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Tryptophan depletion paradigm: Implications for schizophrenia
SATURDAY, MAY 21
Approximately, one-half of the patients were detected as polyuric in each of the four determinations using Goldman's method, one-third using Koczapski's, and one-quarter using Vieweg's method. Therefore, further studies are needed to establish the validity of UCR methods for diagnosing polyuria.
318. TRYPTOPHAN DEPLETION PARADIGM: IMPLICATIONS FOR SCHIZOPHRENIA D. C. D'Souza, R. Gil, A. Abi-Dargham, L. Karper, D. Abi-Saab, K. Morrissey, L. Brenner, D. Charney, & J. Krystal Yale University School of Medicine, Department of Psychiatry / West Haven Veterans Affairs Medical Center The tryptophan depletion paradigm that causes reduction of central serotonin levels by dietary manipulation, transiently exacerbates depression in patients with Major Depression and Bipolar Depression. The neurobiology of depression & negative symptoms occurring in schizophrenia and schizoaffective disorder is poorly characterized. Further, the clinical similagities and coexistence of depression, negative symptoms and neuroleptic induced parkinsonism make the differentiation of these syndromes difficult. The tryptophan depletion paradigm has not been tested in this context. This study aimed to evaluate the effects of transient serotonin reduction on depression symptoms and negative symptoms in neuroleptic treated patients diagnosed with schizophrenia or schizoaffective disorder, before and during treatment with selective serotonin reuptake inhibiting antidepressants (SSRls). During treatment with neuroleptic only, patients underwent in random order tryptophan depletion or placebo depletion separated by a week. The same was done during treatment with neuroleptic and SSRIs. Each test period consisted of three test days: day #1: diet and baseline ratings, day 02: tryptophan depleting amino acid drink, and day #3: follow-up ratings. Outcome measures included: !) behavioral ratings for depression, negative/positive symptoms, 2) movement disorder ratings, 3) memory tests, 4) hormonal, and 5) neurochemical: tryptophan levels and neurotransmitter metabolite levels. Data suggests that tryptophan depletion exacerbated symptoms of depression without effecting psychosis. More patients need to be studied to determine whether this paradigm can be used to I) further characterize the neurobiology of depression, and 2) to differentiate negative symptoms from depression, in the context of s~;hizophreniaand schizoaffective.
319. A NEUROHISTOLOGICAL STUDY OF ELDERLY INSTITUTIONALIZED SCHIZOPHRENIC AND AFFECTIVE DISORDER PATIENTS J. Golier ! , D. Mavidson l, V.H. Haroutunian I, P. Powchik l, D. Purohit2, D. Perl 2, & K.L.Davis 1 IDeoartment of Psychiatry and 2the Neuropathology Division of the ~ p a r t m e n t of'Pathology Mount Sinai School of Medicine, New York, NY Aizheimer'sdisease (AD)-like neuropathology and cognitive dysfunction was studied in elderly institutionalized schizophrenics (N-59, age 76.8:!:! 1.5 years) and nonschizophrenics (primarily affective disorders) (N - ! i, age 71.4:!:1i.2 years). Brain tissue was examined for AD-like pathology using Katchaturian and CERAD (Consortium to Establish a Registry of Alzheimer's Disease) criteria. Four schizophrenics (7%) and no affective patients met Katchaturian criteria for AD, which are based on
BIOL PSYCHIATRY ! 994;35:6 ! 5-747
703
senile plaques and neurofibrillary tangles. However, applying CERAD criteria, which are based primarily on neocortical plaque scores, 46% of all schizophrenics had a neuropathologic diagnosis of possible, probable, or definite AD. Of these cases, only four (7%) met CERAD criteria for definite AD. 15% of schizophrenics had other dementing conditions, and 39% had no significant neuropathology. Among affecfive patients, 18% had AD-like neuropathology and 82% had no significantneuropathology. Among those cognitively impaired, 49% of schizophrenics and 33% of affective patients had AD-like pathology. Neither plaques nor tangles correlated with multiple measures of cognitive impairment. The mean MMSE (8.8:1:8.0) and Clinical Dementia Rating Score (2.3+1.1) of schizophrenics with AD-like pathology did not differ significantly from the scores of those without significant neuropathology, or those with other dementing conditions. These results suggest that few elderly institutionalized schizophrenics meet histologic criteria for AD when comprehensive criteria, such as Katchaturian's, are applied. However, a considerable proportion have elevated neocortical plaque scores by CERAD criteria. AD and other histopathologically identifiable causes of dementia appear insufficient to explain cognitive dysfunction in elderly schizophrenics, which is as severe in those without significant neuropathology as in those with coexisting neuropathology. These results suggest that the most severe forms of schizophrenia and affective disorder may be associated with profound cognitive dysfunction in the absence of AD.like or other currently recognizable neuropathological processes.
