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Subjective effects of neuroleptic drugs
Schizophrenia: New perspectives on etiology and treatment
phyof apical dendrites of hippocampal CASe neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors. NeuroscleflCf/69: 89-98. (2) McKillrick CR.• Blenchard DC. Blanchard RJ. McEwen BS and Sakal RR (1995) Sero• tonin receptor binding In 8 colony model 01 chronic social etreee. BIoi. Psychlalry 37: 383-393.
119-41 Corticosteroid effects on brain S-HT function In man A.H. Young. Department of Psychiatry, School of Neurosciences, University of Newcastle upon Tyne. UK The neuroendocrine response to intravenous infusion of the amino acid L-Tryptophan (L-TRP) Is mediated by the 5-HT1A receptor (Smith et aI. 1991, Psychopharmacology; 103; 140). This response has been found to be blunted in depressive Illness and the degree of attenuation correlates with plasma cortisol levels (Deakin et aI. 1990, Psychopharmacology, 101,85). However, despite strong preclinical evidence It Is unclear if the elevated cor• tisol directly suppresses 5-HTlA receptor function in man. Traskman-Bendz at ai, 1986, (Psychopharmacology, 89. 85) administered the synthetic gluco• corticoid dexamethasone to healthy volunteers and found this enhanced the neuroendocrine responses to L-TRP. The effects of the endogenous gluco• corticoid (cortisol) on 5-HTlA receptor function remain to be determined. The purpose of this experiment was to examine the effects of administration of 100 mgs of cortisol or placebo (both orally) on the neuroendocrine responses to L-TRP Infusion in normal males in a random order, double blind study. Neuroendocrine responses were measured at baseline and over the period of L·TRP infusion. Analysis with repeated measures of ANOVA found a significant effect of drug (F = 9.00, (1.14), P < 0.01), a significant effect of time (F = 17.93, (9.126), P < 0.01) and a significant drug by time Interaction (F '" 4.40 (9.126) P < 0.001). Thus, administration of this dose of cortisol causes an Impairment of the neuroendocrine response to L-TRP similar to that reported In depressed patients. These data suggest that cortisol may have a markedly different effect on 5-HTlA receptor function to that produced by administration of dexamethasone. This may be due to their differing profile and activity at brain corticosteriod receptors. This Interaction between plasma cortisol levels and 5-HTlA receptor function may be central to the pathophysiology of depression.
20. Schizophrenia: New perspectives on etiology and treatment
120-1 1The neurodeve[opmental hypothesis of schizophrenia
D.R. Weinberger. Clinical Brain Disorders Branch, DIRp, NIMH, NIH, Washington, D.C., USA Speculation that schizophrenia Is associated with abnormal brain develop• ment, the so-called neurodevelopmental hypothesis, has become so popular that It is rarely challenged In the literature. This presentation (Weinberger, 1995) will criticaily examine the evidence for this hypothesis, taking primarily the ·devil's adVocate· position. The evidence from neuroimaging studies, while seeming to be Inconsistent with what would be expected of an adult onset brain Injury, are circumstantial with respect to brain development. Studies of prenatal and perinatal Intrauterine events and of premorbld neurological and psychological development are often lumped together as If consistent, yet many are methodologically flawed, and most do not exclude a1tematlve explanations. Evidence from postmortem studies of anomalous cytoarchitecture In limbic and prefrontal cortices Is especially noteworthy, as a developmental defect Is virtually certain if artifacts can be eXCluded. Unfortu• nately the studies responsible for these findings have serious methodological limitations and have not been Independently replicated. The neurobiological plausibility of the hypothesis, which might have been predicted to be its wea~est asp~, has proved surprisingly unshakable in a recent series of animal studies (Ullrank, et ai, 1995). These reports have shown that developmental differentiation of ventral hippocampus can account for much of the neuropharmacology as well as other phenomenology of schizophrenia. Rats with an excitotoxlc lesion of VH during the first week of postnatal life manifest after puberty hyperresponsivity of limbic DA systems to
BIOL. PSYCHIATRY 1997:42:1S--297S
618
experiential and to dopamlnergic stresses and an exaggeration of the effects of NMDA antagonists. They also manifest after puberty a pattern of prepulse inhibition of startle deficits analogous to those reported In patients with schizophrenia. None of these defects are seen in neonaliy lesioned rats prior to pUberty. Moreover, an analogous lesion in adult animals does not produce the same pattem of abnormalities. The effects of the developmental lesion on dopamine related behaviors can be modified In selective genetic strains of rats, illustrating an interaction of genetic predisposition for dopamlnerglc responsivlty and environmental Insults to brain systems Involved in the regulation of such responslvity. Interestingly, these rats grow up to show favorable ameliorative effects after treatment with clozaplne In comparison to haloperidol, perhaps analogous to the favorable treatment effect of clozapine in patients. Social abnormalities and frontal-type cognitive deficits analogous to those observed In patients with schizophrenia also develop. References (1) Ullrank SM. Upska BK, Weinberger DR (1995): Neurodevelopmental animal modele of schizophrenia. Clln Neuroscl3: 98-'04. (2) Weinberger DR (1995): Schizophrenia: From neuropathology to neurodevelopmenL LaflCf/t346: 552-557.
