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Biochemical aspects of schizophrenia
Psychoneuroendocrinology,1975, Vol. 1. pp. 199-201. Perl~amon Press. Printed in Great Britain
MEETING REPORT BIOCHEMICAL ASPECTS OF SCHIZOPHRENIA
Alabama, April 1975
A WORKSHOP on the biochemical aspects of schizophrenia and its treatment was held at Willow Point, Alabama, I0-I I April, 1975. It was sponsored jointlyby the International Societyof Psychoneuroendocrinology, the Department of Psychiatry,Universityof Alabama in Birmingham and the Jefferson County Mental Health Association, and was organized by J. Smythies, R. Bradley and P. Linton. Scientistsattending the workshop surveyed the present state of knowledge in this fieldand discussed promising areas of further development. S. Kety summarized the following established data as seemingly relevant to the specification of possible biochemical abnormalities in the group of schizophrenias: (I) several drugs, i.e.the phenothiazines, thioxanthenes, butyrophenones and several other types of neurolcptic compounds, have specificanti-psychoticeffectsand share a common mode of action, the blockade of transmission at dopamine synapses; (2) the psychosis associated with chronic amphetamine abuse closelyresembles paranoid schizophrenia and responds to the same neuroleptic drugs; (3) there is today good evidence that genetic factors operate in chronic process schizophrenia;'(4) several groups have confirmed and extended the original report by Wyatt and Murphy that monoamine oxidase 0VIAO) activity is reduced in platelets from some chronic schizophrenics; however Friedhoff reports a negative finding.Thus more work remains to be done; (5) the hypothesis that abnormal transmethylation of amines may occur in schizophrenia is stillusefulin directing research. Reports have appeared based on gas chromatography and mass spectrometry that the hallucinogen dimethyltryptamine (DMT) ispresent in body fluidsof schizophrenics; (6) severalcompounds, includingnotably 1-methionine,amphetamine and M A O inhibitors, aggravate schizophrenic symptoms; (7) schizophrenicslack the normal rebound of R E M sleep following its deprivation;(8) a case recentlyreported by Freeman and his colleagues and originally diagnosed as schizophrenic, was found to have a new form of homocysteinuria without elevated blood methionine, due to a defect in the enzyme methylene tetrahydrofolatereductase. This psychosis responded satisfactorilyto treatment with folic acid. R. Baldessarini,S. Matthysse, K. Fuxe, A. Friedhoff and I. Kopin surveyed the evidence relating to excessive activityof dopamine neurotransmission in schizophrenia. All antipsychotic drugs block dopamin¢ (DA) receptors,inhibit D A release and by a feed-back effectincreasethe turnover of brain D A more or lessin proportion to theirclinicalefficacy. Tolerance to these effectsappears in the striatalD A system but not in the limbic D A system. The lattereffectmay be correlatedwith the sustained antipsychoticeffectsof these drugs ~ c I/2--o 199
200
MEET~GR~PORT
and the former, with their Parkinsonian side-effects, to which tolerance occurs. However, direct evidence for disturbed DA function in schizophrenia is, as yet, lacking, although DAreleasing stimulants such as amphetamine and methylphenidate can worsen schizophrenia. There is no clear abnormality of DA-turnover (estimated by the rise of its metabolite HVA in the CSF following probenecid) in schizophrenics; DA-inhibited prolactin response is also normal and no consistent differences have been observed in post-mortem brain amine levels. Fuxe described his work with H6k£elt on the promising new therapeutic possibilities arising out of the discovery that an important descending inhibitory pathway to the DAcell bodies in ventral midbrain is mediated by GABA. Therefore, if dopaminergic neurons are overactive in schizophrenia, then a centrally acting GABA agonist might be of therapeutic benefit. Moreover, one such agent (p-chlorophenyl-GABA) can block the pimozideinduced acceleration of DA turnover in limbic DA terminals, but not in caudate DA terminals. Thus, treatment with a neuroleptic drug plus a GABA-agonist should prevent compensatory increased availability of DA in response to the anti-DA antipsychotic agent in the limbic system, but allow it in the striatum. This should decrease Parkinsonian sideeffects and might even be expected to reduce the incidence of tardive dyskinesia, while potentiating antipsychotic effects. Encouraging preliminary clinical results with p-chlorophenyl-GABA in Sweden have recently been reported. Matthysse presented a model for the regulation of the dopaminergic system involving a multineuronal feed-back loop in which both ACh and GABA neurons play a part, that helps to explain the effects of cholinergic and GABA mimetic