Opparounds

Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis

McIntyre RS, Stahl SM, Shim SR, et al. · JAMA Psychiatry · May 2026

This network meta-analysis pooled 22 randomized trials (10,962 patients) comparing five FDA-approved adjunctive atypical antipsychotics for major depressive disorder: aripiprazole, brexpiprazole, cariprazine, lumateperone, and quetiapine XR.

For efficacy (≥50% MADRS reduction vs placebo), lumateperone ranked highest (risk ratio 1.72), followed by aripiprazole (1.53), brexpiprazole (1.38), cariprazine (1.20), and quetiapine XR (1.15). Acceptability told nearly the opposite story: aripiprazole had the lowest all-cause discontinuation, while lumateperone had the highest (risk ratio 2.30) despite its efficacy edge.

The authors call for weighing efficacy and acceptability together rather than reaching for the single "most effective" agent, and note that maintenance-phase data for all five drugs remains sparse.

Read the paper →  doi:10.1001/jamapsychiatry.2026.0658

Rehospitalization as a Mediator of the Association of Postoperative Delirium With Cognitive Decline in Older Adults

Hshieh TT, Kunicki ZJ, Fong TG, et al. · JAMA Internal Medicine · June 2026

This SAGES-cohort study followed 560 adults aged 70 and older who underwent major surgery, tracking cognition with an 11-test battery every six months for three years, then annually out to six years.

Postoperative delirium was associated with long-term cognitive decline at a rate faster than what's typically seen with mild cognitive impairment, with effects still measurable up to five years after the surgical episode.

The researchers had hypothesized that rehospitalization — a marker of ongoing illness burden and frailty — might explain part of delirium's link to cognitive decline, since delirious patients are rehospitalized more often. It didn't: rehospitalization was itself associated with cognitive decline, but statistically did not mediate the delirium-cognition relationship, meaning delirium's effect on the brain isn't simply standing in for how sick the patient was afterward.

Read the paper →  doi:10.1001/jamainternmed.2026.1910

Risperidone's prolactin problem isn't about potency — it's about a transporter

All antipsychotics block D2 receptors in the tuberoinfundibular pathway, removing dopamine's tonic brake on lactotroph prolactin release. But risperidone and paliperidone cause hyperprolactinemia out of proportion to their clinical dose because both are substrates of the P-glycoprotein efflux pump at the blood-brain barrier: they reach adequate central (therapeutic) D2 occupancy at comparatively low brain concentrations, while still fully occupying pituitary D2 receptors that sit outside the barrier and see the full serum concentration. The result is prolactin elevation disproportionate to antipsychotic effect, unlike an equivalent clinical dose of olanzapine or aripiprazole. Don't screen with routine serum prolactin in asymptomatic patients; screen the history instead — galactorrhea, amenorrhea, decreased libido, erectile dysfunction, and with chronic elevation, bone density. When elevation is symptomatic, the fix isn't always a switch: low-dose aripiprazole augmentation (2 to 5 mg) uses its partial-agonist activity to competitively displace the offending drug from pituitary D2 receptors and can normalize prolactin without sacrificing the primary antipsychotic's efficacy.

The therapist's survival is the intervention — not the interpretation of the attack

Winnicott distinguished relating to an object — encountering it through fantasy and projection, entirely within the patient's omnipotent control — from using an object, which requires recognizing it as real and external. The bridge between them is destruction: in fantasy, the patient repeatedly attacks the object, and the object's survival — not retaliating, not withdrawing, not collapsing — is what proves it exists outside the patient's control. This isn't patience as technique. Survival is the mechanism itself: it is what moves a patient from a world made of their own projections into one with real others in it. A holding environment, on this view, isn't warmth or reassurance — it is the therapist's capacity to be used this way, reliably present and non-retaliatory, without rushing to interpret the aggression away before it has done its developmental work.