Schizophrenia Research Congress Highlights

Twenty years after the initial meeting of the International Congress for Schizophrenia Research (ICSR), this year's biennial ICSR remained true to its mission to serve as a venue for active researchers. ICSR hosted investigators in neuroscience, cognitive neuroscience, basic and clinical psychopharmacology, psychosocial interventions, and genetics. Key presentations among the more clinical offerings included studies on predictors of first-episode psychosis; a novel atypical antipsychotic agent; hormonal therapy for schizophrenia in women; and integrated therapy for substance abuse and first-episode schizophrenia-spectrum disorders.

Predictors of Conversion to Psychosis

Genetic risk combined with declining mental functioning, unusual thought content, suspicion/paranoia, decreasing social functioning, and any drug abuse are predictors of first-episode psychosis, according to North American Prodrome Longitudinal Study (NAPLS) researchers. Tyrone D. Cannon, PhD, of the departments of psychology and psychiatry and biobehavioral sciences at the University of California, Los Angeles, presented preliminary NAPLS findings. With the aim of exploring fundamental questions related to conversion to schizophrenia, schizoaffective disorder, or mood disorders with psychotic features, NAPLS integrates data from 8 independently conceived research projects. Its further goal, Cannon said, is to identify a period "in which there may be dynamic changes in the nervous system that are unfolding before psychosis becomes fully manifest, and to provide an opportunity for preventive intervention that, while perhaps not primary prevention, may prevent chronicity and full disability."

Cannon noted that earlier prodromal studies were hampered by small sample size (N = 13 to 104) and brief follow-up (6 to 12 months), and as a consequence, the range of conversion rates identified (between 4% and 82%) is of limited predictive value.

The NAPLS population (N = 804) was subdivided into a clinical high-risk group, a genetic high-risk group, help-seeking controls, and nonpsychiatric controls. After 2.5 years of follow-up, of 75 potential predictors, 5 factors conferring significantly increased risk have been identified in a cross-domain multivariate analysis. They are genetic risk with reduced functioning (hazard ratio [HR], 2.29), unusual thought content (HR, 1.25), suspicion/paranoia (HR, 1.29), reduced social functioning (HR, 0.71), and any drug abuse (HR, 2.02).

Cannon reported that the high-risk patients in the NAPLS sample had a 35% conversion rate during the study period. The model's predictive power and sensitivity, he added, still falls somewhat short of ideal levels for recruiting at-risk individuals into prevention studies.

No Weight, Glucose, or Prolactin Gain in Bifeprunox Study

A novel atypical antipsychotic demonstrated efficacy along with a benign adverse-effect profile in a study of 450 patients with acute exacerbations of schizophrenia. Bifeprunox (Solvay/ Wyeth) is a novel, potent partial dopamine D2 agonist with moderately potent serotonin (5-HT)_1A agonist activity. Its lack of affinity for 5-HT_2A and 5-HT_2C muscarinic or histaminergic receptors account for its minimal cardiometabolic (weight gain and adverse lipid changes) and extrapyramidal symptoms at the doses studied, according to Herbert Y. Meltzer, MD, professor of psychiatry at Vanderbilt University Medical Center in Nashville.

Patients (mean age, 38 years) who met DSM-IV criteria for schizophrenia with an acute exacerbation were randomized double-blind to once-daily bifeprunox (30 or 40 mg, n = 148 for each), placebo (n = 148), or risperidone (6 mg, n = 154) for 6 weeks. All patients were hospitalized for a minimum of 10 days after randomization.

The primary efficacy end point measure of Positive and Negative Syndrome Scale (PANSS) score was reduced significantly from baseline with bifeprunox 30 mg and with risperidone at each weekly assessment. Meltzer commented that the greater efficacy improvement with risperidone (approximately 19-point drop in PANSS score in the risperidone group; approximately 13-point drop for the bifeprunox 30 mg group) needs to be viewed in light of the minimal differences in dropouts for lack of efficacy (14 of 148 in the bifeprunox 30 mg group; 10 of 154 in the risperidone group). Differences in efficacy during maintenance treatment with the 2 drugs may be less apparent than in these acutely ill patients, he suggested.

