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2007 American Psychiatric Association Annual Meeting

San Diego, California / May 19-24, 2007

Current understanding of the evolution of schizophrenia strongly supports the need for early intervention to improve outcomes. Early intervention at the first episode has the potential to achieve remission and to prevent long-term disability associated with this disorder. These were important themes of the APA’s Adolf Meyer Award Lecture given by Dr. Jeffrey A. Lieberman, Chair of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York.

The evolution of schizophrenia involves a group of susceptibility genes that confer, in additive fashion, vulnerability to development of schizophrenia later in life. These genes affect cell development and cell function, forming neurological circuits with abnormal connectivity. “Having this genetic disability and abnormal connectivity does not guarantee that schizophrenia will develop. Environmental insults, such as trauma or toxins, amplify the likelihood of the disorder,” explained Dr. Lieberman.

Development and Staging of Schizophrenia

Schizophrenia typically emerges during adolescence or early adulthood. In people who develop schizophrenia, maturational triggers destabilize vulnerable neural circuits and produce dysfunction in emotional regulation and cognition, leading to a first episode.

With the advent of imaging, structural differences in brains of patients with schizophrenia became evident. In particular, reductions in cortical volume and enlargement of ventricles and the subarachnoid space were observed. Longitudinal studies showed that as time progressed, further loss of cortical grey matter was seen, as well as further increases in the volume of ventricles and subarachnoid space. These brain changes are associated with relapses and poor long-term outcomes, Dr. Lieberman noted. “Recent evidence suggests the hypothesis that schizophrenia may have neurodevelopmental stages,” he added.

The premorbid stage would be characterized by abnormal brain development, while the prodromal stage would be onset of neurochemical dysregulation. “The prodromal stage may be able to be stabilized with treatment to prevent further deterioration,” he stated. “The therapeutic corollary is to introduce treatment early and maintain patients in remission with the hope of preventing deterioration.”

With each recurrent episode, further deterioration occurs and response to treatment is poorer with each successive break, he noted. After several episodes, patients enter the chronic phase of illness with residual symptoms. Cognitive and negative pathologies worsen and predominate over psychosis.

Research on first-episode patients showed that the time course and likelihood of achieving remission depended on duration of illness. “Shorter duration of illness was associated with improved recovery. Duration of illness is an independent factor for time to remission,” Dr. Lieberman told delegates.

Studies in first-episode patients have observed the effect of atypical antipsychotic treatment on brain structure. Dr. Lieberman discussed one unpublished study conducted in The Netherlands comparing 96 patients with schizophrenia to 113 healthy volunteers. The more antipsychotic drug treatment patients received, the less volume of grey matter was lost. “This study suggested that staying on treatment with an atypical antipsychotic prevents recurrence. We did not see this effect with haloperidol [in a previous study],” he noted.

For any treatment to be effective, adherence is critical. Evidence shows that if first-episode patients do not take their antipsychotic medications, the risk of first and second relapse is about five times greater over the next five years, Dr. Lieberman remarked. “Each successive episode of psychosis compromises treatment response and can be thought of as mini-attacks on the brain.”

Remission

Criteria for remission, as recently defined by the Remission in Schizophrenia Working Group, stipulate improvement in core signs and symptoms of the disorder for at least six months; any remaining symptoms must be of low intensity and not interfere with behaviour for at least six months (Am J Psychiatry 2005;162: 441-9). Remission is now a reasonable goal in treating first-episode patients and in clinically stable adults with schizophrenia.

Two studies with the long-acting injectable antipsychotic risperidone using these criteria were reported. The first was based on a pre-specified one-year interim analysis of a two-year, open-label trial where treatment of a first episode was associated with attaining and maintaining remission according to the criteria. Factors associated with higher probability of remission were early response to treatment and female gender. Remission was associated with improved clinical status, functioning and productivity, reported Dr. Robin Emsley, Department of Psychiatry, Stellenbosch University, Cape Town, South Africa, who presented these results at a poster session.

The study enrolled 51 patients with psychosis; 55% had a diagnosis of schizophrenia and 45% were diagnosed as schizophreniform disorder according to DSM-IV criteria. Fifty per cent of patients treated with 25 to 50 mg achieved remission. Age or baseline Positive and Negative Syndrome Score (PANSS) did not predict remission, he remarked. Median time to remission was 213 days. Lower resource use (hospitalization and emergency room) was seen in remitted vs. non-remitted patients, he noted.

The majority of adverse events were mild to moderate in severity (97%), and patients recovered from 82.7% of these events without the need for dose adjustments.

Long-term remission for up to 18 months is also feasible, as demonstrated by the second study that included 529 patients from seven European countries who were enrolled in the original StoRMi (Switch to Risperidone Microspheres) trial. Patients in the trial opted to continue on the long-acting injectable. Results of the trial were reported at a poster session by Dr. Pierre-Michel Llorca, Centre Hospitalier Universitaire Clermont-Ferrand, France.

Among those who achieved or maintained remission during the initial six months of the trial, 93.7% experienced sustained remission at 18 months. Significant improvement from baseline was seen on all PANSS parameters at 18 months (P<0.001) for positive symptoms, negative symptoms, depression/anxiety, disorganized thoughts and excitement/hostility. At study end point, 47% of patients exhibited at least 20% improvement on total PANSS. Treatment was well tolerated with safety findings consistent with those reported in previous studies.

Hospitalizations

Lower resource utilization was observed when patients were treated for one year with long-acting risperidone, with fewer mental health-related hospitalizations, visits to the emergency department, and mental health-related hospital days compared with 12 months prior to treatment initiation. These were the findings of an interim one-year analysis of 109 patients with schizophrenia enrolled in a two-year, multicentre observational study. These patients had a mean age of onset of 26 years and a mean duration of illness of 19.8 years, explained Dr. Chris Kozma, University of South Carolina, Columbia, at a poster session.

The study has enrolled 525 patients. Dr. Kozma presented data on 109 patients who completed five visits. Mean age was 49 years and 64% were male. During the 12-month period prior to study enrolment, 28.4% of patients were hospitalized vs. 17.4% one year after treatment (P=0.046); mean hospital days per patient decreased from eight in the pre-treatment period to four in the post-treatment period. The percentage of patients who visited the emergency department decreased from 19.6% to 9.8% (P=0.05). Further analyses will examine factors related to relapse and hospitalization, he noted.

Lipid Profiles

Safety concerns have been raised with second-generation antipsychotics relating to increased cardiovascular risk. Dr. Erica Duncan, Mental Health Service, Atlanta VA Medical Center, Decatur, Georgia, reported the results of a large retrospective study that compared plasma lipids in 6331 individuals during exposure to haloperidol, risperidone, olanzapine and quetiapine. Results showed that lipid levels varied according to the antipsychotic agent taken.

Between-group comparisons showed that risperidone and quetiapine achieved significantly higher HDL-C levels compared with olanzapine (P<0.05 between risperidone and olanzapine, P=0.001 for risperidone and quetiapine vs. olanzapine), while triglyceride levels were significantly higher during treatment with olanzapine and quetiapine than risperidone (P<0.001 for olanzapine vs. risperidone, P<0.01 for olanzapine and quetiapine vs. risperidone). Further analysis showed that risperidone was associated with lower total cholesterol, LDL-C, and triglyceride levels, as well as a lower per cent of patients with low HDL-C compared with olanzapine (P<0.05).

Dr. Duncan stated that these findings should be considered when treating patients with antipsychotics who have pre-existing cardiovascular risk factors.