agents on dopamine turnover and the reported ability of physostigmine to reverse the schizophrenic-worsening actions of methylphenidate. It also leads to the specific prediction that pilocarpine might be clinically useful in schizophrenia. Friedhoff related the dopamine hypothesis to the pathogenesis of the symptoms of schizophrenia and suggested that altered DA function may represent compensatory mechanisms for a basic lesion elsewhere. Smythies raised the point that pimozide--a relatively pure DA receptor blocker--seems to have a different clinical effect from phenothiazines, which are norepinephrine (NE) blockers as well. The latter are more effective in acute cases of psychosis showing mainly "positive" symptoms (delusions, hallucinations, agitation), whereas pimozide appears to bemore effective in chronicwithdrawn schizophrenics with mainly"negative" symptoms (ruminative withdrawal and passivity). Thus something more than an overactive DA system may be involved in the former cases. K. Fuxe, J. Beaton, F. Benington, T. Christian, L. Corbett, L. Mandell and R. Morin discussed the possible involvement of serotonergic mechanisms. In most brain areas hallucinogens such as DMT and d-LSD have 5-HT-like action. Christian described binding experiments in synaptosomes that show that d-LSD and 5-HT bind to different high affinity binding sites. Moreover, a drug "THPC" (based chemically on the isolated D ring of d-LSD), which blocks the behavioral effects of d-LSD, also blocks d-LSD binding but not 5-HT binding to synaptosomes. Drugs structurally related to THPC may offer therapeutic potential in schzophrenia, particularly if reports, discussed at the meeting, are correct that N,N-dimethyltryptamine (DMT) and related hallucinogens are present in schizophrenic blood and possibly CSF. D. Murphy presented the most recent data on MAO activity in platelets. These are reported to be lower than normal in bipolar manic depressives (58 ~ of controls) and
MEETING REPORT
201
chronic schizophrenics (41%) but not in unipolar depressives or acute schizophrenia. Friedhoff presented evidence that 5-methyltetrahydrofolate is not a methyl donor in formation of hallucinogens from biogenic amines. A. MandeU reviewed the occurrence of indoleamine-N-methyltransferase in human tissues, including brain, where it occurs in low activity. He also stressed the possible relevance to schizophrenia of fl-carbolines and other condensation products of dopamine or 5-HT and formaldehyde, which can be produced enzymatically from N-methyltetrahydrofolate (MTHF). The possible role of folio acid and the one-carbon cycle were discussed by S. Matthysse, W. Bridgers and J. Beaton. The single best established fact about the abnormal physiology of schizophrenics is the discovery by Kety and his colleagues that some 40 ~ of chronic schizophrenics respond to L-methionine with an acute psychosis. Beaton reported that mice and rats respond to methionine in behavioral tests in the same manner as to amphetamine and several hallucinogens. This effect is blocked by serine, suggesting that a disturbance of the one-carbon cycle is somehow involved. Bridgers reported a high concentration of folio acid in isolated nerve endings (synaptosomes) from brain tissue, which suggests a role for one-carbon cycle metabolism in neurotransmitter function. Leading from this work a clinical trial of 1-serine in schizophrenia is currently under way. M. Lipton and J. Saavedra surveyed the contribution of endocrinology and some new regional neurochemical techniques. A number of sophisticated new investigative procedures in schizophrenic patients were suggested which permit an appraisal of central synaptic functions based on peripherally assayable pituitary hormonal responses. A. Goldstein and R. Aeton reviewed the impact of modern immunology and suggested its potential contributions to developmental aspects of brain structure. Goldstein is investigating the responses of thymus-type lymphocytes (T-cells) in schizophrenia following Russian claims that serum from schizophrenics will induce lysis in mouse thymoeytes. Acton proposed a new theory of schizophrenogenesis based on the discovery that T-cells and neurones share an antigenic group. The recognition problems involved in the construction of proper neuronal connections may be chemically similar to those involved in immune responses. Some cases of schizophrenia may result from faulty chemical coding on neuronal surfaces leading to "mis-wiring" of central connections. V. Pegram, J. Beaton and T. Vaughan discussed the relationship of abnormal sleep EEGs to schizophrenia, including the lack of REM rebound following REM deprivation in patients, and the reduction of sleeping time induced by methionine in mice and the increased percentage REM induced by nicotinamide in rodents and humans.
