- Email: [email protected]
Affective disease and peptides
genetic factors but a mode of genetic transmission cannot yet be established. Recent efforts in genetic epldemiology have focused on genetic hnkage studies as a means of piecing together the environmental and genetic puzzle pieces of schizophrenia However, linkage studies of schizophrenia have been disappointing, suggesting that
advances in diagnosis and nosology are needed to clarify the genetic and phenotypic heterogeneity of the illness We discuss novel approaches to this problem including use of different measures and approaches to pheno~pe defmition.
Neuropathology of schizophrenia Joel E. K l e i n m a n Neuroscience Center, NIMH, NIH, Bethesda, MD, USA Key words Neuropathology, Schizophrenia, Dopamine receptors, Glutamate receptors; Serotonm receptors, Frontal cortex; Temporal cortex
Research in the neuropathology of schlzophrema has led to a number of replicable findings over the last 20 years. These findings revolve both biochemical and structural abnormalities The former involve increases in dopamine type II receptors m basal ganglia/nucleus accumbens. These changes may be secondary to neuroleptic treatment. On the other hand, decreases in frontal and temporal glutamate and serotonln receptors may be related to schizophrenia. Structural abnormalities in schizophrenia, especmlly ventnculomegaly have been demonstrated in over 100
neuroimagmg studies. The most consistent post-mortem finding revolves a reduction m the size of the parahippocampal gyrus which may be associated with neuronal disorganizataon In order to more fully elucidate the pathophysiologyof these abnormalities autoradiographic and m situ hybridization studies are in progress in a number of brain regions (basal ganglia/nucleus accumbens, entorhinal cortex w~th amygdala and hippocampus, dorsolateral prefrontal cortex and brainstem). Results o f these studies will be presented as well
Functional brain imaging in psychiatric disease M a r c u s E. R a i c h l e Washmgton Umverstly School of Medtcme, St Louts, MO 63110, USA Key words Brain imaging, Human behawor, Psychiatric disease
The past 20 years have seen the development of techniques that provide a truly effectwe means of testing specific hypotheses about normal and abnormal human behavior in terms of actwity of underlying brain circuits. These techniques include positron emission tomography (PET) and, more recently, magnetic resonance imaging (MRI)~ By functional imaging I refer specifically to those techniques designed to measure changes in brain blood flow or metabolism that accompany changes in neuronal
actxvity. Recent functional tmaglng studies of familial unipolar depression reveal changes withm spec!fic brain circuits. Knowledge of the role of areas within these circuits in the normal brain, also obtained with PETfunctional imaging, provides an important means of conceptually understanding how a symptom like depression or cognitive impairment in the case of schizophrenia results from altered function in specific brain pathways
Affective disease and peptides Charles B. N e m e r o f f Department of Psychzatry and Behamoral Sc:ences, Emory Umverstty School of Medwme, Atlanta, GA 30322, USA Key words Neuropeptlde-contammgneurons, Mood disorders, Neuroendocnne abnormahtles
In the past decade considerable evidence has accrued concerning a preeminentrole for dysfunction ofneuropeptide-containmg neurons in pathophysiology of mood dis-
orders, particularly depression. The major impetus for these studies have been the well documented neuroendocrine abnormahtles that have been demonstrated to
occur in drug-free depressed patients. These include hyperactivity of the hypothalamlc-pituitary-adrenal (HPA) axis, as well as alterations in both growth hormone secretion and the hypothalamlc-pltultary-thyrold (HPT) axis In brief, HPA axis hyperactivity as demonstrated by increased tmnary free cortisol secretion and dexamethasone non-suppression appears to also be associated with hypersecretion of corticotropln-releasxng factor (CRF) Moreover, the administration of CRF to laboratory animals produces a medley of behavioral effects that are very similar to the signs and symptoms of major depression In ad&tion to hypersecretlon of CRF, there is evidence for alterations in the synaptlc availabihty of both
somatostatm (SRIF) and thyrotropln-releasmg hormone (TRH). A myriad of studies have shown reductions in CSF concentrations of somatostatm in depressed patients, and there are at least two reports of increased concentrations of TRH. In addition, post mortem tissue studies have revealed alterations in receptor density of peptidergic receptors in the CNS of depressed suicide victims and studies are now focusing on mRNA expression of both neuropeptides and their receptors These novel techniques will undoubtedly shed further light on the role of neuropeptldes in the pathophysiology of affectwe &sorders.