120-21 Subjective effects of neuro[eptlc drugs D. Naber. University of Hamburg. Dept. of Psychiatry. Hamburg. Germany
Clinical trials of potential neuroleptic drugs focus on treatment of acutely psy• chotic patients. However, most schizophrenic patients suffer from a chronic course of Illness and require long-term therapy. Wanted and unwanted effects of maintenance treatment differ markedly from those of short-term treatment and should be Investigated more In the development of anti-schizophrenic drugs. One major problem Is the low compliance (30-40%), explained by extrapyramidal motor side effects (EPMS) and by a reduced well-being, described as "pharmacogenetic depression·, "akinetic depression· or "neu• roleptic-Induced deficit syndrome·. These effects are hardly measurable by the usual clinical rating scales. but probably of major clinical relevance. To Investigate this Issue, a self-rating scale (Ukert. 38 items, 5 sub• factors) was developed to measure subjective well-being under neuroleptic drugs (SWN). First analyses indicate reliability (Cronbach's alpha 0.87-0.91) and practicability: Alter subsidence of acute psychosis, everyone of 230 schizophrenic patients was able to complete the questionnaire in 15-20 minutes. Data. obtained from remitted In-patients shortly before dismissal (n = 112) or from out-patients (n = 118) with subchronlc or chronic course of illness revealed that SWN is barely correlated to psychopathology (positive symptoms r -0.1-0.2; negative symptoms r -0.3--0.4), but much more to quality of life (r = 0.6-0.7). A repeated application after 3 months in 82 patients did not show any altered SWN in those with constant neuroleptic medication, but marked alterations, if dosage or drug was changed. SWN In 40 patients, negatively selected because of therapy-resistance or major slde-effects, and therefore treated with clozapine, was significantly (t = 1.79. P '" 0.03) better than In 40 patients under typical neuroleptics. Moreover, already at dismissal, patients, who 4-6 months later were non-compliant (n = 14), differed significantly (t= 3.21. P =0.02) in SWN. but not In psychiatrists' ratings (BPRS, PANSS) or other self-ratings (POMS, SDS, Bf-S) from those who remained compliant (n = 34). Ongoing studies Indicate that clozapine, another atypical neuroleptic, Is also associated with high compliance, high SWN score and high quality of life. Results on 120 olanzapine patients will be presented. These data agree with clinical experience and indicate that SWN Is a useful tool to Investigate a hitherto neglected dimension. Subjective effects of neuroleptlcs are probably of critical relevance regarding compliance.
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References [1] Naber 0 (1995): A Sen-rating 10 Measure Subjective Effects of Neuroleptic Drugs, Relationships to Objective Psychopathology, Quality of Lne, Compliance and other Clinical variables. International Clinical Psychopharmacology 10. Supplement 3: 133-138.