Department of Psychiatry and the Neurosciences Program University of Alabama in Birmingham
J. R. SMYTHIES R . J . BRADLEY P. H. LINTON
MEETING REPORT BIOCHEMICAL ASPECTS OF SCHIZOPHRENIA
Alabama, April 1975
A WORKSHOP on the biochemical aspects of schizophrenia and its treatment was held at Willow Point, Alabama, I0-I I April, 1975. It was sponsored jointlyby the International Societyof Psychoneuroendocrinology, the Department of Psychiatry,Universityof Alabama in Birmingham and the Jefferson County Mental Health Association, and was organized by J. Smythies, R. Bradley and P. Linton. Scientistsattending the workshop surveyed the present state of knowledge in this fieldand discussed promising areas of further development. S. Kety summarized the following established data as seemingly relevant to the specification of possible biochemical abnormalities in the group of schizophrenias: (I) several drugs, i.e.the phenothiazines, thioxanthenes, butyrophenones and several other types of neurolcptic compounds, have specificanti-psychoticeffectsand share a common mode of action, the blockade of transmission at dopamine synapses; (2) the psychosis associated with chronic amphetamine abuse closelyresembles paranoid schizophrenia and responds to the same neuroleptic drugs; (3) there is today good evidence that genetic factors operate in chronic process schizophrenia;'(4) several groups have confirmed and extended the original report by Wyatt and Murphy that monoamine oxidase 0VIAO) activity is reduced in platelets from some chronic schizophrenics; however Friedhoff reports a negative finding.Thus more work remains to be done; (5) the hypothesis that abnormal transmethylation of amines may occur in schizophrenia is stillusefulin directing research. Reports have appeared based on gas chromatography and mass spectrometry that the hallucinogen dimethyltryptamine (DMT) ispresent in body fluidsof schizophrenics; (6) severalcompounds, includingnotably 1-methionine,amphetamine and M A O inhibitors, aggravate schizophrenic symptoms; (7) schizophrenicslack the normal rebound of R E M sleep following its deprivation;(8) a case recentlyreported by Freeman and his colleagues and originally diagnosed as schizophrenic, was found to have a new form of homocysteinuria without elevated blood methionine, due to a defect in the enzyme methylene tetrahydrofolatereductase. This psychosis responded satisfactorilyto treatment with folic acid. R. Baldessarini,S. Matthysse, K. Fuxe, A. Friedhoff and I. Kopin surveyed the evidence relating to excessive activityof dopamine neurotransmission in schizophrenia. All antipsychotic drugs block dopamin¢ (DA) receptors,inhibit D A release and by a feed-back effectincreasethe turnover of brain D A more or lessin proportion to theirclinicalefficacy. Tolerance to these effectsappears in the striatalD A system but not in the limbic D A system. The lattereffectmay be correlatedwith the sustained antipsychoticeffectsof these drugs ~ c I/2--o 199
200
MEET~GR~PORT
and the former, with their Parkinsonian side-effects, to which tolerance occurs. However, direct evidence for disturbed DA function in schizophrenia is, as yet, lacking, although DAreleasing stimulants such as amphetamine and methylphenidate can worsen schizophrenia. There is no clear abnormality of DA-turnover (estimated by the rise of its metabolite HVA in the CSF following probenecid) in schizophrenics; DA-inhibited prolactin response is also normal and no consistent differences have been observed in post-mortem brain amine levels. Fuxe described his work with H6k£elt on the promising new therapeutic possibilities arising out of the discovery that an important descending inhibitory pathway to the DAcell bodies in ventral midbrain is mediated by GABA. Therefore, if dopaminergic neurons are overactive in schizophrenia, then a centrally acting GABA agonist might be of therapeutic benefit. Moreover, one such agent (p-chlorophenyl-GABA) can block the pimozideinduced acceleration of DA turnover in limbic DA terminals, but not in caudate DA terminals. Thus, treatment with a neuroleptic drug plus a GABA-agonist should prevent compensatory increased availability of DA in response to the anti-DA antipsychotic agent in the limbic system, but allow it in the striatum. This should decrease Parkinsonian sideeffects and might even be expected to reduce the incidence of tardive dyskinesia, while potentiating antipsychotic effects. Encouraging preliminary clinical results with p-chlorophenyl-GABA in Sweden have recently been reported. Matthysse presented a model for the regulation of the dopaminergic system involving a multineuronal feed-back loop in which both ACh and GABA neurons play a part, that helps to explain the effects of cholinergic and GABA mimetic agents on dopamine turnover and the reported ability of physostigmine to reverse the