Psychotic prodrome: Are antipsychotics effective? Ethical?

Current Psychiatry. 2005 March;04(03):32-46

March 1, 2005|Psychiatry

Meera Narasimhan, MD;Peter F. Buckley, MD

Evidence is mixed but risk is high when abnormal cognition falls short of schizophrenia

These instruments may identify prodromal symptoms in psychiatric practice, but further validation of clinical criteria is needed before they could be recommended for routine patient assessment.

PROPHYLACTIC ANTIPSYCHOTICS?

Atypical antipsychotics may be the standard of care for patients with a first psychotic episode, but this intervention is based on few double-blind controlled trials. Not surprisingly, only a handful of studies have examined antipsychotic therapy for the prodrome’s less clear-cut symptoms.

Risperidone. An 8- to 12-week open-label study in adolescents with first- and second-degree relatives with schizophrenia¹³ included four prodromal and six first-episode psychosis patients who met criteria for a cluster A personality disorder. Risperidone, 1.0 mg/d and 1.8 mg/d, respectively, improved thought disorder and attention symptoms, as measured with the Child Behavior Checklist. Verbal memory improved minimally, and no medication side effects were reported.

An open-label observational study¹⁴ identified four middle-aged subjects with a genetic risk of schizophrenia who reported negative symptoms and neurocognitive deficits. Risperidone, started at 0.25 mg/d and gradually increased to a maximum of 2 mg/d, improved negative symptoms, attention, and working memory. Mild side effects including tremors, sedation, dry mouth, and anxiety symptoms were reported.

An open-label, randomized, comparator trial¹⁵ examined psychotic transition rates in 59 subjects (mean age, 20) who met ultra high-risk criteria. They received:

a needs-based intervention (NBI) comprising case management, psychotropics excluding antipsychotics, and supportive psychotherapy
or a specific preventive intervention (SPI) that included risperidone, 1 to 2 mg/d, and a modified cognitive-behavioral therapy (CBT).

Table 2

Should you intervene with patients in suspected psychotic prodrome?

Arguments for:
Early treatment may prevent psychosocial decline Treatment may delay or ameliorate psychosis onset Treatment may improve patient awareness and acceptance of diagnosis Antipsychotics are effective for symptoms and may be neuroprotective Medications may improve overall outcome Neuroimaging findings may predict psychosis Outcome scales have improved diagnosis Treatment may reduce prodrome duration and improve prognosis
Arguments against:
Treatment would likely be given to persons who would not develop psychosis Treatment would unnecessarily stigmatize individuals who do not have schizophrenia Exposing patients with uncertain diagnoses to treatment risks is an ethical dilemma Antipsychotics are associated with side effects Psychotic prodrome studies are inconclusive, with small sample sizes and short follow-up No biological markers exist to predict psychosis

After 6 months, 10 of 28 (36%) in the NBI group had converted to a first episode of psychosis, compared with 3 of 31 (10%) in the SPI group (P = 0.03). At this point, risperidone was stopped, and all patients were offered NBI for 6 more months.

At 12-months’ follow-up, another 3 SPI patients who had been partially adherent or non-adherent to antipsychotic therapy had converted to psychosis. For adherent SPI patients, protection against conversion appeared to persist for 6 months after risperidone therapy ended. All medication side effects were mild and transient.

Table 3

Psychotic prodrome: Unanswered clinical questions

Does prodrome reflect a vulnerability for progression to psychosis? Can prodrome progress to psychosis in the absence of early interventions? Does duration of untreated psychosis predict prognosis? Do treatments reduce the risk of conversion to psychosis? Do interventions alter disease severity and prevent relapses? Can early interventions prevent cognitive and functional impairment?

Does prodrome reflect a vulnerability for progression to psychosis?
Can prodrome progress to psychosis in the absence of early interventions?
Does duration of untreated psychosis predict prognosis?
Do treatments reduce the risk of conversion to psychosis?
Do interventions alter disease severity and prevent relapses?
Can early interventions prevent cognitive and functional impairment?

Olanzapine. One double-blind, randomized, placebo-controlled trial has been published using olanzapine in patients with a prodromal syndrome.¹⁶ Sixty patients received olanzapine, 5 to 15 mg/d, or placebo. The olanzapine group showed significant reductions in positive, negative, and disorganization subscale scores and total SOPS and Positive and Negative Syndrome Scale scores, compared with the placebo group.

In the first year, 11 of 29 placebo-group patients and 5 of 31 receiving olanzapine converted to psychosis. Among patients receiving no treatment in the second year, 2 of 8 former placebo patients and 3 of 9 former olanzapine patients converted to psychosis.

Discontinuation rates were 35% and 28%, respectively. Compared with the placebo group, patients taking olanzapine experienced greater weight gain, suggesting that risks associated with antipsychotic therapy may exceed unproven benefits in this population.

Discussion. Little information exists on using quetiapine, ziprasidone, or aripiprazole in prodromal patients. As cited above, preliminary studies with risperidone and olanzapine suggest that these agents may improve several domains of psychotic prodrome. The evidence does not support firm conclusions, however, given the trials’ small sample sizes and brief duration.

The prevalence of obesity and metabolic syndrome in patients with schizophrenia and the added metabolic risks associated with atypical antipsychotics make their use during the prodrome controversial. Weighing the potential advantages and disadvantages (Table 2), we consider antipsychotics to be the last resort after psychosocial interventions have failed to improve prodromal symptoms.

Low-dose atypical antipsychotics may be warranted for some patients, but their use requires stringent monitoring of:

References

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