Tandy J. Miller

Symptom assessment in schizophrenic prodromal states.

Individuals who develop schizophrenia often suffer long standing deficits. All too often available treatments remain palliative and do not improve the long-term course of illness. The neurobiological deficits associated with the onset of schizophrenia may be most active and damaging in the early stages of this life long illness, a fact which has shifted the focus of research and clinical work toward the early or prodromal stages of this disorder. Results from limited studies suggest that early intervention may lead to a better prognosis. Early interventions that could delay or prevent the onset of psychotic illnesses have obvious public health implications and rely on being able to identify true prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale of Prodromal Symptoms are assessment instruments developed for operationally defining diagnosis and for quantitatively rating symptom severity for patients prodromal for psychosis.

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.

Neuropsychological status of subjects at high risk for a first episode of psychosis

Thirty-six subjects aged 16 years or older judged at risk for a first episode of psychosis within a North American multi-site study of the schizophrenia prodrome [McGlashan et al., Schizophr. Res. (2003); Miller et al., Schizophr. Res. (2003)] performed at levels intermediate to population norms and data reported for schizophrenia samples on a comprehensive neuropsychological exam. In the context of normal intelligence, this intermediate status suggests that, as a group, these subjects are not fully normal in neuropsychological functioning. Conversely, the finding that they do not show the levels of impairment commonly observed in schizophrenia, including within the first episode, suggests that prodromal interventions might conceivably prevent, delay, or lessen the severity of declines associated with first psychotic episodes.

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.

Aripiprazole in the treatment of the psychosis prodrome

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.

Instrument for the Assessment of Prodromal Symptoms and States

Certain constellations of prodromal symptoms have recently been shown to predict the onset of psychosis with a high degree of accuracy, thus making treatment intervention in the prodromal phase more feasible scientifically and ethically. Here we present a structured interview, the Structured Interview for Prodromal Symptoms (SIPS) and a severity scale, the Scale of Prodromal Symptoms (SOPS), to identify operationally the presence of these prodromal constellations and to measure their severity over time, including their conversion to actively psychotic states.

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.

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.

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.

Estimated yield of early detection of prodromal or first episode patients by screening first degree relatives of schizophrenic patients

Screening a population of relatives of current schizophrenic patients could be an efficient means to accrue a sample of early first episode or prodromal patients for a prediction study or an intervention study. The risk of new onset schizophrenia cases in any one year in a population of relatives depends on the number of schizophrenic probands and three additional factors: (1) the age of onset distribution for schizophrenia; (2) the lifetime risk of the at-risk group of relatives selected; and (3) the number of at-risk relatives per proband and their age distribution. Estimates are made for each of these parameters, and calculations are presented. The base model suggests that screening all siblings and children of patients with schizophrenia would yield approximately 19 new cases of schizophrenia per year per 10,000 relatives screened. The results of the calculation are relatively insensitive to reasonable variation of most model parameter estimates. The yield of new cases obtained by screening relatives of current patients appears to be low if the purpose is to recruit a sample for an early intervention study over a relatively short period of time.