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Olanzapine Use Associated With Change in Brain Structure

March 04, 2020

Sustained use of the antipsychotic olanzapine in patients with remitted psychotic depression was associated with a thinning of the cortex, when compared with placebo, according to a study published online in JAMA Psychiatry.

“We found that the mean reduction in cortical thickness caused by 36 weeks of exposure to olanzapine is equivalent to loss of approximately 1.2% of a person’s cortex,” researchers wrote. “For context, mean annual change in cortical thickness across the adult life span is 0.35% and 0.59% in normal aging individuals aged 60 to 91 years.”

The double-blind, randomized study was a prespecified secondary analysis of a trial that took place at 5 academic centers. Adults up to 85 years of age who were diagnosed with major depressive disorder with psychotic features received olanzapine and the antidepressant sertraline for up to 5 months. After psychosis remission and remission or near remission of depression, participants were randomized to either continue olanzapine and sertraline or switch to placebo and sertraline for an additional 9 months.

Cognitive Decline May Be Accelerated in Adults With Psychotic Disorders

Among 72 participants who received magnetic resonance imaging (MRI) scans at the time of randomization and then again after 36 weeks or at symptom relapse, researchers found significant decreases in cortical thickness in patients who continued olanzapine compared with those who switched to placebo.

However, MRI scans also revealed potential decreases in cortical thickness in another group of patients: those switched to placebo who went on to experience a relapse of psychotic symptoms (compared with patients switched to placebo who sustained remission).

“When taken together,” researchers wrote, “both olanzapine and illness relapse have an effect on brain structure.”

All in all, researchers believe their findings could have an immediate effect on current clinical practice.

“Antipsychotic medications remain the cornerstone of treatment for primary psychotic illnesses, but caution should be exercised with their off-label use for other conditions when psychosis is not present,” said researcher Aristotle Voineskos, MD, PhD, chief of the schizophrenia division at the Centre for Addiction and Mental Health in Toronto, Canada. “This may be especially true in children and the elderly, when the brain is changing more rapidly.”

—Jolynn Tumolo


Voineskos AN, Mulsant BH, Dickie EW, et al. Effects of antipsychotic medication on brain structure in patients with major depressive disorder and psychotic features: neuroimaging findings in the context of a randomized placebo-controlled clinical trial. JAMA Psychiatry. 2020 February 26;[Epub ahead of print].

Antipsychotic medication linked to potentially adverse changes in brain structure [press release]. Toronto, Canada: Centre for Addiction and Mental Health; February 26, 2020.


Submitted on March 09, 2020

I appreciate that this article may point to possible issues with olanzapine. Yet how does one interpret the results? Sometimes studies lead to interesting findings that can't be easily explained.
What do we already know about how psychotropics effect the cortex? Have they been associated with similar MRI findings? If not, what was the motivation for selecting olanzapine? Could there be explanations, other than a cause- effect scenario that led to these findings? If there's an inflammatory component to psychosis, perhaps antipsychotics, when they work, decrease cortex inflammation so they appear "thinner " but are actually closer to "normal." What do the cortices of those who are psychotic and pre-treatment look like? Are they usually thicker, or is it unpredictable or highly individualized? Averaging numbers can't help us if the sample is heterogenous.
I am also puzzled by the second part of the study, that those who responded to placebo had thicker cortices than those who relapsed. In order to reach the conclusion that medication and psychosis thins out the cortex, the individual would need to be his own control. That way constitutional differences between patients would not obscure the shift the author is describing. Methodology here is key.
Research about meds can have tremendous impact on clinical practice. I agree. Studies that support NOT using a med that is generally helpful, even with the significant adverse effects, should be affirmed by unambiguous results. I hope these unknowns are, or will become clarified.
Personally, I find olanzapine, and other antipsychotics dosed way too high. Too high for clinical effectiveness and too high to avoid side effects. Sometimes less is more, as with hormones or energetic stimulation. For example, ECT has become more effective with targeting and reducing the dose. Rather than overwhelm the body with stimulation which leads to shut-down, you try to make whatever is offered in the similar magnitude to what the body is used to. Like feeding someone with anorexia.
Peggy Finston MD

Submitted bylumielsquare_249591 on March 15, 2020
I always thought that consistent use, of the new antipsychotics such as Zyprexa, was neuro protective. With new agents coming out all of the time (with similar properties) this is not good news. I would like to read more studies on this topic. I'd like to see more variables in the research such as long term consistent use of one particular agent vs those who were non compliant most of the time, with various agents.
Providers are still:
----Rxing Dilantin, which causes cerebellar degeneration, etc when there are safer options available,
----and paxil with all of its side effects (ED, inorgasmia, severe withdrawal side effects if doses are missed, etc.)
----Depakote in young women despite warnings on that, (PCOS, weight gain, acne, hair loss, birth defects with most being sexually active and not on birth control consistently
---Risperdal when Invega is available which is well tolerated with limited side effects
Sometimes I wonder if anyone cares about our patients on a deeper level???? Am I alone in this thought? I treat everyone like a loved one (son, daughter, mom, dad, etc.) why don't the majority do as well? Is it lack of keeping up to date on issues such as this?

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