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Schizophrenia: Correlation with phencyclidine-induced psychosis and neurochemical mechanisms
S-43 Neurobiological Basis ofRelapse Prediction in Stimulant-Induced Psychosis and Schizophrenia previous MAP psychosis. We studied the process that triggered flashbacks, along with monoamine neurotransmitter function, in flashbacks due to previous MAP psychosis. The process triggering flashbacks were studied in 41 female flashbackers, along with 87 female non-flashbackers with previous MAP psychosis. Plasma levels of norepinephrine (NE), dopamine and 5-hydroxytryptamine, and their respective metabolites were compared among 25 of the 41 flashbackers, 16 of the 87 nonflashbackers, and 9 who were suffering from persistent MAP psychosis for at least 6 months. Control data were available from 28 normal healthy females including 20 MAP users and 8 non-users, none of the 28 had become psychotic. The subject subgroups were age matched. The triggering factor was a mild fear of others, actualizing a frightening image encoded through overwhelmingly threatening experiences the flashbackers underwent during previous MAP abuse. Plasma epinephrine levels and the state form of the Spielberger State-Trait Anxiety inventory did not increase during flashbacks, indicating that no serious stress or anxiety was evident. The 25 flashbackers showed higher NE levels during flashbacks than during periods of normalcy, and higher levels than the user and non-user controls. The NE levels during flashbacks were significantly higher than those in the user controls. The 9 subjects with persistent MAP psychosis had significantly higher NE levels than the user controls. The 16 nonflashbackers had significantly higher 3-methoxy-4-hydroxyphenylglycol (MHPG) levels than the users. The present study suggests that MAPinduced sensitization to frightening images may cause flashbacks through an increase in peripheral noradrenergic activity.
I8-43-21 Schizophrenia: Correlation with Phencyclidine-Induced Psychosis and Neurochemical Mechanisms. S.P. Ali I, H.S. Bracha 2. I Neurochemistry Laboratory, Division of Neurotoxicology, NCTRlFDA, Jefferson, AR; 2 VA Pacific Center for PTSD, Honolulu, HI, USA Phencyclidine (PCP; angel dust) is one of the most widely used drugs of abuse known to produce psychotic effects in human. PCP is a noncompetitive NMDA receptor antagonist, and produces a variety of behaviors in rats including circling. Circling behavior has been described in patients with severe psychotic symptoms. The present study was designed to evaluate the effect of acute injection of PCP or a noncompetitive NMDA receptor antagonists (+) MK-80 I on circling preference in rats and on lateralization of activity in dopamine (DA) system of the forebrain. Adult female rats were dosed with PCP (10 mglkg, ip) or (+) MK-801 (0.1 mg/kg, ip), and circling preference was recorded for two hours before sacrifice to determine monoamine levels by HPLCIEC. Animals injected with PCP or (+) MK-801 showed a preference to turn to the left (65%, and 72%, respectively). PCP and (+) MK-801 also produced significant increases of DA metabolites DOPAC and HVA in striatum, nucleus accumbens and olfactory tubercles on both sides of the brain. Further dissection of the striatum into medioventral and dorsolateral regions revealed that HVA was increased bilaterally except in globus pallidus where we found significant increases in DA. DOPAC and HVA only on the left side after PCP and (+) MK-801 administration. These data suggest that PCP and (+) MK-80l produce a greater preference to turn left than right, a finding similar to that found in human psychosis. Furthermore, it is possible that this preference to turn toward the left hemispace is due to an asymmetry in DA function found in the globus pallidus after administration of PCP and similar drugs.
I8-43-31
Behavioral and Neurotransmitter Responses to a "Binge" Pattern of Amphetamine Administration
R. Kuczenski, D.S. Segal. Department of Psychiatry, University of California, San Diego, CA, USA Stimulant-induced psychosis is most frequently associated with "binge" or "run" patterns of stimulant abuse. To further understand the mechanisms responsible for this drug model of paranoid psychosis, we attempted to simulate this pattern of drug exposure in rats. Animals were administered gradually increasing doses (Escalating Dose; ED) of amphetamine (AMPH) prior to repeated injections of a high (8 mglkg) dose of AMPH at two hour intervals. The behavior of the animals was continuously
155
monitored, and. during the AMPH "run", microdialysate dopamine (DA), serotonin (5HT) and norepinephrine (NE) concentrations in several brain regions were concurrently evaluated. Results were compared to animals receiving a single injection of 8 mg/kg AMPH. Baseline levels of the three neurotransmitters were not altered by the ED pretreatment. In response to the first injection of the "run", there were no differences in the neurotransmitter responses between the control and experimental groups, although the ED pretreated rats exhibited typical signs of a sensitized behavioral response. Animals remained in continuous stereotype between successive injections, but, by the fourth injection, both the intensity and the duration of the stereotype had declined. Concomitantly, the peak DA and 5HT concentrations in both caudate-putamen and nucleus accumbens following each AMPH injection progressively declined to less than 60% of the initial response. In contrast, in both hippocampus and frontal cortex, peak NE concentrations did not decline following each AMPH injection. These results suggest that the relationship between NE and DA may be implicated in AMPH-induced psychosis.
