Antipsychotics and Metabolic Harm

We covered a first attempt at this question in COaST, which ended at 31 participants. A second Danish trial has now answered it at more than twice the size, in people taking clozapine or olanzapine whose blood sugar had begun to drift — and it reports the result this group needs most: metabolic improvement with no worsening of psychiatric symptoms.^[1]

What this trial adds

Three things separate it from the earlier work. It is larger — 73 randomized against 31. It includes olanzapine alongside clozapine, widening the question beyond the single hardest case. And it selected for people whose blood sugar had already started to move but who were not yet on any diabetes treatment, which makes it a trial about prevention rather than about rescue.

That last point sets up the whole reading of the numbers below. The standard advice — switch to something metabolically kinder — is unavailable to many of the people who most need it, because these drugs are prescribed when others have failed. Treating the metabolic consequence rather than removing the cause is not a compromise here. It is frequently the only route open.

What was done

Across three Danish sites between 2021 and 2024, adults aged 18 to 65 with a schizophrenia spectrum disorder, taking clozapine or olanzapine started within the previous five years, with an HbA1c between 5.4% and 7.4% and no diabetes treatment, were randomized to weekly semaglutide 1 mg or matching placebo for 26 weeks alongside their existing therapy. Of 104 screened, 73 were randomized and 57 (78%) finished. Average age was 35, 65% were women, and average BMI was 36.1.

What changed

A quarter of a percentage point of HbA1c reads as unimpressive until you look at who was enrolled. Entry required an HbA1c between 5.4% and 7.4% with no diabetes medication — a mostly prediabetic group with very little room to fall. In that setting the proportion crossing into low-risk territory is the better measure, and 43% of the semaglutide group (12 of 28) reached an HbA1c below 5.4%, against 3% on placebo.

A small mean difference in a population already near normal is not a small effect.

Lipids, liver function and blood pressure did not differ between groups — a reminder that 26 weeks is short for outcomes that move slowly, and that weight loss does not automatically improve everything measurable.

A third trial, and the mechanism question it answers

HISTORI is the largest of the three. It randomized 154 people with schizophrenia, prediabetes and excess weight, all taking second-generation antipsychotics, to semaglutide 1.0 mg or placebo for 30 weeks — and 91.5% completed.^[2]

The 9.2 kg weight loss matches the Danish trial above almost exactly, in a separate population, which is the kind of agreement that makes a result believable.

That distinction has a practical edge. If the improvement depends on the weight loss, it depends on the weight loss persisting — and everything this register documents about what happens when these drugs stop applies here with particular force, in people who will remain on the antipsychotics that caused the problem.

The psychiatric result

For someone stable on clozapine, the question is not whether a drug will reduce their weight. It is whether adding it will destabilize an illness that took years to control. The trial found no difference in psychiatric symptoms between groups and no difference in psychiatric adverse events. Gastrointestinal effects were common, mild and temporary, as they are everywhere else in this class.

Within that limit it is genuinely useful, because the alternative evidence is worse. Much of the public conversation about these drugs and mental health runs on registry signals and anecdote. A randomized trial conducted specifically in people with serious mental illness, measuring psychiatric symptoms as an outcome, is a better instrument than either — even a small one.

What this does not say

• It is not an argument to change psychiatric medication. Clozapine and olanzapine are prescribed when other drugs have failed. Nothing here bears on that decision, which belongs entirely to a psychiatrist.
• It is 26 weeks. Antipsychotic-associated metabolic risk accumulates over decades.
• Everyone had early glycemic changes and no diabetes treatment. This is prevention in a group heading toward diabetes, not treatment of established disease.
• It reports no cardiovascular outcomes — the mortality gap that motivates the whole question is not something a 73-person, six-month trial can address.

For what these drugs do to mood and motivation in other psychiatric settings, see semaglutide and motivation.