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CAN WE EXPLAIN THE EPIDEMIOLOGY OF SCHIZOPHRENIA ON THE BASIS OF THE PATHOLOGY OF DOPAMINE?
156
Abstracts
STRESS AND HPA FUNCTIONING IN FIRST EPISODE PSYCHOSIS Patrick D. McGorry, B. Garner, C. Phassiouliotis, L. Phillips, R. Parslow, S. Bendall, G. Berger University of Melbourne Melbourne, Victoria, Australia Two studies focusing on stress and HPA in first episode psychosis (FEP) will be presented. The first study prospectively investigated circulating cortisol, Dehydroepiandrosterone sulfate (DHEAS) and their ratio in FEP compared to healthy controls, and their relationship to psychotic, negative and mood symptoms. Blood cortisol and DHEAS levels were obtained in 39 neuroleptic-naïve or minimally-treated FEP patients and 25 controls. Twenty three patients and 15 controls received repeat assessments after 12 weeks. At baseline, no differences were observed in cortisol, DHEAS or the cortisol/DHEAS ratio between patients and controls. Within FEP patients, decreases in cortisol and the cortisol/ DHEAS ratio over time were directly related to the improvement in depression (p=0.031, p=0.01), negative (p=0.006, p=0.008) and psychotic symptoms (cortisol only, p=0.01). Perceived stress significantly correlated with DHEAS (r=0.51; p=0.019) and the cortisol/ DHEAS ratio (r=-0.49; p=0.024) in controls, but not patients, possibly reflecting an impaired hormonal response to stress in FEP patients. These findings further support the involvement of the stress system in the pathophysiology of psychotic disorders, with implications for treatment strategies that modulate these neurosteroids. The second study focused on the level of activity of the HPA axis in FEP and examined the cortisol response to the administration of low dose dexamethasone in FEP patients and its relationship to childhood trauma. Low (0.5 mg) and very low (0.25 mg) dose Dexamethasone Suppression Tests (DST) were performed in neuroleptic naïve or minimally-treatment FEP patients and healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. In the 0.25 mg DST, FEP patients (n=21) reported significantly higher rates of childhood trauma compared to controls (n=20; p<0.001), exhibited lower basal cortisol (p<0.02) and an increased rate of cortisol hyper-suppression following dexamethasone compared to controls (33% (7/21) vs. 5% (1/20), respectively; p=0.04). Similarly, in the 0.5 mg DST, a greater proportion of FEP patients suppressed cortisol compared to controls, although this was not significant (63% (5/8) vs. 36% (5/14), respectively; p=0.4). This study shows for the first time that a subset of patients experiencing their first-episode of psychosis display enhanced cortisol suppression, similar to that observed in PTSD. These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored. doi:10.1016/j.schres.2010.02.157
STRESS AND THE HIPPOCAMPUS SUBICULUM: KEY SITE FOR INTERVENTION IN THE PREVENTION AND TREATMENT OF DOPAMINE HYPER-RESPONSIVITY IN PSYCHOSIS Anthony A. Grace, K.M. Fox, W.J. Lipski, O. Valenti, M.M. Behrens, D.J. Lodge University of Pittsburgh Pittsburgh, PA, USA Increasing evidence has implicated the anterior hippocampus (ventral subiculum in rats) in the pathophysiology of schizophrenia. Thus, imaging studies in humans have demonstrated hyperactivity in this region that correlates with psychosis, and postmortem studies have shown loss of parvalbumin interneuron staining. We have shown analogous changes using a rat neurodevelopmental disruption model of schizophrenia based on prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM) during
gestational day 15. In adult offspring of MAM-treated dams, we found that neurons were hyperactive, and this led to an increase in dopamine neuron population activity and hyper-responsivity to amphetamine. This hyperactivity correlated with a loss of parvalbumin interneuron staining and during behavioral tests this same region of the hippocampus showed selective loss of gamma rhythm activation to a conditioned tone. Our studies show that the ventral subiculum is also activated by known risk factors for schizophrenia. Thus, both amphetamine sensitization and stress activate the ventral subiculum-nucleus accumbens pathway, leading to increased dopamine neuron population activity and hyper-responsivity to amphetamine. Moreover, preliminary evicence shows that pharmacological reversal of ventral subicular hyperactivity in the MAM-treated rat by a novel GABA alpha-5 benzodiazepine agonist reversed the increased dopamine neuron population activity. Given that the ventral subiculum is potently driven by stressors, the strong drive of the hippocampus by the basolateral