Antipsychotic Tested in 'Prodromal Syndrome'

Psychiatric TimesPsychiatric Times Vol 20 No 9
Volume 20
Issue 9

Can olanzapine (Zyprexa) delay or even prevent psychosis in patients with prodromal symptoms of schizophrenia? A new study being conducted in four research centers in North America is attempting to answer that question. Prevention Through Risk Identification Management and Education (PRIME) uses several new scales developed specifically for this study to identify and rate symptoms of prodromal symptoms to assist in early intervention research.

A clinical trial of olanzapine (Zyprexa) to determine whether early intervention can delay or prevent onset of psychosis in prodromally symptomatic patients is underway (McGlashan et al., 2003). Prevention Through Risk Identification Management and Education (PRIME) is being conducted at four sites: Yale University; the University of North Carolina at Chapel Hill; the University of Toronto; and Foothills Hospital, Calgary, Alberta, Canada.

Although a prodromal phase of psychotic illness is usually recognized in retrospect after the first psychotic break, study investigators have employed new criteria to diagnose and treat prodromal patients. Sixty study subjects were identified through responders to advertisements about mental illness development or through referrals from practitioners and health services receiving study recruitment materials on early intervention.

The PRIME study is the first randomized, double-blind, placebo-controlled trial of an atypical antipsychotic in this newly defined clinical population. The study incorporates long-term phases with and without medication to ascertain rate of psychotic-onset conversion in this population, as well as the safety and efficacy of antipsychotic intervention at this stage of illness development.

"Whereas the idea is not new, several recent developments have made early intervention research feasible, ethical and compelling," observed lead investigator Thomas McGlashan, M.D., and colleagues (McGlashan et al., 2003).

There are indications that early antipsychotic treatment administered before (Falloon, 1992; McGorry et al., in press) or soon after psychotic onset (Lieberman and Fenton, 2000) can heighten treatment response and produce better long-term outcome. Although there have not been controlled trials, treatment in the prodromal phase has appeared to exert some preventive effect (McGorry et al., in press).

The development of atypical antipsychotics has also provided opportunity for safer early intervention, in the assessment of the investigators. Although acknowledging such side effects as weight gain and somnolence, McGlashan and colleagues consider the risks of acute adverse reaction to atypical antipsychotics in the prodromal phase to be lower than that with older agents. There remains, however, the particular hazard in attempting pre-emptive, preventive medication treatment in patients who may be incorrectly diagnosed as prodromal.

"While these risks accompany any treatment study of neuroleptics in schizophrenia," McGlashan and colleagues (2003) noted, "they are magnified in prodromal intervention because such samples may contain people who are false positive prodromals who are exposed to the risks, but not necessarily the benefits of diagnosis and antipsychotic treatment."

Diagnosing Prodrome

An accurate method of identifying and rating symptoms of the prodromal syndrome was essential, then, for early intervention research to progress. The Scale of Prodromal Symptoms (SOPS) developed by McGlashan and colleagues (2001) provided a six-point scale and anchoring criteria for rating five attenuated positive symptoms, four disorganization symptoms and four general symptoms. The SOPS is distinguished from other scales of psychotic illness severity by having greater sensitivity for subpsychotic or attenuated symptoms.

The PRIME investigators embedded the SOPS rating scale into the diagnostic interview format of the Structured Interview for Prodromal Syndrome (SIPS) (Miller et al., 2002b). With this interview process, investigators could assess positive symptoms of the SOPS, employ the Global Assessment of Functioning (GAF) scale and obtain family history of mental illness. These assessments were then applied against the Criteria of Prodromal Syndromes (COPS) to classify patients into three high-risk prodromal subgroups having, respectively, genetic risk and deterioration state, attenuated positive symptom state, or brief intermittent psychotic state. These classifications have previously been reported predictive of psychosis onset within one year (Yung and McGorry, 1996).

To establish rate of psychosis development as well as treatment efficacy in this population, a final scale was developed to define onset of psychotic symptoms or "conversion" from the prodromal phase. The Presence of Psychosis Scale (POPS) marks onset by the presence of positive symptoms at the psychotic level of intensity and of sufficient frequency and duration (McGlashan et al., 2003).

The investigators have reported the SIPS to have high interrater reliability and predictive validity (Miller et al., 2002a; Miller et al., 2002b). Across study sites, patients meeting prodromal criteria experienced psychotic onset at a rate of between 36% and 54% within one year. Most patients converted within the first six months of baseline assessment. This indicated that the instruments and criteria were useful in identifying patients in the late prodromal phase of their illness: "The results support the validity of these criteria as defining prodromal states that mark high imminent risk for psychosis" (McGlashan et al., 2003).

PRIME Study Design

During the study, following screening and baseline assessment, patients are randomized to double-blind, one-year tracks of 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.




Davidson M, Reichenberg A, Rabinowitz J et al. (1999), Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am J Psychiatry 156(9):1328-1335 [see comments].


Falloon IR (1992), Early intervention for first episodes of schizophrenia: a preliminary exploration. Psychiatry 55(1):4-15 [see comments].


Lieberman JA, Fenton WS (2000), Delayed detection of psychosis: causes, consequences, and effect on public health. Am J Psychiatry 157(11):1727-1730 [see comments].


Maurer K, Hafner H (1995), Methodological aspects of onset assessment in schizophrenia. Schizophr Res 15(3):265-276.


McGlashan TH, Miller TJ, Woods SW et al. (2001), A scale for the assessment of prodromal symptoms and states. In: Early Intervention in Psychotic Disorders, Miller TJ, Mednick S, McGlashan TH et al., eds. Boston: Kluwer Academic Publishing, pp135-150.


McGlashan TH, Zipursky RB, Perkins D et al. (2003), The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design. Schizophr Res 61(1):7-18.


McGorry PD, Yung AR, Phillips LJ et al. (in press), Can first episode psychosis be delayed or prevented? A randomized controlled trial ofinterventions during the prepsychotic phase ofschizophrenia and related psychosis. Arch Gen Psychiatry.


Miller TJ, McGlashan TH, Rosen ML et al. (2002a), Diagnosis and symptom assessment in theschizophrenia syndrome. 82B. Presented at the 155th Annual American Psychiatric Association Meeting. May 23; Philadelphia.


Miller TJ, McGlashan TH, Rosen JL et al. (2002b), Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 159(5):863-865.


Miller TJ, Zipursky RB, Perkins D et al. (2003), The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the "prodromal" sample. Schizophr Res 61(1):19-30.


Yung AR, McGorry PD (1996), The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry 30(5):587-599.

Related Videos
Erin Crown, PA-C, CAQ-Psychiatry, and John M. Kane, MD, experts on schizophrenia
nicotine use
brain schizophrenia
exciting, brain
© 2024 MJH Life Sciences

All rights reserved.