Glycine treatment of the risk syndrome for psychosis: report of two pilot studies.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.

Aripiprazole in the treatment of the psychosis prodrome: an open-label pilot study.

BACKGROUND: Research studies for the treatment of the putative prodromal phase of psychotic disorders have begun to appear. AIMS: To obtain preliminary evidence of the short-term efficacy and safety of aripiprazole treatment in people with the psychosis prodrome. METHOD: Fifteen participants meeting prodrome criteria (mean age 17.1 years, s.d.=5.5) enrolled in an open-label, single-site trial with fixed-flexible dosing of aripiprazole (5-30 mg/day) for 8 weeks. RESULTS: In the mixed-effects repeated-measures analysis, improvement from baseline on the Scale of Prodromal Symptoms total score was statistically significant by the first week. No participant converted to psychosis and 13 completed treatment. Neuropsychological measures showed no consistent improvement; mean weight gain was 1.2 kg. Akathisia emerged in 8 participants, but the mean Barnes Akathisia Scale score fell to baseline levels by the final visit. Adverse events were otherwise minimal. CONCLUSIONS: Aripiprazole shows a promising efficacy and safety profile for the psychosis prodrome. Placebo-controlled studies are indicated.

Comorbid diagnoses in patients meeting criteria for the schizophrenia prodrome.

While schizophrenia is often associated with a variety of concurrent psychiatric symptoms, little attention has been paid to the prevalence of psychiatric comorbidity in prodromal patients. The current study examines the presence of comorbid current and lifetime psychiatric conditions in prospectively identified prodromal patients. The results suggest that like their schizophrenic counterparts, prodromal patients experience a wide array of comorbid psychiatric syndromes, with the most common being Major Depressive Disorder and Cannabis Dependence. Results also suggest that Cannabis Dependence may be more common among prodromal versus help-seeking control patients. These findings lay the groundwork for further examination of the role that comorbid conditions play in the development, course, and severity of schizophrenia.

Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

OBJECTIVE: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia. METHOD: This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores. RESULTS: During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24). CONCLUSIONS: A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

A qualitative research study of the evolution of symptoms in individuals identified as prodromal to psychosis.

Because schizophrenia is difficult to treat and exacts large personal and societal costs, there is an effort underway to identify adolescents and young adults at high risk for psychosis. Theory-derived criteria of subthreshold positive symptoms identify a "prodromal" or clinically at-risk population who have conversion rates to psychosis of 40 to 50% within one to two years. However, further characterization of the psychosis prodrome by qualitative research methods could increase the predictive value of the "prodromal" designation. We conducted open-ended interviews with 20 parents of prodromal adolescents that focused on changes observed. The narratives fell into two thematically distinct subgroups, identified as "declining" and "never normal." The prodromal adolescents described as "declining" had a higher subsequent rate of conversion to psychosis than did the "never normal" group. Although preliminary, these results suggest that a trajectory of change in personality, relationships, and behavior from an essentially normal baseline may be consistent with increased risk for psychosis among prodromal adolescents.

Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome.

BACKGROUND: The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. METHODS: This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. RESULTS: In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). CONCLUSIONS: This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.

Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability.

As the number of studies related to the early identification of and intervention in the schizophrenia prodrome continues to grow, it becomes increasingly critical to develop methods to diagnose this new clinical entity with validity. Furthermore, given the low incidence of patients and the need for multisite collaboration, diagnostic and symptom severity reliability is also crucial. This article provides further data on these psychometric parameters for the prodromal assessment instruments developed by the Prevention through Risk Identification, Management, and Education (PRIME) prodromal research team at Yale University: the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms. It also presents data suggesting that excellent interrater reliability can be established for diagnosis in a day-and-a-half-long training workshop.

Prospective diagnosis of the initial prodrome for schizophrenia based on the Structured Interview for Prodromal Syndromes: preliminary evidence of interrater reliability and predictive validity.

OBJECTIVE: This study was conducted to determine the interrater reliability and predictive validity of a set of diagnostic criteria for the prodrome of the first episode of schizophrenic psychosis when based on the Structured Interview for Prodromal Syndromes. METHOD: The subjects were patients referred for evaluation because of a suspected schizophrenia prodromal syndrome. For the reliability study, two to four raters independently diagnosed 18 patients on the basis of face-to-face or videotaped interviews. For the validity study, 6- and 12-month outcome data were collected for 29 patients. RESULTS: Agreement in differentiating prodromal from nonprodromal patients was 93%. The prodromal features had converted to schizophrenic psychosis for 46% of the prodromal patients at 6 months and for 54% at 12 months. CONCLUSIONS: In small groups of subjects, these diagnostic criteria for the schizophrenic prodrome and the Structured Interview for Prodromal Syndromes showed promising interrater reliability and predictive validity.

Treatment histories of patients with a syndrome putatively prodromal to schizophrenia.

Recent reports suggest that a symptomatic state that is often prodromal to schizophrenia can be identified prospectively. We examined treatment-seeking histories and psychiatric services received among patients with a syndrome similar to a prodromal state. The records of 47 patients who met the criteria for a prodromal state were reviewed. Most patients had previously sought and received psychiatric services (90 percent), including medications (64 percent), and 51 percent had previously received a psychiatric diagnosis. These data suggest that patients who present with a syndrome putatively prodromal to schizophrenia constitute a clinical population. Research into treatment interventions is indicated.

Prospective observations of emerging psychosis.

Because delays in treatment of psychosis may be associated with poorer outcomes, intervention focus has shifted to the prodromal phase of illness. However, knowledge about this phase has been limited to retrospective reconstructions of symptoms once psychosis is already present. The following article offers a new, prospective view of the development of schizophrenia starting from the late prodromal phase of illness. As we use the term, late prodromal phase of illness means at imminent risk of conversion to schizophrenia. In this article, entry, conversion, and discharge data are presented on a sub-population of eight patients who received treatment for psychosis at onset while participating in a prospective double-blind placebo-controlled treatment study of the prodrome to psychosis. Through disguised case examples, this article then focuses on the course of illness progression in three of eight cases who converted to schizophreniform psychosis while randomized on either active medication or placebo. Discussion focuses on the dimensional quality of the transition both from the prodrome to psychosis and from psychosis to recovery.