amygdale and the noradrenergic system, and the known susceptibility of the hippocampal formation to damage secondary to maintained stressors, we examined whether we could circumvent the pathological alterations observed in the ventral subiculum of MAMtreated rats. Our data show that MAM-treated rats that are administered diazepam intraperitoneally for 10 days spanning the time of puberty (postnatal days 31-40) fail to develop the increased dopamine neuron population activity that parallels the hyperdopaminergic state observed in adults; no effect was observed in controls. These data suggest that treatment of the heightened responsivity to stress in at-risk individuals may be an effective means to circumvent the onset of psychosis. doi:10.1016/j.schres.2010.02.158
CAN WE EXPLAIN THE EPIDEMIOLOGY OF SCHIZOPHRENIA ON THE BASIS OF THE PATHOLOGY OF DOPAMINE? Robin M. Murray Institute of Psychiatry London United Kingdom The relationship between epidemiology and pathogenesis has been established for many medical disorders eg. coronary artery disease, cancer; this is as it should be. In contrast, the two lines of investigation have remained quite separate in schizophrenia. Now much evidence suggests that the final common pathway to at least the positive symptoms of schizophrenia is dopamine dysregulation in the striatum. Furthermore, it has become clear that many of the risk factors associated with schizophrenia also impact the dopamine system. These include genes regulating the dopamine system such as DRD2 and COMT; not surprisingly some of the relatives of schizophrenic patients show similar abnormalities of striatal dopamine to patients. Furthermore, the risk-increasing effect of obstetric complications is well known, and these are known to be associated with dopamine dysregulation. The excessive use of stimulant drugs and cannabis also increases risk of schizophrenia, and once again this appears to be via their effect on striatal dopamine. Finally there is increasing evidence implicating exposure to adverse social factors including migration, urbanisation, and childhood maltreatment; it is suggested that such factors may have in common the experience of social defeat which in animals can be shown to influence the dopamine system. This presentation will therefore make the case that it is now time to integrate the epidemiology and pathogenesis of schizophrenia.
doi:10.1016/j.schres.2010.02.159
Abstracts
STRESS AND HPA FUNCTIONING IN FIRST EPISODE PSYCHOSIS Patrick D. McGorry, B. Garner, C. Phassiouliotis, L. Phillips, R. Parslow, S. Bendall, G. Berger University of Melbourne Melbourne, Victoria, Australia Two studies focusing on stress and HPA in first episode psychosis (FEP) will be presented. The first study prospectively investigated circulating cortisol, Dehydroepiandrosterone sulfate (DHEAS) and their ratio in FEP compared to healthy controls, and their relationship to psychotic, negative and mood symptoms. Blood cortisol and DHEAS levels were obtained in 39 neuroleptic-naïve or minimally-treated FEP patients and 25 controls. Twenty three patients and 15 controls received repeat assessments after 12 weeks. At baseline, no differences were observed in cortisol, DHEAS or the cortisol/DHEAS ratio between patients and controls. Within FEP patients, decreases in cortisol and the cortisol/ DHEAS ratio over time were directly related to the improvement in depression (p=0.031, p=0.01), negative (p=0.006, p=0.008) and psychotic symptoms (cortisol only, p=0.01). Perceived stress significantly correlated with DHEAS (r=0.51; p=0.019) and the cortisol/ DHEAS ratio (r=-0.49; p=0.024) in controls, but not patients, possibly reflecting an impaired hormonal response to stress in FEP patients. These findings further support the involvement of the stress system in the pathophysiology of psychotic disorders, with implications for treatment strategies that modulate these neurosteroids. The second study focused on the level of activity of the HPA axis in FEP and examined the cortisol response to the administration of low dose dexamethasone in FEP patients and its relationship to childhood trauma. Low (0.5 mg) and very low (0.25 mg) dose Dexamethasone Suppression Tests (DST) were performed in neuroleptic naïve or minimally-treatment FEP patients and healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. In the 0.25 mg DST, FEP patients (n=21) reported significantly higher rates of childhood trauma compared to controls (n=20; p<0.001), exhibited lower basal cortisol (p<0.02) and an increased rate of cortisol hyper-suppression following dexamethasone compared to controls (33% (7/21) vs. 5% (1/20), respectively; p=0.04). Similarly, in the 0.5 mg DST, a greater proportion of FEP patients suppressed cortisol compared to controls, although this was not significant (63% (5/8) vs. 36% (5/14), respectively; p=0.4). This study shows for the first time that a subset of patients experiencing their first-episode of psychosis display enhanced cortisol suppression, similar to that observed in PTSD. These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored. doi:10.1016/j.schres.2010.02.157