I8-43-4 [ Evidence for Sensitization in the EarlyStageof Schizophrenia 1.A. Lieberman. Department of Psychiatry, University ofNorth Carolina, Chapel Hill, NC, USA
Schizophrenia is known to have a chronic course associated with clinical deterioration in a significant proportion of patients. However, the nature of disease progression and its underlying pathophysiological process have not been clearly demonstrated. We will present data from a prospective study of psychobiology in first episode schizophrenics which demonstrates clinical manifestations of disease progression and the underlying pathophysiological mechanisms. We have interpreted preliminary results as indicating that a process of sensitization occurs in the early stage of schizophrenia which is caused by enhanced stimulation of endogenous DA. This process may be compounded subsequently by the effects of chronic neuroleptic treatment. This process underlies the clinical progression of schizophrenia in its early stages. The evidence of this hypothesis follows. I) Duration of psychosis prior to treatment is strongly correlated with time to (P = 0.03) and level of remission (r = 0.41. P = 0.001). 2) Patients have a poorer response to treatment in their subsequent (2nd and 3rd) episodes of illness despite receiving the same treatment as in their first episode, (median time to remission by episode 4 [2.5] weeks, 7 [1.6] weeks, 24 [2.5] weeks, P = 0.001).3) Patients who are sensitive to psychotic exacerbation by methylphenidate are more likely to develop TD with subsequent neuroleptic treatment. Patients with TD when in remission are more susceptible to psychotic exacerbation with methylphenidate (X 2 = 5, P '" 0.03). These and additional results will be presented in the context of whether schizophrenia has a neurodegenerative as well as neurodevelopmental pathophysiological process.
I8-43-51 Predicting Duration of Clinical Stability Following Haloperidol Withdrawal in Schizophrenia
D.P. van Kammen, M.E. Kelley, J.A. Gurklis, M.W. Gilbertson, J.K. Yao, R. Condray, J.L. Peters. Veterans Affairs Medical Center, Pittsburgh, PA, USA To develop a model consisting of behavioral and mono-aminergic variables to identify the risk of symptom exacerbation, the authors obtained in the week prior to haloperidol discontinuation global behavioral ratings and cerebrospinal fluid (CSF) for monoamine metabolites in a sample of 109 DSM III-R schizophrenic patients. Patients were followed until specific criteria for increases in psychosis were met for up to one year, and then returned to antipsychotic drug treatment. Cox regression analysis identified predictors of the survival function. or the probability of relapse at a given time drug free. The best model indicated that increased psychosis, decreased anxiety, an increased CSF homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5HIAA) ratio, and decreased CSF MHPG were associated with early increases in psychosis. Our study indicates that it is possible to identify those patients who are more likely to remain clinically stable without medication. When the model is validated, it will assist clinicians in assessing the relapse risk over time, in lowering doses
I8-43-21 Schizophrenia: Correlation with Phencyclidine-Induced Psychosis and Neurochemical Mechanisms. S.P. Ali I, H.S. Bracha 2. I Neurochemistry Laboratory, Division of Neurotoxicology, NCTRlFDA, Jefferson, AR; 2 VA Pacific Center for PTSD, Honolulu, HI, USA Phencyclidine (PCP; angel dust) is one of the most widely used drugs of abuse known to produce psychotic effects in human. PCP is a noncompetitive NMDA receptor antagonist, and produces a variety of behaviors in rats including circling. Circling behavior has been described in patients with severe psychotic symptoms. The present study was designed to evaluate the effect of acute injection of PCP or a noncompetitive NMDA receptor antagonists (+) MK-80 I on circling preference in rats and on lateralization of activity in dopamine (DA) system of the forebrain. Adult female rats were dosed with PCP (10 mglkg, ip) or (+) MK-801 (0.1 mg/kg, ip), and circling preference was recorded for two hours before sacrifice to determine monoamine levels by HPLCIEC. Animals injected with PCP or (+) MK-801 showed a preference to turn to the left (65%, and 72%, respectively). PCP and (+) MK-801 also produced significant increases of DA metabolites DOPAC and HVA in striatum, nucleus accumbens and olfactory tubercles on both sides of the brain. Further dissection of the striatum into medioventral and dorsolateral regions revealed that HVA was increased bilaterally except in globus pallidus where we found significant increases in DA. DOPAC and HVA only on the left side after PCP and (+) MK-801 administration. These data suggest that PCP and (+) MK-80l produce a greater preference to turn left than right, a finding similar to that found in human psychosis. Furthermore, it is possible that this preference to turn toward the left hemispace is due to an asymmetry in DA function found in the globus pallidus after administration of PCP and similar drugs.
