During the study, following screening and baseline assessment, patients are randomized to double-blind, one-year tracks of olanzapine(Drug information on olanzapine) 5 mg/day to 15 mg/day or placebo. Psychosocial interventions are available, but vary in nature across study sites from a problem-solving training approach, to psychoeducation on symptoms and medications, to stress management.
Patients are followed for an additional year after medication or placebo is discontinued. At the end of this second year, if they have not manifested psychosis, patients are triaged to appropriate non-study clinical oversight. If psychotic symptoms emerge in this period or earlier, patients are entered into a six-month rescue phase with open-label olanzapine 5 mg/day to 20 mg/day. A third one-year follow-along phase is open to completing patients and to those who have discontinued the study but wish to maintain contact. The open inclusion is intended to facilitate determining the rate of psychotic conversion among these patients with putative prodromal syndrome.
The study population is described in detail in a separate report (Miller et al., 2003). Each patient had some form of psychiatric contact prior to entering the study. Antidepressants were the most frequently prescribed psychiatric medication class, with approximately 40% of the patients reporting their use. All patients who had received antidepressant treatment had discontinued the medication prior to the study baseline evaluation due either to lack of effect or to becoming more symptomatic and/or functionally compromised while taking the medication.
The investigators noted, however, that the level of affective symptoms was not high at enrollment. They speculated that the antidepressant treatment could have served to screen out patients whose symptoms were prodrome of affective rather than psychotic illness. "It may be that we see prodromally symptomatic people for whom antidepressant treatment has not worked because the underlying pathophysiology is not affective in nature," they indicated. "Treatment with antidepressant, in a sense, triages patients with primary affective disorders to a different path" (Miller et al., 2003).
Most patients (93%) met criteria for the attenuated positive symptom prodromal state. Ten of these patients also met criteria for genetic risk and deterioration state, along with three others in this category. No patients were found with brief intermittent psychotic state.
Although the severity of psychiatric symptoms generally did not exceed the level measured with SOPS, the GAF scores reflected substantial functional disability; with a 15-point loss of functional capacity in the year prior to contacting the study clinic. "This is a population that is clearly disabled despite a relative quiescence of symptomatic expression," the investigators observed (Miller et al., 2003).
This finding was consistent with Miller and colleagues' review of the literature, which indicated that prodrome symptoms ultimately emerge alongside functional decline (Davidson et al., 1999; Maurer and Hafner, 1995). "The prodromal phase appears to start with loss of complex instrumental capacities such as social and intellectual functioning," the investigators noted. "Symptom formation usually follows such developments, first with symptoms that are negative and/or affective, then with symptoms that are positive" (Miller et al., 2003).
The principal question posed in the PRIME study--whether early antipsychotic intervention can delay or prevent psychosis onset--will likely be broadened to consider whether such intervention improves level of functioning. These results probably comprising patients in late prodrome, given the high levels of functional disability, will also beg the question of whether, given sufficient diagnostic criteria, there would be additional benefit of intervening in early prodrome.