STRESS AND THE HIPPOCAMPUS SUBICULUM: KEY SITE FOR INTERVENTION IN THE PREVENTION AND TREATMENT OF DOPAMINE HYPER-RESPONSIVITY IN PSYCHOSIS Anthony A. Grace, K.M. Fox, W.J. Lipski, O. Valenti, M.M. Behrens, D.J. Lodge University of Pittsburgh Pittsburgh, PA, USA Increasing evidence has implicated the anterior hippocampus (ventral subiculum in rats) in the pathophysiology of schizophrenia. Thus, imaging studies in humans have demonstrated hyperactivity in this region that correlates with psychosis, and postmortem studies have shown loss of parvalbumin interneuron staining. We have shown analogous changes using a rat neurodevelopmental disruption model of schizophrenia based on prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM) during
gestational day 15. In adult offspring of MAM-treated dams, we found that neurons were hyperactive, and this led to an increase in dopamine neuron population activity and hyper-responsivity to amphetamine. This hyperactivity correlated with a loss of parvalbumin interneuron staining and during behavioral tests this same region of the hippocampus showed selective loss of gamma rhythm activation to a conditioned tone. Our studies show that the ventral subiculum is also activated by known risk factors for schizophrenia. Thus, both amphetamine sensitization and stress activate the ventral subiculum-nucleus accumbens pathway, leading to increased dopamine neuron population activity and hyper-responsivity to amphetamine. Moreover, preliminary evicence shows that pharmacological reversal of ventral subicular hyperactivity in the MAM-treated rat by a novel GABA alpha-5 benzodiazepine agonist reversed the increased dopamine neuron population activity. Given that the ventral subiculum is potently driven by stressors, the strong drive of the hippocampus by the basolateral amygdale and the noradrenergic system, and the known susceptibility of the hippocampal formation to damage secondary to maintained stressors, we examined whether we could circumvent the pathological alterations observed in the ventral subiculum of MAMtreated rats. Our data show that MAM-treated rats that are administered diazepam intraperitoneally for 10 days spanning the time of puberty (postnatal days 31-40) fail to develop the increased dopamine neuron population activity that parallels the hyperdopaminergic state observed in adults; no effect was observed in controls. These data suggest that treatment of the heightened responsivity to stress in at-risk individuals may be an effective means to circumvent the onset of psychosis. doi:10.1016/j.schres.2010.02.158
CAN WE EXPLAIN THE EPIDEMIOLOGY OF SCHIZOPHRENIA ON THE BASIS OF THE PATHOLOGY OF DOPAMINE? Robin M. Murray Institute of Psychiatry London United Kingdom The relationship between epidemiology and pathogenesis has been established for many medical disorders eg. coronary artery disease, cancer; this is as it should be. In contrast, the two lines of investigation have remained quite separate in schizophrenia. Now much evidence suggests that the final common pathway to at least the positive symptoms of schizophrenia is dopamine dysregulation in the striatum. Furthermore, it has become clear that many of the risk factors associated with schizophrenia also impact the dopamine system. These include genes regulating the dopamine system such as DRD2 and COMT; not surprisingly some of the relatives of schizophrenic patients show similar abnormalities of striatal dopamine to patients. Furthermore, the risk-increasing effect of obstetric complications is well known, and these are known to be associated with dopamine dysregulation. The excessive use of stimulant drugs and cannabis also increases risk of schizophrenia, and once again this appears to be via their effect on striatal dopamine. Finally there is increasing evidence implicating exposure to adverse social factors including migration, urbanisation, and childhood maltreatment; it is suggested that such factors may have in common the experience of social defeat which in animals can be shown to influence the dopamine system. This presentation will therefore make the case that it is now time to integrate the epidemiology and pathogenesis of schizophrenia.
doi:10.1016/j.schres.2010.02.159