Clinical biology Mode of action of antidepressants
Dennis S. Chamey Department of Psychtatr); Yale Umverszty School of Medwme, WestHaven VA Medmal Center, WestHaven, CT, USA Key words Antidepressantdrugs, Mode of actmn, Brain
The major hypotheses of the mode of action of antidepressant drugs has involVed the monoamlne systems in the brain For example, it has been suggested that decreased function of J3- and ct l-adrenerglc receptors, and enhanced neurotransmlsslon through postsynaptlc serotonln receptor subtypes have all been suggested to play an important role In the therapeutic effects of antidepressant drugs. These hypotheses have been primarily generated from prechnical investigations. More recently
clinical research paradigms have been developed to determine which changes in noradrenerglc and serotonerglc function are most related to antidepressant effects and whether or not antidepressant drugs act via common or disparate mechamsms This presentation will review a spectrum of clinical investigations relevant to these questions, including studies determining the effects of depletion of noradrenergic, dopamlne and serotonin concentrations on depressed mood.
Dopamine biology in schizophrenia revisited R.S. Kahn Dzwszon of Psychmtry, Academic Hospttal Utrecht, Utrecht, The Netherlands Key words Dopamme, Schazophrema, Hyperdopammerglcstate
Although the onginal hypothesis that schizophrenia IS a manifestation of a hyperdopamlnerglc state appears too hmited, several new findings suggest that abnormal, although not necessarily increased, dopamIne activity is an important factor in schizophrenia Increased dopamlne activity in schizophrenia is suggested by intracellular recording studies in animals and measurement of dopamine metabolltes in plasma, both indicating that neuroleptics act by reducing dopamine activity In mesohmblc dopamine neurons. Moreover, post-mortem studies report increased dopamxne and homovanlllic acid concentrations in various subcortlcal brain regions and
increased dopamlne receptor density m the brains of schizophrenic patients Decreased dopamlne activity in schizophrenia is suggested by the association between negative symptoms of schizophrenia and decreased function of the prefrontal cortex in these patients. Since prefrontal dopamine neurons appear to inhibit activity of subcortlcal dopamlne neurons, schizophrenia may be characterized by decreased prefrontal dopamine activity (causing negative symptoms) and (consequently) by increased dopamxne activity in mesolimblc dopamlne neurons (causing "positive" symptoms). This would explain the concurrent presence of negative and positive
advances in diagnosis and nosology are needed to clarify the genetic and phenotypic heterogeneity of the illness We discuss novel approaches to this problem including use of different measures and approaches to pheno~pe defmition.
Neuropathology of schizophrenia Joel E. K l e i n m a n Neuroscience Center, NIMH, NIH, Bethesda, MD, USA Key words Neuropathology, Schizophrenia, Dopamine receptors, Glutamate receptors; Serotonm receptors, Frontal cortex; Temporal cortex
Research in the neuropathology of schlzophrema has led to a number of replicable findings over the last 20 years. These findings revolve both biochemical and structural abnormalities The former involve increases in dopamine type II receptors m basal ganglia/nucleus accumbens. These changes may be secondary to neuroleptic treatment. On the other hand, decreases in frontal and temporal glutamate and serotonln receptors may be related to schizophrenia. Structural abnormalities in schizophrenia, especmlly ventnculomegaly have been demonstrated in over 100
neuroimagmg studies. The most consistent post-mortem finding revolves a reduction m the size of the parahippocampal gyrus which may be associated with neuronal disorganizataon In order to more fully elucidate the pathophysiologyof these abnormalities autoradiographic and m situ hybridization studies are in progress in a number of brain regions (basal ganglia/nucleus accumbens, entorhinal cortex w~th amygdala and hippocampus, dorsolateral prefrontal cortex and brainstem). Results o f these studies will be presented as well
Functional brain imaging in psychiatric disease M a r c u s E. R a i c h l e Washmgton Umverstly School of Medtcme, St Louts, MO 63110, USA Key words Brain imaging, Human behawor, Psychiatric disease
The past 20 years have seen the development of techniques that provide a truly effectwe means of testing specific hypotheses about normal and abnormal human behavior in terms of actwity of underlying brain circuits. These techniques include positron emission tomography (PET) and, more recently, magnetic resonance imaging (MRI)~ By functional imaging I refer specifically to those techniques designed to measure changes in brain blood flow or metabolism that accompany changes in neuronal