120-31 The psychoblo[ogy of first episode schizophrenia J. Ueberman, A. Koreen, S. Geisler, R. Bilder, B. Bogerts, J. AIvlr, T. Cooper. University of North Carolina, USA
Heterogeneity has been a consistent problem In the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to
phyof apical dendrites of hippocampal CASe neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors. NeuroscleflCf/69: 89-98. (2) McKillrick CR.• Blenchard DC. Blanchard RJ. McEwen BS and Sakal RR (1995) Sero• tonin receptor binding In 8 colony model 01 chronic social etreee. BIoi. Psychlalry 37: 383-393.
119-41 Corticosteroid effects on brain S-HT function In man A.H. Young. Department of Psychiatry, School of Neurosciences, University of Newcastle upon Tyne. UK The neuroendocrine response to intravenous infusion of the amino acid L-Tryptophan (L-TRP) Is mediated by the 5-HT1A receptor (Smith et aI. 1991, Psychopharmacology; 103; 140). This response has been found to be blunted in depressive Illness and the degree of attenuation correlates with plasma cortisol levels (Deakin et aI. 1990, Psychopharmacology, 101,85). However, despite strong preclinical evidence It Is unclear if the elevated cor• tisol directly suppresses 5-HTlA receptor function in man. Traskman-Bendz at ai, 1986, (Psychopharmacology, 89. 85) administered the synthetic gluco• corticoid dexamethasone to healthy volunteers and found this enhanced the neuroendocrine responses to L-TRP. The effects of the endogenous gluco• corticoid (cortisol) on 5-HTlA receptor function remain to be determined. The purpose of this experiment was to examine the effects of administration of 100 mgs of cortisol or placebo (both orally) on the neuroendocrine responses to L-TRP Infusion in normal males in a random order, double blind study. Neuroendocrine responses were measured at baseline and over the period of L·TRP infusion. Analysis with repeated measures of ANOVA found a significant effect of drug (F = 9.00, (1.14), P < 0.01), a significant effect of time (F = 17.93, (9.126), P < 0.01) and a significant drug by time Interaction (F '" 4.40 (9.126) P < 0.001). Thus, administration of this dose of cortisol causes an Impairment of the neuroendocrine response to L-TRP similar to that reported In depressed patients. These data suggest that cortisol may have a markedly different effect on 5-HTlA receptor function to that produced by administration of dexamethasone. This may be due to their differing profile and activity at brain corticosteriod receptors. This Interaction between plasma cortisol levels and 5-HTlA receptor function may be central to the pathophysiology of depression.
20. Schizophrenia: New perspectives on etiology and treatment
120-1 1The neurodeve[opmental hypothesis of schizophrenia
D.R. Weinberger. Clinical Brain Disorders Branch, DIRp, NIMH, NIH, Washington, D.C., USA Speculation that schizophrenia Is associated with abnormal brain develop• ment, the so-called neurodevelopmental hypothesis, has become so popular that It is rarely challenged In the literature. This presentation (Weinberger, 1995) will criticaily examine the evidence for this hypothesis, taking primarily the ·devil's adVocate· position. The evidence from neuroimaging studies, while seeming to be Inconsistent with what would be expected of an adult onset brain Injury, are circumstantial with respect to brain development. Studies of prenatal and perinatal Intrauterine events and of premorbld neurological and psychological development are often lumped together as If consistent, yet many are methodologically flawed, and most do not exclude a1tematlve explanations. Evidence from postmortem studies of anomalous cytoarchitecture In limbic and prefrontal cortices Is especially noteworthy, as a developmental defect Is virtually certain if artifacts can be eXCluded. Unfortu• nately the studies responsible for these findings have serious methodological limitations and have not been Independently replicated. The neurobiological plausibility of the hypothesis, which might have been predicted to be its wea~est asp~, has proved surprisingly unshakable in a recent series of animal studies (Ullrank, et ai, 1995). These reports have shown that developmental differentiation of ventral hippocampus can account for much of the neuropharmacology as well as other phenomenology of schizophrenia. Rats with an excitotoxlc lesion of VH during the first week of postnatal life manifest after puberty hyperresponsivity of limbic DA systems to
BIOL. PSYCHIATRY 1997:42:1S--297S
618
experiential and to dopamlnergic stresses and an exaggeration of the effects of NMDA antagonists. They also manifest after puberty a pattern of prepulse inhibition of startle deficits analogous to those reported In patients with schizophrenia. None of these defects are seen in neonaliy lesioned rats prior to pUberty. Moreover, an analogous lesion in adult animals does not produce the same pattem of abnormalities. The effects of the developmental lesion on dopamine related behaviors can be modified In selective genetic strains of rats, illustrating an interaction of genetic predisposition for dopamlnerglc responsivlty and environmental Insults to brain systems Involved in the regulation of such responslvity. Interestingly, these rats grow up to show favorable ameliorative effects after treatment with clozaplne In comparison to haloperidol, perhaps analogous to the favorable treatment effect of clozapine in patients. Social abnormalities and frontal-type cognitive deficits analogous to those observed In patients with schizophrenia also develop. References (1) Ullrank SM. Upska BK, Weinberger DR (1995): Neurodevelopmental animal modele of schizophrenia. Clln Neuroscl3: 98-'04. (2) Weinberger DR (1995): Schizophrenia: From neuropathology to neurodevelopmenL LaflCf/t346: 552-557.