schizophrenic-worsening actions of methylphenidate. It also leads to the specific prediction that pilocarpine might be clinically useful in schizophrenia. Friedhoff related the dopamine hypothesis to the pathogenesis of the symptoms of schizophrenia and suggested that altered DA function may represent compensatory mechanisms for a basic lesion elsewhere. Smythies raised the point that pimozide--a relatively pure DA receptor blocker--seems to have a different clinical effect from phenothiazines, which are norepinephrine (NE) blockers as well. The latter are more effective in acute cases of psychosis showing mainly "positive" symptoms (delusions, hallucinations, agitation), whereas pimozide appears to bemore effective in chronicwithdrawn schizophrenics with mainly"negative" symptoms (ruminative withdrawal and passivity). Thus something more than an overactive DA system may be involved in the former cases. K. Fuxe, J. Beaton, F. Benington, T. Christian, L. Corbett, L. Mandell and R. Morin discussed the possible involvement of serotonergic mechanisms. In most brain areas hallucinogens such as DMT and d-LSD have 5-HT-like action. Christian described binding experiments in synaptosomes that show that d-LSD and 5-HT bind to different high affinity binding sites. Moreover, a drug "THPC" (based chemically on the isolated D ring of d-LSD), which blocks the behavioral effects of d-LSD, also blocks d-LSD binding but not 5-HT binding to synaptosomes. Drugs structurally related to THPC may offer therapeutic potential in schzophrenia, particularly if reports, discussed at the meeting, are correct that N,N-dimethyltryptamine (DMT) and related hallucinogens are present in schizophrenic blood and possibly CSF. D. Murphy presented the most recent data on MAO activity in platelets. These are reported to be lower than normal in bipolar manic depressives (58 ~ of controls) and
MEETING REPORT
201
chronic schizophrenics (41%) but not in unipolar depressives or acute schizophrenia. Friedhoff presented evidence that 5-methyltetrahydrofolate is not a methyl donor in formation of hallucinogens from biogenic amines. A. MandeU reviewed the occurrence of indoleamine-N-methyltransferase in human tissues, including brain, where it occurs in low activity. He also stressed the possible relevance to schizophrenia of fl-carbolines and other condensation products of dopamine or 5-HT and formaldehyde, which can be produced enzymatically from N-methyltetrahydrofolate (MTHF). The possible role of folio acid and the one-carbon cycle were discussed by S. Matthysse, W. Bridgers and J. Beaton. The single best established fact about the abnormal physiology of schizophrenics is the discovery by Kety and his colleagues that some 40 ~ of chronic schizophrenics respond to L-methionine with an acute psychosis. Beaton reported that mice and rats respond to methionine in behavioral tests in the same manner as to amphetamine and several hallucinogens. This effect is blocked by serine, suggesting that a disturbance of the one-carbon cycle is somehow involved. Bridgers reported a high concentration of folio acid in isolated nerve endings (synaptosomes) from brain tissue, which suggests a role for one-carbon cycle metabolism in neurotransmitter function. Leading from this work a clinical trial of 1-serine in schizophrenia is currently under way. M. Lipton and J. Saavedra surveyed the contribution of endocrinology and some new regional neurochemical techniques. A number of sophisticated new investigative procedures in schizophrenic patients were suggested which permit an appraisal of central synaptic functions based on peripherally assayable pituitary hormonal responses. A. Goldstein and R. Aeton reviewed the impact of modern immunology and suggested its potential contributions to developmental aspects of brain structure. Goldstein is investigating the responses of thymus-type lymphocytes (T-cells) in schizophrenia following Russian claims that serum from schizophrenics will induce lysis in mouse thymoeytes. Acton proposed a new theory of schizophrenogenesis based on the discovery that T-cells and neurones share an antigenic group. The recognition problems involved in the construction of proper neuronal connections may be chemically similar to those involved in immune responses. Some cases of schizophrenia may result from faulty chemical coding on neuronal surfaces leading to "mis-wiring" of central connections. V. Pegram, J. Beaton and T. Vaughan discussed the relationship of abnormal sleep EEGs to schizophrenia, including the lack of REM rebound following REM deprivation in patients, and the reduction of sleeping time induced by methionine in mice and the increased percentage REM induced by nicotinamide in rodents and humans.
Department of Psychiatry and the Neurosciences Program University of Alabama in Birmingham
J. R. SMYTHIES R . J . BRADLEY P. H. LINTON