Five Adjunctive Antipsychotics Compared: Tolerability, Tapering, and Deprescribing

In "Five Adjunctive Antipsychotics Compared: Tolerability, Tapering, and Deprescribing," the panel compares the five adjunctive atypical antipsychotics approved for MDD.

Dr. Citrome walks through the five agents approved for augmentation outside the treatment-resistant indication. Aripiprazole is used extensively and tolerable at the lower doses his practice favors, though it carries an akathisia risk. Quetiapine extended-release he avoids because sedation and weight gain drive high dropout rates. The newer options, brexpiprazole, cariprazine, and lumateperone, he considers generally better tolerated: brexpiprazole with less akathisia, cariprazine largely free of sedation and weight gain, and lumateperone free of drug-induced movement disorders and weight gain, though it can cause some sedation.

He references two network meta-analyses, one he co-authored and one led by Dr. Roger McIntyre, noting that authors on both have industry ties worth disclosing. Lumateperone performed well on efficacy in McIntyre's analysis, but Dr. Citrome stresses that discontinuation due to adverse events matters just as much, returning the decision to a direct conversation about which side effects a given patient fears most. Effectiveness, he says, ultimately comes down to whether a drug works, whether the patient will actually take it, and whether it's tolerable enough to stay on, which requires blending clinical judgment, current literature, and the patient's own values.

Dr. Harding agrees and adds that short-term augmentation followed by a deliberate taper is underused in practice. She stresses matching side-effect profile to personality: an already anxious patient will never tolerate akathisia long enough to reach a therapeutic dose, while a sedated, low-energy patient may actually benefit from a bit of activation. She illustrates her own low tolerance for weight gain as an example of how personal a side-effect threshold can be. She raises deprescribing, citing Dr. Joe Goldberg's work, as a genuinely underdiscussed topic. Dr. Citrome agrees, noting that long-term duration data for adjunctive antipsychotics remain scarce since most studies are short-term, leaving deprescribing timing an open question.

The next episode, "Starting With the Non-Negotiables: Selecting Adjunctive Therapy in MDD," features Erin Crown, MHS, PA-C, CAQ-Psychiatry on how weight, metabolic risk, and anxious depression shape her choice of adjunctive agent.