Early intervention in ultrahigh risk for psychosis ineffective

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In a new study in JAMA Psychiatry, researchers tested an increasingly intensive, multi-stage approach to early intervention for people at “ultrahigh risk” of psychosis. Their findings? The intervention failed in every way.

“In this sequential multiple assignment randomized trial including 342 individuals, a specialized psychological intervention (cognitive-behavioural case management [CBCM]) and a psychopharmacological intervention (CBCM and antidepressant medication) were not more efficacious than control conditions in improving remission and functional recovery. Relapse rates among individuals who remitted were high.”

Despite being classed as “ultrahigh risk,” few people transition to psychosis anyway. Moreover, the intervention didn’t lead to more remission, relapse rates were high for those who did remit after treatment, maintenance therapy after remission was no more effective than simple monitoring (watchful waiting), and no treatment (for instance, CBCM or drugs) was more effective than any other.

The study was led by Patrick McGorry and other researchers at Australian early intervention nonprofit Orygen, affiliated with The University of Melbourne. Also, it included researchers from Columbia University, UC Davis, and UCSF. Participants were 342 people between 12 and 25 who sought treatment for being at “ultrahigh risk” (UHR) of psychosis.

 

UHR is a theoretical construct that first appeared in the 1990s. It’s based on the idea that people with schizophrenia or other psychotic diagnoses could be identified early—before they meet the criteria for those diagnoses—based on traits such as subthreshold psychosis (e.g., “unusual thoughts,” “disorganized speech,” “perceptual abnormalities”).

The current study was called Staged Treatment in Early Psychosis (STEP) and had three stages, beginning with six weeks of support and problem-solving (SPS). If that didn’t result in “remission” of UHR symptoms (symptomatic and functional improvement), patients underwent 20 weeks of either continued SPS or CBCM. If that didn’t result in remission either, patients received 26 weeks of CBCM with fluoxetine (Prozac) or CBCM with placebo. If patients did remit, they received either maintenance SPS or simple monitoring.

The theory is that if treatment can cause “remission” of these undiagnosable, subthreshold symptoms, it will prevent people from eventually transitioning to full psychosis. Generally, though, the high-risk model does an extremely poor job of predicting who will eventually graduate to full psychosis. Previous research has also found that interventions for those considered UHR, such as giving them antipsychotic drugs, can lead to worse outcomes.

The researchers had six hypotheses, all predictions about how effective they thought the early intervention treatment would be. But their hypotheses were all proven wrong:

  1. Hypothesis 1 was that stage 1 (SPS) would result in a 50% remission rate. Instead, it resulted in a much smaller remission rate of 8.5%.
  2. Hypothesis 2a was that in stage 2, those who received the more intensive intervention, CBSM, would do significantly better than those who continued SPS. Instead, there was no difference between the groups.
  3. Hypothesis 2b was that in the CBCM group, they could predict outcomes based on specific factors (“cognitive biases or vulnerabilities”). Instead, they found no differences in these factors.
  4. Hypothesis 2c was that those specific factors would improve more for those who did better in CBCM. Instead, they found no differences in these factors.
  5. Hypothesis 3 was that in stage 3, Prozac added to CBCM would be better than CBCM plus placebo. Instead, there was no benefit for Prozac over placebo.
  6. Hypothesis 4 was that in those who remitted, maintenance treatment with SPS would be better than simple monitoring to prevent relapse. Although there was a difference in the early weeks after treatment, there was no difference between groups at the follow-up point of one year.

Ultimately, after one year, 27.2% were said to have “remitted” at some point, although most of them then “relapsed.” Consistent with previous research showing that the UHR model is a poor predictor, only 13.5% actually transitioned to clinical psychosis.

The researchers conclude:

“The findings suggest that enhancing the intensity of treatment with psychological interventions (CBCM) or antidepressant medication in real-world youth mental health services does not produce benefit over continuing simpler care for a longer period.”

One of the major limitations of the study also indicates how much the patients disliked the interventions: By the end of the third stage, 248 out of 342 (72.5%) had dropped out of the study.

The researchers explicitly compare this to the STAR*D antidepressant trial’s enormously high drop-out rate, which led to the researchers in STAR*D fraudulently pumping up their numbers, violating their pre-specified protocol in numerous ways, including considering 606 study drop-outs—and 570 who weren’t depressed enough to be in the study to begin with or never got a baseline score—to be treatment successes.

 

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McGorry, P. D., Mei, C., Amminger, P., Yuen, H. P., Kerr, M., Spark, J., . . . & Nelson, B. (2023). A sequential adaptive intervention strategy targeting remission and functional recovery in young people at ultrahigh risk of psychosis: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial. JAMA Psychiatry. 2023;80(9):875-885. doi:10.1001/jamapsychiatry.2023.1947 (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.