While patients receiving bifeprunox 30 mg experienced a mean weight loss of about 1 kg (P = .001 vs placebo), those receiving placebo gained slightly and those receiving risperidone gained nearly 1.5 kg (P = .0003 vs placebo). Mean plasma glucose level dropped nearly 5 mg/dL with bifeprunox 30 mg and increased more than 1 mg/dL with risperidone. While risperidone produces relatively small increases in weight, bifeprunox appears even more benign than risperidone, Dr Meltzer said. Plasma prolactin levels decreased significantly with bifeprunox and increased significantly with risperidone.

"The main point regarding bifepru- nox," Meltzer told Psychiatric Times, "is that it probably has the most benign metabolic adverse-effect profile of any of the atypical antipsychotic agents, and perhaps of the typicals as well."

The bifeprunox recommended dos- age, Meltzer said, based on this and other research, will be 20 mg daily. A new drug application for bifeprunox was submitted to the FDA in early October 2006.

Potential Role for Estrogen in Women With Schizophrenia

Results of a trial among 102 women with schizophrenia showed 100 µg of estradiol administered through a transdermal patch to significantly reduce positive, negative, and general psychopathological symptoms, according to Jayashri Kulkarni, PhD, professor of psychiatry at Monash University and Alfred Hospital in Melbourne.

Postpartum and menopausal hormonal changes make women more vulnerable to either a first episode or relapse of psychosis, Kulkarni noted. In this study, 102 women meeting DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder, all with PANSS scores indicating acute illness (60 or higher), were randomized double-blind to estradiol (100 µg/d) or placebo patches for 28 days. All women continued to receive antipsychotic medications during the trial.

PANSS general psychopathological symptoms decreased significantly from baseline in the estradiol group (P < .001) but not in the placebo group (P = .79). Differences between the groups were significant (P = .004). PANSS total symptom scores were similarly reduced in the estradiol group only.

Kulkarni concluded, "These findings open the door for a preventive role for estrogen in women with schizophrenia who deteriorate in periods of hormonal change."

Because of known risks of long-term hormone therapy, Kulkarni is also looking at selective estrogen receptor modulators as a treatment for schizophrenia in women. These agents, also called "brain estrogens," do not affect breast, uterine, or ovarian tissues. Initial experience with 60 mg/d of raloxifene suggested that a higher dosage (120 mg/d), now being tested, may be effective.

Integrated, Intensive Treatment Reduces Substance Abuse

An intensive, integrative treatment strategy for first-episode psychosis can reduce substance abuse and improve clinical outcomes, according to results of a study among 547 first-episode psychosis patients from the OPUS project. OPUS is a clinical treatment and research project funded by the Danish Ministries of Health and Social Affairs.

The study aim was to evaluate whether integrated treatment supplied by OPUS, in comparison with standard treatment, could reduce the number of patients with substance abuse and improve clinical and social outcomes over a 2-year period in a group of substance abusers, stated Merete Nordentoft, MD, associate professor at Copenhagen University Hospital. Intensive treatment included home visits, invitations to families to participate in both individual and group sessions, and substance abuse intervention. Standard treatment offered contact with a community mental health center. The main outcome measure of the study was reduction in comorbid substance abuse.

Investigators enrolled first-episode patients in equal numbers to intensive or standard treatment. Among 36% of males with substance abuse, cannabis was the most frequently abused substance (18%), with alcohol second (7%). Among 14% of females with substance abuse, alcohol abuse was most common (6%), with cannabis second (4%).

After 2 years of follow-up, 17% of patients with intensive and 21% with standard treatment met criteria for substance abuse (odds ratio, 0.5). Intensive treatment significantly reduced negative and disorganized symptoms in the substance abuser group. Bed days were also significantly fewer in the intensive treatment group (109 vs 167 days at 2 years), both during the 2 years of treatment and in the subsequent 3 years.

"This is an effective, cost-saving kind of treatment. We could have done even better-our treatment was not specialized for substance abuse. We're proceeding with a trial that includes focused substance abuse treatment," Nordentoft said.