and these drugs also have a class warning from the FDA regarding cardiometabolic risk. Predictors of antipsychotic weight gain include younger age, non-white race, low baseline body mass index, female sex, and pharmacogenetic predictors (5HT2C -759T allele, MTHFR 677C/T “CC” genotype). Physicians should take a family history of weight problems at baseline, as well as monitor weight, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile. “This is the minimum we should be doing, but unfortunately studies show that we are not adhering to this protocol,” he said.

“If a patient is doing well on an antipsychotic but gaining weight, there are non-pharmacologic things we can do,” said Dr. Cutler. Diet and exercise should be recommended to augment weight gain, and adjunct medications can be considered, including amantadine, bupropion, lamotrigine, lorcaserin, metformin, naltrexone-bupropion, orlistat, phentermine-topiramate, topiramate, zonisamide, and glucagon-like peptide-1 agonists.

The FDA is currently considering the combination of the atypical antipsychotic olanzapine and the opioid modulator samidorphan for the treatment of schizophrenia and bipolar I disorder (with a PDUFA data of Nov. 15). The drugs aims to provide the efficacy of olanzapine without the associated weight gain. In a clinical trial of patients taking olanzapine/samidorphan, patients gained weight for up to four weeks of treatment, but then it leveled off instead of continuing to rise compared with olanzapine alone.

Presentation: My Medication Made Me Do It: Side Effects Associated with Antipsychotics. Presented at the Neuroscience Education Institute Max! Virtual Meeting, Nov. 5-8, 2020.