I8-43-31
Behavioral and Neurotransmitter Responses to a "Binge" Pattern of Amphetamine Administration
R. Kuczenski, D.S. Segal. Department of Psychiatry, University of California, San Diego, CA, USA Stimulant-induced psychosis is most frequently associated with "binge" or "run" patterns of stimulant abuse. To further understand the mechanisms responsible for this drug model of paranoid psychosis, we attempted to simulate this pattern of drug exposure in rats. Animals were administered gradually increasing doses (Escalating Dose; ED) of amphetamine (AMPH) prior to repeated injections of a high (8 mglkg) dose of AMPH at two hour intervals. The behavior of the animals was continuously
155
monitored, and. during the AMPH "run", microdialysate dopamine (DA), serotonin (5HT) and norepinephrine (NE) concentrations in several brain regions were concurrently evaluated. Results were compared to animals receiving a single injection of 8 mg/kg AMPH. Baseline levels of the three neurotransmitters were not altered by the ED pretreatment. In response to the first injection of the "run", there were no differences in the neurotransmitter responses between the control and experimental groups, although the ED pretreated rats exhibited typical signs of a sensitized behavioral response. Animals remained in continuous stereotype between successive injections, but, by the fourth injection, both the intensity and the duration of the stereotype had declined. Concomitantly, the peak DA and 5HT concentrations in both caudate-putamen and nucleus accumbens following each AMPH injection progressively declined to less than 60% of the initial response. In contrast, in both hippocampus and frontal cortex, peak NE concentrations did not decline following each AMPH injection. These results suggest that the relationship between NE and DA may be implicated in AMPH-induced psychosis.
I8-43-4 [ Evidence for Sensitization in the EarlyStageof Schizophrenia 1.A. Lieberman. Department of Psychiatry, University ofNorth Carolina, Chapel Hill, NC, USA
Schizophrenia is known to have a chronic course associated with clinical deterioration in a significant proportion of patients. However, the nature of disease progression and its underlying pathophysiological process have not been clearly demonstrated. We will present data from a prospective study of psychobiology in first episode schizophrenics which demonstrates clinical manifestations of disease progression and the underlying pathophysiological mechanisms. We have interpreted preliminary results as indicating that a process of sensitization occurs in the early stage of schizophrenia which is caused by enhanced stimulation of endogenous DA. This process may be compounded subsequently by the effects of chronic neuroleptic treatment. This process underlies the clinical progression of schizophrenia in its early stages. The evidence of this hypothesis follows. I) Duration of psychosis prior to treatment is strongly correlated with time to (P = 0.03) and level of remission (r = 0.41. P = 0.001). 2) Patients have a poorer response to treatment in their subsequent (2nd and 3rd) episodes of illness despite receiving the same treatment as in their first episode, (median time to remission by episode 4 [2.5] weeks, 7 [1.6] weeks, 24 [2.5] weeks, P = 0.001).3) Patients who are sensitive to psychotic exacerbation by methylphenidate are more likely to develop TD with subsequent neuroleptic treatment. Patients with TD when in remission are more susceptible to psychotic exacerbation with methylphenidate (X 2 = 5, P '" 0.03). These and additional results will be presented in the context of whether schizophrenia has a neurodegenerative as well as neurodevelopmental pathophysiological process.
I8-43-51 Predicting Duration of Clinical Stability Following Haloperidol Withdrawal in Schizophrenia
D.P. van Kammen, M.E. Kelley, J.A. Gurklis, M.W. Gilbertson, J.K. Yao, R. Condray, J.L. Peters. Veterans Affairs Medical Center, Pittsburgh, PA, USA To develop a model consisting of behavioral and mono-aminergic variables to identify the risk of symptom exacerbation, the authors obtained in the week prior to haloperidol discontinuation global behavioral ratings and cerebrospinal fluid (CSF) for monoamine metabolites in a sample of 109 DSM III-R schizophrenic patients. Patients were followed until specific criteria for increases in psychosis were met for up to one year, and then returned to antipsychotic drug treatment. Cox regression analysis identified predictors of the survival function. or the probability of relapse at a given time drug free. The best model indicated that increased psychosis, decreased anxiety, an increased CSF homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5HIAA) ratio, and decreased CSF MHPG were associated with early increases in psychosis. Our study indicates that it is possible to identify those patients who are more likely to remain clinically stable without medication. When the model is validated, it will assist clinicians in assessing the relapse risk over time, in lowering doses