Antipsychotics lead to worse outcomes in first-episode psychosis

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What happens when you give antipsychotic drugs at the first sign of psychosis? Worse outcomes, according to a new study in Schizophrenia Bulletin Open.

Those who did not receive antipsychotics within the first month after being diagnosed with their first episode of psychosis were, on average, almost twice as likely to be in recovery five years later than those who did immediately receive the drugs. According to the researchers, this means there are many patients who do not need antipsychotics, at least not right away.

The authors of the study were Tomi Bergström at the University of Jyväskylä and the Wellbeing Services County of Lapland, Finland, and Tapio Gauffin at the Wellbeing Services County of Lapland, Finland.

“Immediate antipsychotic medication was associated with a poorer 5-year outcome compared to a 1-month antipsychotic postponement, after controlling for observable confounders. These findings align with previous research on need-adapted approaches and recent controlled trials, suggesting that there is a significant subgroup of patients with acute psychosis who do not require immediate antipsychotic treatment, and postponing medication, particularly in first-episode cases, may help identify those patients,” they write.

 

Bergström and Gauffin used the Finnish National Health Registry to identify all those who met the study criteria. This included 3714 adolescents ages 13-20 who received a diagnosis of a psychotic disorder between 2003 and 2013 and had never before taken antipsychotic drugs. The researchers followed their records for five years (or until death). During the first month after diagnosis, 1549 (42%) did not receive antipsychotics. Over five years, 29% ended up never taking the drugs.

The researchers found that, on average, those 1549 people were 1.8 times as likely to be in recovery after five years.

Those in recovery, in this study, were defined as those who were still alive and had not received any form of psychiatric treatment, supportive housing, or disability allowances at five years. The researchers note that these services are provided to the entire population as needed and recorded in the registry based on their universal healthcare system.

Next, the researchers wanted to see if those who eventually did end up on antipsychotics fared worse if there was a delay. That is, is there a subset of patients who need to be put on the drugs immediately and who will be harmed by waiting a month?

To test this, Bergström and Gauffin looked at only the patients who took the drugs by the end of the study and compared those who started immediately with those who ended up taking the drugs later.

They found that there was no difference in most outcomes—recovery and mortality rates—but that those who started the drugs immediately were more likely to receive disability payments and to die younger than those who delayed taking the drugs.

The researchers write:

“Since there may still be a subgroup of psychosis patients who require immediate or preventive antipsychotic treatment to prevent a deteriorated course of [first-episode psychosis], it was hypothesized that postponement of antipsychotics for those who eventually used antipsychotics would be associated with poor outcomes. However, the findings did not support this hypothesis. There was no indication that antipsychotics initiated prior to the formal diagnosis of psychosis or immediate antipsychotic treatment for those who eventually required antipsychotics would improve treatment outcomes.”
They add, “In fact, contrary to our hypothesis, the time to death after [first-episode psychosis] was found to be significantly longer for individuals whose antipsychotic medication was postponed. Furthermore, after controlling for confounding factors in both sub-samples, immediate antipsychotic medication was associated with a notably higher disability ratio at the end of the 5-year follow-up period.”

One explanation often floated against this type of study is “confounding by indication”—that those who have the most severe baseline symptoms are the ones who receive the drugs and also the ones who would be expected to have the worst outcomes. Thus, those who receive the drugs would have worse outcomes not because of the drugs but because of baseline severity.

To account for this, the researchers used a statistical model called stabilized inverse probability of treatment weighting (SIPTW) to control for these possible confounds. After their analysis, all of their results remained the same, indicating that the finding was not due to confounding by indication.

This latest study builds on Bergström’s previous work, particularly a 2020 study that looked at cumulative exposure to antipsychotics for all patients with first-episode psychosis over 19 years. That study also found that those who took the most drugs for the longest period had worse outcomes, including higher mortality rates. And the researchers controlled for confounding by indication in that study as well.

“Moderate and high cumulative exposure to antipsychotics within the first five years from FEP was consistently associated with a higher risk of adverse outcomes during the 19-year follow-up, as compared to low or zero exposure,” they wrote in that 2020 study.

Researchers have found that cognitive-behavioral therapy without antipsychotics is just as effective for first-episode psychosis—that adding drugs provided no additional improvement.

Previous research has also found that interventions for those considered at ultrahigh risk for psychosis, including antipsychotic drugs, can lead to worse outcomes.

And decades of research by luminaries like WunderinkHarrow, and Jobe have found that those who stop taking antipsychotics have better long-term outcomes.

Researchers have increasingly identified childhood trauma as the primary cause of psychosis, even as biological theories involving dopamine and genetics have been debunked. This is consistent with previous studies that found that experiencing childhood trauma, not heritability, was associated with psychosis.

Thus, interventions that focus on healing from trauma and those that foster empathy, empowerment, and human connection—and respect those with lived experience—may be a more successful route to recovery.

 

 

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Bergström, T., & Gauffin, T. (2023). The association of antipsychotic postponement with 5-year outcomes of adolescent first-episode psychosis. Schizophrenia Bulletin Open, 4(1), sgad032. https://doi.org/10.1093/schizbullopen/sgad032 (Link)

 

Editor’s Note: Part of MITUK’s core mission is to present a scientific critique of the existing paradigm of care. Each week we will be republishing Mad in America’s latest blog on the evidence supporting the need for radical change.

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Peter Simons was an academic researcher in psychology. Now, as a science writer, he tries to provide the layperson with a view into the sometimes inscrutable world of psychiatric research. As an editor for blogs and personal stories at Mad in America, he prizes the accounts of those with lived experience of the psychiatric system and shares alternatives to the biomedical model.