actxvity. Recent functional tmaglng studies of familial unipolar depression reveal changes withm spec!fic brain circuits. Knowledge of the role of areas within these circuits in the normal brain, also obtained with PETfunctional imaging, provides an important means of conceptually understanding how a symptom like depression or cognitive impairment in the case of schizophrenia results from altered function in specific brain pathways
Affective disease and peptides Charles B. N e m e r o f f Department of Psychzatry and Behamoral Sc:ences, Emory Umverstty School of Medwme, Atlanta, GA 30322, USA Key words Neuropeptlde-contammgneurons, Mood disorders, Neuroendocnne abnormahtles
In the past decade considerable evidence has accrued concerning a preeminentrole for dysfunction ofneuropeptide-containmg neurons in pathophysiology of mood dis-
orders, particularly depression. The major impetus for these studies have been the well documented neuroendocrine abnormahtles that have been demonstrated to
occur in drug-free depressed patients. These include hyperactivity of the hypothalamlc-pituitary-adrenal (HPA) axis, as well as alterations in both growth hormone secretion and the hypothalamlc-pltultary-thyrold (HPT) axis In brief, HPA axis hyperactivity as demonstrated by increased tmnary free cortisol secretion and dexamethasone non-suppression appears to also be associated with hypersecretion of corticotropln-releasxng factor (CRF) Moreover, the administration of CRF to laboratory animals produces a medley of behavioral effects that are very similar to the signs and symptoms of major depression In ad&tion to hypersecretlon of CRF, there is evidence for alterations in the synaptlc availabihty of both
somatostatm (SRIF) and thyrotropln-releasmg hormone (TRH). A myriad of studies have shown reductions in CSF concentrations of somatostatm in depressed patients, and there are at least two reports of increased concentrations of TRH. In addition, post mortem tissue studies have revealed alterations in receptor density of peptidergic receptors in the CNS of depressed suicide victims and studies are now focusing on mRNA expression of both neuropeptides and their receptors These novel techniques will undoubtedly shed further light on the role of neuropeptldes in the pathophysiology of affectwe &sorders.
Clinical biology Mode of action of antidepressants
Dennis S. Chamey Department of Psychtatr); Yale Umverszty School of Medwme, WestHaven VA Medmal Center, WestHaven, CT, USA Key words Antidepressantdrugs, Mode of actmn, Brain
The major hypotheses of the mode of action of antidepressant drugs has involVed the monoamlne systems in the brain For example, it has been suggested that decreased function of J3- and ct l-adrenerglc receptors, and enhanced neurotransmlsslon through postsynaptlc serotonln receptor subtypes have all been suggested to play an important role In the therapeutic effects of antidepressant drugs. These hypotheses have been primarily generated from prechnical investigations. More recently
clinical research paradigms have been developed to determine which changes in noradrenerglc and serotonerglc function are most related to antidepressant effects and whether or not antidepressant drugs act via common or disparate mechamsms This presentation will review a spectrum of clinical investigations relevant to these questions, including studies determining the effects of depletion of noradrenergic, dopamlne and serotonin concentrations on depressed mood.
Dopamine biology in schizophrenia revisited R.S. Kahn Dzwszon of Psychmtry, Academic Hospttal Utrecht, Utrecht, The Netherlands Key words Dopamme, Schazophrema, Hyperdopammerglcstate
Although the onginal hypothesis that schizophrenia IS a manifestation of a hyperdopamlnerglc state appears too hmited, several new findings suggest that abnormal, although not necessarily increased, dopamIne activity is an important factor in schizophrenia Increased dopamlne activity in schizophrenia is suggested by intracellular recording studies in animals and measurement of dopamine metabolltes in plasma, both indicating that neuroleptics act by reducing dopamine activity In mesohmblc dopamine neurons. Moreover, post-mortem studies report increased dopamxne and homovanlllic acid concentrations in various subcortlcal brain regions and
increased dopamlne receptor density m the brains of schizophrenic patients Decreased dopamlne activity in schizophrenia is suggested by the association between negative symptoms of schizophrenia and decreased function of the prefrontal cortex in these patients. Since prefrontal dopamine neurons appear to inhibit activity of subcortlcal dopamlne neurons, schizophrenia may be characterized by decreased prefrontal dopamine activity (causing negative symptoms) and (consequently) by increased dopamxne activity in mesolimblc dopamlne neurons (causing "positive" symptoms). This would explain the concurrent presence of negative and positive