Abstract
COMMON PATHOPHYSIOLOGICAL VARIABLES UNDERLYING DOPAMINE SYSTEM DYSREGULATION IN SCHIZOPHRENIA, AND THEIR RAPID REVERSAL BY ANTIPSYCHOTIC DRUG ADMINISTRATION
Departments of Neuroscience, Psychiatry, and Psychology, University of Pittsburgh, Pittsburgh, PA USA
There is increasing evidence that schizophrenia psychosis involves hyperactivity within the hippocampal complex, and that this is associated with increased responsivity within the dopamine system. In a developmental disruption model of schizophrenia in rodents, administration of the mitotoxin methylazoxymethanol acetate (MAM) to pregnant dams at gestational day 17 yields adult offspring that exhibit anatomical, behavioral, and neurochemical responses, including hyper-responsivity to amphetamine, that are consistent with schizophrenia in humans. Moreover, there is hyperactivity in the ventral subiculum of the hippocampus that leads to hyperactivation of tonic dopamine neuron population activity. Inactivation of the ventral subiculum restores normal dopamine neuron firing and baseline responses to amphetamine. Interestingly, two factors that are known to precipitate or exacerbate psychosis, stress and repeated amphetamine, also cause hyperactivity in the ventral subiculum and increased tonic dopamine neuron firing. Therefore, stress, psychostimulant sensitization, and schizophrenia appear to sensitize the dopamine system to stimuli via a common pathway.
The psychotic symptoms of schizophrenia are known to be attenuated by antipsychotic drug administration. Early studies show that with 3 weeks of antipsychotic drug treatment there is an inactivation of dopamine neuron firing known as depolarization block. In contrast, recent evidence from our group suggests that, in the MAM model, the already heightened activation of the dopamine system causes a more rapid onset of depolarization block of ventral tegmental dopamine neurons. Therefore, as suggested by clinical studies, psychosis in schizophrenia may respond rapidly to antipsychotic drug administration in individuals depending on the baseline state of the dopamine system.
TIME COURSE OF ANTIPSYCHOTIC DRUG RESPONSE IN SCHIZOPHRENIA
John Kane
1 The Zucker Hillside Hospital, Glen Oaks, New York, USA
2 The Albert Einstein College of Medicine
When patients are treated with antipsychotic medications it is expected that there will be clinically meaningful improvement in psychopathology, particularly positive symptoms. However, it is clear that many patients respond minimally or only partially to antipsychotic medications. A major clinical question in this context is, how long should we wait before deciding that an initial trial is not efficacious? In addition, we would need to ask, what metric should be utilized in determining efficacy?
It had been assumed for many years that antipsychotics took a week or two to produce meaningful improvement. Recently it has been shown that a substantial proportion of ultimate response occurs within the first week or two. These considerations lead to the next logical question, to what extent can improvement within the first week or two be used as an indicator of the likely degree of subsequent response? Recent studies suggest that a 20% improvement on the PANSS total score after two weeks of treatment can be used as a meaningful threshold for predicting likelihood of subsequent response.
Those patients who do not experience that degree of improvement appear to experience a different degree of response, even when followed for six months, in comparison to those patients who do experience at least a 20% improvement on the PANSS at two week. These findings have important clinical and heuristic implications.
PARTICIPATORY ACTION RESEARCH METHODS FOR QUALITY IMPROVEMENT: CONSUMER PROGRAM EXEMPLAR
Resource Centre for Mental Health Consumer Developed Initiatives (CDI)
This presentation will highlight the development of consumer participation for quality improvement and a unique consumer evaluation tool that facilitates changes to mental health services.
TREATING SUBSYNDROMAL SCHIZOPHRENIA: WHY THE UPROAR?
TH McGlashan
Yale University School of Medicine, 301 Cedar St., New Haven, CT 06519 USA
Early detection and intervention offers a new perspective on the diagnosis and treatment of schizophrenic spectrum disorders. Relevant investigations include studies of efforts to reduce post-onset duration of untreated psychosis and studies of efforts to identify and treat prodromally symptomatic high risk patients in the pre-onset phase of disorder. There appears to be consensus that the benefits outweigh the risks in studies aiming to treat first psychotic patients as soon as possible. In contrast, less consensus exists about pre-onset detection and intervention studies. The author and colleagues have conducted such a study, a randomized double-blind placebo controlled clinical trial of atypical antipsychotic medicine in prodromally at risk patients. Among the ethical issues raised, the following are paramount: The false positive rate of case identification, the evidence of benefit, the side effects of treatment, the potential harm from hearing that one is at risk for psychosis, the false negative rate of case identification, and the inclusion of adolescents. Each of these issues is elaborated and discussed in terms of the existing studies informing risk and benefit, including our own clinical experience conducting this research. It is concluded that we do not have enough data yet to justify pre-onset drug intervention as standard practice but we do have enough data concerning risk and benefit to justify proceeding with such research without delay.