SATURDAY, MAY 21 320. 31 PHOSPHOROUS MRSI OF THE TEMPORAL LOBES IN CHRONIC SCHIZOPHRENIA R.F. Deicken 1'2,3,G. Calabrese I, E. Merrin 2,3, W. Dillon 4, M.W. Weiner 1,4,s, & G. Fein 2.3 ~Magnetic Resonance Unit and 2Psychiatry Service, San Francisco Dept. of Veterans Affairs Medical Center SFVAMC, and the Departments of 3psychiatry, 4Radiology, and SMedicine, University of California, San Francisco, CA The objective of this study was to determine if there was asymmetry of brain high energy phosphorous and phospholipid metabolism in the temporai lobes of patients with schizophrenia using in-vivo 31Phosphorous (3tp) Magnetic Resonance Spectroscopic Imaging (MRSl). Eighteen chronic schizophrenic patients and 14 control subjects underwent 3tp MRSl using a Philips Gyroscan MRI/MRS system at the SFVAMC Magnetic Resonance Unit. The schizophrenic patients were diagnosed by the Structured Clinical Interview for DSM-ilI-R (SCID) and clinically rated using the Brief Psychiatric Rating Scale (BPRS). 3tp MRSi was performed using a spin-echo sequence (TR-350 ms, TE-3.5 ms) with 3-dimensional gradient phase encoding and MRS! data volumes were processed on a micro-VAX workstation. 31p spectra selected from a single voxel (25 cm3) on T2 weighted MR axial images in each of the right and left temporal lobes were fit by NMR-! curve fitting software. No structural abnormalities, anatomical asymmetries, or atrophy of the temporal lobes were found on MRI images of the patients and controls. MANOVA analysis revealed that compared to the left temporal lobe the schizophrenic patients demonstrated significantly increased right temporal lobe phosphocreatine/adenosine triphosphate (PCr/ATP) (p-.003), pbosphocreatine/inorganic phosphate (PCr/Pi) (p-.007) as well as increased right temporal PCr (p-.003) and decreased right temporal ATP (i)-.009). No such asymmetry was noted in the control groups. The thinking disturbance subscale of the BPRS was highly correlated with left temporal PCr (r--.65, p-.003) and the degree of temporal lobe PCr asymmetry (R-L/R+L) (rm.68, p-.002). The results provide support for temporal lobe metabolic asymmetry in schizophrenia and its possible association with clinical symptoms.
Approximately, one-half of the patients were detected as polyuric in each of the four determinations using Goldman's method, one-third using Koczapski's, and one-quarter using Vieweg's method. Therefore, further studies are needed to establish the validity of UCR methods for diagnosing polyuria.
318. TRYPTOPHAN DEPLETION PARADIGM: IMPLICATIONS FOR SCHIZOPHRENIA D. C. D'Souza, R. Gil, A. Abi-Dargham, L. Karper, D. Abi-Saab, K. Morrissey, L. Brenner, D. Charney, & J. Krystal Yale University School of Medicine, Department of Psychiatry / West Haven Veterans Affairs Medical Center The tryptophan depletion paradigm that causes reduction of central serotonin levels by dietary manipulation, transiently exacerbates depression in patients with Major Depression and Bipolar Depression. The neurobiology of depression & negative symptoms occurring in schizophrenia and schizoaffective disorder is poorly characterized. Further, the clinical similagities and coexistence of depression, negative symptoms and neuroleptic induced parkinsonism make the differentiation of these syndromes difficult. The tryptophan depletion paradigm has not been tested in this context. This study aimed to evaluate the effects of transient serotonin reduction on depression symptoms and negative symptoms in neuroleptic treated patients diagnosed with schizophrenia or schizoaffective disorder, before and during treatment with selective serotonin reuptake inhibiting antidepressants (SSRls). During treatment with neuroleptic only, patients underwent in random order tryptophan depletion or placebo depletion separated by a week. The same was done during treatment with neuroleptic and SSRIs. Each test period consisted of three test days: day #1: diet and baseline ratings, day 02: tryptophan depleting amino acid drink, and day #3: follow-up ratings. Outcome measures included: !) behavioral ratings for depression, negative/positive symptoms, 2) movement disorder ratings, 3) memory tests, 4) hormonal, and 5) neurochemical: tryptophan levels and neurotransmitter metabolite levels. Data suggests that tryptophan depletion exacerbated symptoms of depression without effecting psychosis. More patients need to be studied to determine whether this paradigm can be used to I) further characterize the neurobiology of depression, and 2) to differentiate negative symptoms from depression, in the context of s~;hizophreniaand schizoaffective.