120-21 Subjective effects of neuro[eptlc drugs D. Naber. University of Hamburg. Dept. of Psychiatry. Hamburg. Germany
Clinical trials of potential neuroleptic drugs focus on treatment of acutely psy• chotic patients. However, most schizophrenic patients suffer from a chronic course of Illness and require long-term therapy. Wanted and unwanted effects of maintenance treatment differ markedly from those of short-term treatment and should be Investigated more In the development of anti-schizophrenic drugs. One major problem Is the low compliance (30-40%), explained by extrapyramidal motor side effects (EPMS) and by a reduced well-being, described as "pharmacogenetic depression·, "akinetic depression· or "neu• roleptic-Induced deficit syndrome·. These effects are hardly measurable by the usual clinical rating scales. but probably of major clinical relevance. To Investigate this Issue, a self-rating scale (Ukert. 38 items, 5 sub• factors) was developed to measure subjective well-being under neuroleptic drugs (SWN). First analyses indicate reliability (Cronbach's alpha 0.87-0.91) and practicability: Alter subsidence of acute psychosis, everyone of 230 schizophrenic patients was able to complete the questionnaire in 15-20 minutes. Data. obtained from remitted In-patients shortly before dismissal (n = 112) or from out-patients (n = 118) with subchronlc or chronic course of illness revealed that SWN is barely correlated to psychopathology (positive symptoms r -0.1-0.2; negative symptoms r -0.3--0.4), but much more to quality of life (r = 0.6-0.7). A repeated application after 3 months in 82 patients did not show any altered SWN in those with constant neuroleptic medication, but marked alterations, if dosage or drug was changed. SWN In 40 patients, negatively selected because of therapy-resistance or major slde-effects, and therefore treated with clozapine, was significantly (t = 1.79. P '" 0.03) better than In 40 patients under typical neuroleptics. Moreover, already at dismissal, patients, who 4-6 months later were non-compliant (n = 14), differed significantly (t= 3.21. P =0.02) in SWN. but not In psychiatrists' ratings (BPRS, PANSS) or other self-ratings (POMS, SDS, Bf-S) from those who remained compliant (n = 34). Ongoing studies Indicate that clozapine, another atypical neuroleptic, Is also associated with high compliance, high SWN score and high quality of life. Results on 120 olanzapine patients will be presented. These data agree with clinical experience and indicate that SWN Is a useful tool to Investigate a hitherto neglected dimension. Subjective effects of neuroleptlcs are probably of critical relevance regarding compliance.
=
=
References [1] Naber 0 (1995): A Sen-rating 10 Measure Subjective Effects of Neuroleptic Drugs, Relationships to Objective Psychopathology, Quality of Lne, Compliance and other Clinical variables. International Clinical Psychopharmacology 10. Supplement 3: 133-138.
120-31 The psychoblo[ogy of first episode schizophrenia J. Ueberman, A. Koreen, S. Geisler, R. Bilder, B. Bogerts, J. AIvlr, T. Cooper. University of North Carolina, USA
Heterogeneity has been a consistent problem In the research and treatment of schizophrenia. Despite marked variation in the onset, phenomenology, treatment response and outcome of schizophrenic patients, our ability to