ADOLESCENT SCHIZOPHRENIA: CLINICAL IMPLICATIONS OF MEDICATION RESEARCH
Hastings Endowed Chair and Professor and Head, Department of Psychiatry, University of Minnesota Medical School
The Onset of schizophrenia and related psychotic disorders is frequently seen during adolescence with some studies indicating that as many as 40% of males have symptoms before age 19. Recent research has encouragingly noted better outcomes associated with reduced Duration of Untreated Psychosis (DUP) in the first episode patient, but little has been done to provide empiric data for the younger age group (younger than age 18).
A relatively recent FDA initiative has lead to the first three placebo controlled trials of antipsychotic medications in three decades and a few new comparison studies have been conducted. Although the new data is welcome, an assessment of the trials is necessary to translate the research into clinical practice.
To this end, the presentation will review the recent trials, assess the dosing strategies of the studies, explore the side-effect profiles, and examine the comparison studies to determine if there is a proven superior medication for this age group.
The presentation will conclude with practical points of medication management for adolescents with schizophrenia and related psychosis.
ENVIRONMENTAL SUPPORTS IMPROVE TARGET BEHAVIORS AND GLOBAL FUNCTIONAL OUTCOME FOR INDIVIDUALS WITH SCHIZOPHRNEIA
1 University of Texas Health Science Center, San Antonio, USA
2 University of Texas at Houston, School of Public Health, USA
Cognitive Adaptation Training (CAT) is a psychosocial treatment using environmental supports such as signs, alarms, pill containers, checklists and the organization of belongings to cue and sequence adaptive behavior in the home environment. Supports are customized for specific cognitive and behavioral impairments, and maintained on weekly home visits. In two studies, 240 participants with schizophrenia were randomized to either standard treatment as usual (TAU) or to TAU plus one of several treatments using various intensities of environmental supports (Full CAT treatment, PharmCAT treatment–focused only on medication and appointment adherence, or Generic Environmental Supports (GES)–which provides a generic set of supports at routine clinic visits. Treatment lasted for a minimum of 9 months and patients were followed after treatment decreased in intensity or was withdrawn for 6 to 9 months. Participants were assessed at baseline and every 3 months. The highest intensity CAT treatment consistently produced the best outcomes with respect to global functioning, but some functional gains were seen with stepped down treatments. Functional gains decreased when treatment was withdrawn, but booster sessions maintained some of the gains seen in CAT treatment. Medication adherence improved in CAT and PharmCAT more than in treatment as usual. In these treatments, adherence rates were around 80% versus 60% for treatment as usual. Effects on medication adherence remained when home visits were withdrawn. Survival time to relapse or exacerbation was significantly longer in CAT and PharmCAT compared to TAU. Environmental supports can improve important target behaviors and global functional outcome for individuals with schizophrenia.
CAN NEUROBIOLOGY PREDICT PSYCHOSIS? A REVIEW OF THE CLINICAL HIGH-RISK FIELD
Dr Stephen Wood
University Of Melbourne, Melbourne Neuropsychiatry Centre, Victoria, Australia
Although the underlying neurobiology of emerging psychotic disorders is not well understood, there is a growing conviction that the study of patients at clinical high risk for the illness will provide important insights. Further, a better understanding of the transition period may help the development of novel therapies. In this talk, I will summarize the extant neuroimaging and neuropsychological studies of people at clinical high risk for psychosis. By and large, there are few definitive markers that distinguish those who go on to develop the illness from those who do not. The 2 most consistently abnormal brain regions in schizophrenia research, the hippocampi and the lateral ventricles, are not significantly different from healthy controls prior to psychosis onset. However, frontal lobe measures (eg, cortical thickness in the anterior cingulate) do show promise, as do cognitive measures sensitive to prefrontal cortex dysfunction. Further, longitudinal magnetic resonance imaging findings in individuals at ultrahigh risk for developing a psychotic illness show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal cortical regions. While the pathological processes underlying such changes remain unclear, speculatively they may refiect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. Active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.
