Study Identifies Critical Components of Early Psychosis Intervention

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Relapse during treatment of early psychotic illness was less likely to occur over a 3 year study in early psychosis intervention (EPI) programs that maintain low caseloads and provide access to clozapine for those who are eligible.¹

The study, conducted in the UK with approximately 15,000 patients treated in EPI programs between 2019 and 2020, is described by Ryan Williams, MBBS, MRCPsych, Division of Psychiatry, Imperial College London, London, England, UK, and colleagues as the first to relate real world outcomes from population-level health data to distinct components of EIP care.

"EIP involvement has been shown to improve outcomes compared with treatment as usual, in a cost effective manner," the investigators relate. "However, despite calls for research into the 'active ingredients' of EIP care, it remains unclear which specific components drive these improved outcomes."¹

Williams and colleagues drew on data from the UK's National Clinical Audit of Psychosis quality monitoring program to distinguish EPI programs by care components of their service model; they determined the treatment and outcomes of individuals from several sources, including the Mental Health Services Data Set, Hospital Episode Statistics, the Emergency Care Data Set and mortality records.

The studied components of the EPI programs were those specified as necessary by the National Institute for Health and Care Excellence of England and Wales: antipsychotic medication (including clozapine for eligible patients meeting criteria for treatment resistance), cognitive behavioral therapy for psychosis (CBTp), family intervention, vocational support, caregiver focused intervention, physical health interventions, and "average" care coordinator caseload and waiting time.

The primary outcome measure of this national retrospective cohort study was relapse within the 3 year follow-up period, as indicated by inpatient admission or referral to a crisis resolution and home treatment team (CRHTT). Secondary measures included time to inpatient admission or CRHTT referral, duration of inpatient stay, time to detention under the UK Mental Health Act (MHA), number of acute general hospital or emergency department admissions, and all-cause mortality.

The investigators calculated hazard rate ratios for a care component association with a specified outcome. The 2 care components found strongly associated with reduction in the primary outcome measure of relapse were smaller care coordinator caseload, and the use of clozapine in eligible patients. These had similar association with secondary outcomes of reduced time to psychiatric hospital admission, to CRHTT referral, and to detention under MHA.

The investigators noted that the median caseload of programs in this study of 17.4 per full time care coordinator exceeded the 15 currently recommended in the UK. They calculated that hazard rates for relapse increased by 2% for each additional person on the care coordinator's caseload (hazard rate 1.02, 95% CI 1.01-1.02).

In addition to the statistically lower risk of relapse with clozapine treatment, there was a numerical trend in reduced detention under MHA and in the length of stay in hospital and emergency departments. They noted that eligible individuals not offered or declining clozapine had worse outcomes, while recipients had risks comparable with, or lower than, those ineligible for clozapine.

These statistics are “striking in light of historically poor outcomes for people with treatment resistant psychosis," remarked Williams and colleagues. "Treatment resistance is common even in the early stages of psychosis and may be under identified."

The care components not linked to reduction in relapse but found beneficial in secondary measures included CBTp, which was associated with lower risk of admission and the duration of inpatient psychiatric treatment, and for detention under MHA. Hazard rate ratios for mortality were increased for those with an indication for, but not receiving interventions for, alcohol or substance use and for weight loss. There was also "suggestive" evidence of lower rates of emergency department attendance among those with an identified caregiver.

"Our findings may reflect the greater importance of intensive, personalized treatment in EIP, and we feel they are more valid in the context of modern psychosis care," Williams and colleagues observed. "They align with recent studies identifying care coordination as one of the most impactful elements of an EIP package of care and associating smaller caseloads with improvements in patient-reported outcomes."

Findings Applicable to EPI Programs in US

Jacob Ballon, MD, MPH, codirector of the INSPIRE Clinic at Stanford School of Medicine in Stanford, California, shared his assessment of the study and applicability of the findings to other EPI programs with Psychiatric Times.

Ballon appreciated the size of the cohort, and that the studied care components were largely those that are integral to EPI programs in the US. He also noted, however, that there have been developments in treatment since the 2019-2020 period studied, including availability of xanomeline and trospium chloride (COBENFY), which have likely affected the algorithm for initiating clozapine. Ballon thought the value of lower caseload "makes a lot of intuitive sense," and would have liked the study to define the base level from which the risk of relapse was calculated to increase by 2% with each additional patient.

Ballon found the timing of the study fortuitous, coinciding with the recent launch of a new first episode program at Stanford, Inspire 360, with a targeted maximum caseload of 25 patients per full time care coordinator. "This certainly reinforces my beliefs, as we expand our program, about including more case management," he remarked.

Although the algorithm for initiating clozapine may have been altered by recent treatment options, Ballon saw the results of the study as a reminder of the benefit of clozapine in persons who are eligible to receive it, even early in the psychotic illness.

"The clozapine result is a really fascinating finding, because one doesn't typically think of clozapine in a first episode program; though we know that it ought to be considered, especially in people who have continued symptoms in spite of more than a couple of medication trials," Ballon said.

He also noted that the timing of this evidence of clozapine benefit in EPI closely coincides with the latest relaxing of restrictions on its use. The Risk Evaluation and Mitigation Strategies program was revoked in February, although the indication and requirement for absolute neutrophil count (ANC) monitoring remains. Years earlier, weekly ANC and white blood cell monitoring was modified to ANC biweekly for 6 months and monthly thereafter.

"If you are required to have a weekly blood test in order to stay on your medicine—amongst all of the other barriers that come with taking medicine for psychosis—it just added such a high risk barrier if someone could suddenly be cut off from their medicine because they couldn't get a blood test result." Ballon said. "It made it really hard to feel safe using that."

Ballon pointed out that although the other care components were not associated with reduced relapse rates, they were generally beneficial on secondary measures. "These other interventions may or may not impact relapse rate, but they're going to contribute to the therapeutic process."

"If there's going to be a kind of trajectory toward symptom improvement, having CBTp, which appeared to facilitate voluntary hospitalization, is going to make that process go more smoothly and hopefully get people back on track," he suggested.

Ballon credited other care components such as vocational support with similar contributions to healthful outcomes, despite not having impacted the study's primary outcome measure of relapse.

"Vocational support is helping a person maintain the scaffolding of their life, and chances of greater success, although it may or may not necessarily stop them from having increased symptoms," Ballon explained. "It may have other sort of downstream benefits that, again, aren't necessarily captured by hospitalizations or involuntary commitments. It's yet another example of how successful treatment is more than just the reduction of symptoms."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Williams R, Penington E, Gupta V, et al. Critical components of 'early intervention in psychosis': national retrospective cohort study. Br J Psychiatry. 2025;1-9.