319. A NEUROHISTOLOGICAL STUDY OF ELDERLY INSTITUTIONALIZED SCHIZOPHRENIC AND AFFECTIVE DISORDER PATIENTS J. Golier ! , D. Mavidson l, V.H. Haroutunian I, P. Powchik l, D. Purohit2, D. Perl 2, & K.L.Davis 1 IDeoartment of Psychiatry and 2the Neuropathology Division of the ~ p a r t m e n t of'Pathology Mount Sinai School of Medicine, New York, NY Aizheimer'sdisease (AD)-like neuropathology and cognitive dysfunction was studied in elderly institutionalized schizophrenics (N-59, age 76.8:!:! 1.5 years) and nonschizophrenics (primarily affective disorders) (N - ! i, age 71.4:!:1i.2 years). Brain tissue was examined for AD-like pathology using Katchaturian and CERAD (Consortium to Establish a Registry of Alzheimer's Disease) criteria. Four schizophrenics (7%) and no affective patients met Katchaturian criteria for AD, which are based on
BIOL PSYCHIATRY ! 994;35:6 ! 5-747
703
senile plaques and neurofibrillary tangles. However, applying CERAD criteria, which are based primarily on neocortical plaque scores, 46% of all schizophrenics had a neuropathologic diagnosis of possible, probable, or definite AD. Of these cases, only four (7%) met CERAD criteria for definite AD. 15% of schizophrenics had other dementing conditions, and 39% had no significant neuropathology. Among affecfive patients, 18% had AD-like neuropathology and 82% had no significantneuropathology. Among those cognitively impaired, 49% of schizophrenics and 33% of affective patients had AD-like pathology. Neither plaques nor tangles correlated with multiple measures of cognitive impairment. The mean MMSE (8.8:1:8.0) and Clinical Dementia Rating Score (2.3+1.1) of schizophrenics with AD-like pathology did not differ significantly from the scores of those without significant neuropathology, or those with other dementing conditions. These results suggest that few elderly institutionalized schizophrenics meet histologic criteria for AD when comprehensive criteria, such as Katchaturian's, are applied. However, a considerable proportion have elevated neocortical plaque scores by CERAD criteria. AD and other histopathologically identifiable causes of dementia appear insufficient to explain cognitive dysfunction in elderly schizophrenics, which is as severe in those without significant neuropathology as in those with coexisting neuropathology. These results suggest that the most severe forms of schizophrenia and affective disorder may be associated with profound cognitive dysfunction in the absence of AD.like or other currently recognizable neuropathological processes.
SATURDAY, MAY 21 320. 31 PHOSPHOROUS MRSI OF THE TEMPORAL LOBES IN CHRONIC SCHIZOPHRENIA R.F. Deicken 1'2,3,G. Calabrese I, E. Merrin 2,3, W. Dillon 4, M.W. Weiner 1,4,s, & G. Fein 2.3 ~Magnetic Resonance Unit and 2Psychiatry Service, San Francisco Dept. of Veterans Affairs Medical Center SFVAMC, and the Departments of 3psychiatry, 4Radiology, and SMedicine, University of California, San Francisco, CA The objective of this study was to determine if there was asymmetry of brain high energy phosphorous and phospholipid metabolism in the temporai lobes of patients with schizophrenia using in-vivo 31Phosphorous (3tp) Magnetic Resonance Spectroscopic Imaging (MRSl). Eighteen chronic schizophrenic patients and 14 control subjects underwent 3tp MRSl using a Philips Gyroscan MRI/MRS system at the SFVAMC Magnetic Resonance Unit. The schizophrenic patients were diagnosed by the Structured Clinical Interview for DSM-ilI-R (SCID) and clinically rated using the Brief Psychiatric Rating Scale (BPRS). 3tp MRSi was performed using a spin-echo sequence (TR-350 ms, TE-3.5 ms) with 3-dimensional gradient phase encoding and MRS! data volumes were processed on a micro-VAX workstation. 31p spectra selected from a single voxel (25 cm3) on T2 weighted MR axial images in each of the right and left temporal lobes were fit by NMR-! curve fitting software. No structural abnormalities, anatomical asymmetries, or atrophy of the temporal lobes were found on MRI images of the patients and controls. MANOVA analysis revealed that compared to the left temporal lobe the schizophrenic patients demonstrated significantly increased right temporal lobe phosphocreatine/adenosine triphosphate (PCr/ATP) (p-.003), pbosphocreatine/inorganic phosphate (PCr/Pi) (p-.007) as well as increased right temporal PCr (p-.003) and decreased right temporal ATP (i)-.009). No such asymmetry was noted in the control groups. The thinking disturbance subscale of the BPRS was highly correlated with left temporal PCr (r--.65, p-.003) and the degree of temporal lobe PCr asymmetry (R-L/R+L) (rm.68, p-.002). The results provide support for temporal lobe metabolic asymmetry in schizophrenia and its possible association with clinical symptoms.