Opparounds

Clozapine After 1 Failed Antipsychotic Drug Trial in First-Episode Psychosis: A Randomized Clinical Trial

Xuan Li, Chang Lu, Zhaolin Zhai, Robert C. Smith, John M. Davis, Stefan Leucht, Dengtang Liu, et al. · JAMA Psychiatry · June 2026

This was a sequential, assessor-blind trial with two randomizations across seven centers in China, enrolling patients with first-episode psychosis between 2019 and 2022. In phase 1, 654 eligible participants (mean age 26.9 years) were randomized to olanzapine, risperidone, amisulpride, aripiprazole, or perphenazine for eight weeks; response rates clustered around 60 percent for olanzapine and risperidone and were lower for aripiprazole and perphenazine.

Participants who did not respond were then re-randomized in phase 2 to olanzapine, amisulpride, or clozapine for another eight weeks. Among these single-failure nonresponders, clozapine produced a 62.5 percent response rate, compared with 44.7 percent for amisulpride and 31.7 percent for olanzapine. In other words, switching to a second non-clozapine agent roughly halved the chance of response relative to going straight to clozapine.

Read the paper →  doi:10.1001/jamapsychiatry.2026.0086

Venous Thromboembolism After Mechanical Restraint in Psychiatric Hospitals: Population Based Cohort and Self-Controlled Case Series Study

Jakob H. Viuff, Lars Pedersen, Irene Petersen, Jan P. Vandenbroucke, Søren D. Østergaard, Henrik T. Sørensen · The BMJ · July 2026

Using Danish national registries from 2000 to 2022, the investigators followed 24,423 psychiatric inpatients exposed to mechanical or chemical restraint, and additionally ran a self-controlled case series in the 1,285 patients who developed an incident venous thromboembolism during or shortly after admission. At 30 days, cumulative VTE incidence was 3.5 per 1,000 after mechanical restraint versus 1.7 per 1,000 after chemical restraint, a risk ratio of 2.07 (95% CI 1.25 to 3.71).

The self-controlled analysis, in which each patient serves as their own control and so removes confounding by fixed patient characteristics, found an incidence rate ratio of 4.49 (95% CI 3.09 to 6.54) in the 14 days after restraint. The absolute risk remained low: number needed to harm was 548.

Read the paper →  doi:10.1136/bmj-2026-100016

Lamotrigine dosing is really three different drugs, depending on what else is on the list

Lamotrigine is cleared almost entirely by UGT1A4 glucuronidation, and that single pathway is unusually easy to push in both directions. Valproate is a potent UGT inhibitor and roughly doubles lamotrigine's half-life, which is why the titration schedule with valproate on board is halved at every step — 25 mg every other day to start, with a target maintenance often near 100 to 200 mg rather than 200 to 400 mg. Enzyme inducers do the opposite: carbamazepine, phenytoin, phenobarbital, and rifampin roughly double clearance, so the induced titration schedule starts at 50 mg daily and targets 400 mg or more.

The interaction that gets missed in clinic is estrogen. Combined oral contraceptives induce UGT1A4 and drop lamotrigine levels by about 50 percent — and because most formulations include a hormone-free week, levels rebound upward during that week, which is precisely when patients report the dizziness, diplopia, and ataxia of supratherapeutic lamotrigine. If a patient on a stable dose starts or stops a combined contraceptive, or switches to a continuous-cycle formulation, the dose needs to move with it. The same logic applies in pregnancy, where lamotrigine clearance can rise more than twofold by the third trimester and then fall back within days of delivery — plan the postpartum dose reduction before the delivery, not after the toxicity.

Clarification, confrontation, interpretation — the sequence is the technique

Trainees learn the TFP triad as three tools and then reach for whichever one feels most insightful, usually interpretation. Kernberg's point is that the order is not stylistic; it is what makes an interpretation survivable. Clarification asks the patient to elaborate their own experience until it is fully explicit — not to gather facts for you, but because a patient who is asked to articulate a confused state often discovers the confusion themselves. Confrontation then places two pieces of the patient's own material side by side and asks them to hold both at once: what they just said next to what they said last week, or what they are saying next to what their face is doing. It is not adversarial; it is the tactful pointing out of a contradiction the patient is not tracking.

Only then does interpretation — a hypothesis about the unconscious meaning organizing the contradiction — have anywhere to land. Skipping to interpretation with a patient organized at a borderline level is not merely premature; the interpretation gets absorbed into whichever self-state is currently dominant and becomes evidence for it. The contradiction has to be the patient's problem before it can be interpreted.