Early intervention – bust or breakthrough?

OPUS II – results announced

In OPUS II the primary endpoint of the study was change in the negative dimension as assessed using the Scale for the Assessment of Negative Symptoms, Nikolai Albert, Denmark, reported at SIRS, Florence 2016. Altogether, 417 patients were recruited to OPUS II all of whom had received 2 years of intensive OPUS treatment following first episode psychosis. Eligible patients were then randomized to receive either a further 3 years OPUS treatment or treatment as usual (TAU).

Attrition over 5 years noted

Thus, a total of 197 patients received 5 years OPUS treatment and 203 received 2 years of OPUS treatment plus 3 years TAU. These well-matched patients, 74% of whom had schizophrenia, were followed for two years post termination of treatment. However, attrition bias was noted – some of the illest patients did not attend the follow-up interview.

No significant differences in any of the assessed negative dimension symptoms were found between patient groups except in working alliance (p<0.001) and client satisfaction (p<0.001). Similarly, there was no significant difference in hospital bed use – an important cost driver.

‘Where early intervention teams intervene, there has been major progress’ Max Birchwood, UK.

Treatment as usual may have improved for all patients

An important clue that could explain these seemingly disappointing findings is that the number of patient contacts in the TAU group was high. Since the benefits of the original OPUS I study were announced, Denmark has adopted the OPUS approach nationwide as part of its mental health programme. Thus, the Danish TAU is a version of OPUS, albeit a standardised version. Sadly, because it has moved from experimental to clinical practice, it can now take 1 year for patients to enter an OPUS-based programme. This means that the shorter duration of untreated psychosis seen originally may now be being compromised possibly to the detriment of patients’ long-term mental wellbeing.

PEPP 5 year programme

In Canada, a similar initiative to extend the early intervention care period from 2 years to 5 years was undertaken, Ashok Malla, Montreal, Canada,  explained, but with an additional 3 years of less intensive therapy rather than a five-year programme of intensive early intervention therapy. A total of 220 patients were recruited: 109 received less intensive care and 111 standard care.

High attrition rates and treatment limbo

In this study, it was clear that patients were not happy to receive less intensive care. Additionally, there was an average five-month period between leaving early intervention therapy and receiving standard care which left patients in a kind of treatment ‘limbo’. Dr Malla considered this the biggest obstacle that had to be overcome.

Strict exit policy

Consequently, study attrition rates were high: 55-58% in standard care group and 22-38% in the less intensive care group, depending on primary contact. This was compounded by a strict exit policy: if a patient missed two consecutive appointments, they were deemed to have left the study.

‘Disability is rapid and occurs in the prodromal and early phases. Therapeutic delay at FEP is crucial’ Max Birchwood, UK.

Accidental exposure of treatment blinding by patients over the course of such a long-study also proved challenging.

As with OPUS II, disappointingly, no significant differences were seen between treatment groups except in time in positive remission. Clearly, this study exemplifies the challenges surrounding management of schizophrenia patients long-term within ‘the system’.

Hong Kong – EASY

In Hong Kong, the standard of care is a 5-10 minute consultation with a psychiatrist every 2-3 months. Eric Chen conducted the EASY study which compared standard of care and 2 or 3 years of early intervention two years after therapy discontinuation. Primary functioning was the principal study outcome.

Better functioning – increased benefit

Interestingly, in this study only those patients who were doing poorly and whose functioning was low were offered an additional third year of early intervention therapy. Two-years of therapy appeared to offer additional functional benefit compared to standard of care. Intriguingly, both the two-year study subjects and the controls appeared to show continued improvements 2 years post-cessation of therapy. Additional benefit was gained by those patients receiving an additional year of therapy, however, this benefit was not maintained 2 years later. Clearly, the better functioning patients gained most from intensive intervention in this study.

Dopamine – key to early intervention?

Neurobiological changes seen during the early phases of psychosis support the need to treat early possibly using a combination of treatment approaches. This was the message with which Oliver Howse, UK, concluded his review of the evidence supporting roles for frontal cortex glutamate and striatum dopamine in psychosis.

Essentially, at no point during the early evolution of psychosis is any relationship between changes in glutamate (assessed by MR spectroscopy) and psychotic symptoms apparent. Dopamine synthesis and release, however, does appear to link to symptoms. Increases in dopamine synthesis intensify as psychosis develops.

Dopamine synthesis remains ‘on’ even in remission

In FEP patients, changes in presysnaptic dopamine levels ‘predict’ the response to antipsychotic therapy - the lower the dopamine synthesis induced, the greater the improvement in symptoms. However, in multiple episode patients, dopamine levels remain elevated compared to normal controls even when patients are in remission. This latter observation, Dr Howse suggested, might be due to a differential sensitivity of the system occurring over time. It also allows creation of a model to explain how this neurobiological circuit is operating. And how it might also be modulated by appropriate interventions for the benefit of patients.