- Email: [email protected]
CAG repeat polymorphism in schizophrenia
0-19 Depression: Clinical (19%) the amount of eH]spiperone binding sites in the limbic forebrain without affecting [3H]spiperone binding in the caudate-putamen. In the limbic forebrain, the DA displacement of [3H]spiperone in normal and RO-treated animals was best described by a three site model; the high affinity site (Ki 2.4 nM, 15%) - tentatively representing the D3 receptor - was lost in 4 out of 5 ASO treated animals. The administration of ASO induced an increase in DA synthesis in the nucleus accumbens and substantia nigra (but not in the caudate-putamen) and a moderate increase in limbic DA release as measured using in vivo microdialysis. Our data indicate that D3 receptors in the limbic region exert an influence on dopamine turnover and behaviour in rat.
I0-18-9\
CAG Repeat Polymorphism in Schizophrenia
H.G. Hwu, H.C. Hsu, CT. Chu, YL. Lee. Department ofPsychiatry, NTUH, Taipei, Taiwan
To elucidate the role of schizophrenia (SCH) candidate genes on the X-chromosome, we conducted an association study of 69 (male 41, female 28) SCH patients, 64 (male 36, female 28) normal first degree relatives (FDR) and 47 (male 33, female 14) normal control subjects, using polymorphism of (CAG)n repeats of exon 1 of the androgen receptor gene (Xq 11.2-q12) as a marker. Polymerase chain reaction (PCR) products longer than 434 bp were defined as allele group I, while those shorter than or equal to 434 bp were allele group II. The frequency of allele group I in the SCH patients, normal FDRs and normal controls was 56.7%, 63.0% and 68.9% respectively. Allele group II in the SCH patients, normal FDRs and normal controls were 43.3%, 37.0% and 31.1% respectively. Those subjects with allele group II were 36 (52.2%), 29 (45.3%), and 17 (36.2%) in the SCH, normal FOR and normal control subjects respectively. There was a higher frequency (X 2 '=2.89, df e I, P < 0.10) of allele group II in the schizophrenic cases. Asymmetric PCR is being performed for sequence analysis to detect variations of CAG repeat number in male SCH cases. At the present time, CAG repeat number varies from 20 to 30 and from 18 to 30 in SCH and control males. The mean of CAG repeats number in SCH males seems smaller (25.3%) than that of male controls (26.3%). Fewer CAG repeat number might be associated with some proportion of SCH patients. [I] Crow TJ. Brit J Psychiatry 159 (suppl 14) 76-82.
10-191 Depression: Clinical I0-19-1 I Acute Phase Proteins in Major Depression Michael Berk, Ahmed A. Wadee I, Alex J. O'Neill-Kerr. Department of Psychiatry. University of The Witwatersrand Medical School. 7 York Road. Parktown, Johannesburg, 2193. South Africa; I Department of Immunology. University of The Witwatersrand Medical School. 7 York Road. Parktown, Johannesburg, 2193. South Africa
Extensive evidence exists associating depression with immune changes which include an impaired lymphocyte proliferative response to mitogens, reduced lymphocyte phagocytosis and an acute phase response. Venipuncture was performed on 66 hospitalised patients who met DSM III-R diagnostic criteria for major depressive disorder as well as 50 matched controls. There was no significant difference in the mean levels of total compliment of C3 between the depressed group and the controls. The level of C4 was significantlyhigher in the depressed (0.4541 gil) than the control group (0.3552 gil; p '=0.0094, F '= 6.975, d.f. '= I, ANOVA). Levels of interleukin 6 were undetectable in 34 of the 66 depressed patients (51.5%) and 29 of the 50 controls (58%). There was a significant difference between the two groups with respect to the measurable values in the depressed (12.36, N '=28) and control (1.37, N '=21 P '=0.0007, F = 13, 143, dJ,= I). In addition, there was a significantly higher level of C reactive protein in the depressed patients (11.5, N '=38) than the controls (6.00, N '= 43) (p '= 0.0051, F'= 8.320, d.f '= I). These results suggest abnormalities in the acute phase immune response in depression.
141
[0-19-21 Plasma andPlatelet Amino Acids in Major Depressed Patients Treated with Fluvoxamine M.C. Mauri, A. Ferrara, L. Boscati, F. Zamberlan, M. Alecci, G. Invernizzi. Department ofClinical Psychiatry, University ofMilan. Italy; Department ofNeurology, Vicenza. Italy
Plasma and platelet levels of amino acids were measured in 26 outpatients, 14 M and 12 F, age ranging from 24 to 65 yrs, affected by Major Depression according to DSM IV. at TO (basal time) and after 8 weeks (T3).
Patients were treated with fluvoxamine 100-300 mg/day for 8 weeks. Clinical evaluation was performed at TOand after 4 (T2) and 8 weeks (T3) by using BPRS, HRS-D, HRS-A, COl and ACS (check list for anticholinergic side effects). Plasma and platelets levels of amino acids were higher in depressed patients than in healthy controls, in particular plasma glutamate concentrations were 100.05 nmollml in depressed patients vs 15.33 nmollml in healthy controls (p < 0.01). TryptophanelLNAA ratio showed a trend to be lower in depressed patients vs controls (0.07 ± 0.04 SD vs 0.13 ± 0.15 SD, p '= 0.06) while tyrosinelLNAA ratio showed a trend to be higher in depressed patients vs controls (0.16 ± 0.07 SD vs 0.13 ± 0.03 SD, p '=0.06). Platelet concentrations of glutamine, alanine, lysine were correlated with the severity of depression evaluated at HRS-D total score at TO (p < 0.05). Plasma and platelet concentrations of glutamate, glutamine, glycine, alanine, taurine, methionine. tryptophane, phenilalanine, isoleucine and tyrosine reduced after fluvoxamine treatment.
I0-19-31
Refractory Depression a Biochemical Hypothesis
R.K. Gupta I, T.R. Norman 2, G.D. Burrows 2. Canberra, Australia; Victoria, Australia
2 Dept.
I Woden Valley Hospital; Psychiatry, Austin Hospital, Heidelberg.
The current literature though sparse, on treatment resistant depression is reviewed. Nolan et al concluded Monoamine Oxidase Inhibitors (MAOIs) provide effective alternate therapy for those patients with treatment resistant major depression who do not respond to tricyclic antidepressants or such related compounds as the SSRls. In another study Thase et al found strong evidence of utility of MAOIs in tricyclic resistant depression. Amsterdam and Berwish using high doses of Tranylcypromine successfully treated 5 of 7 treatment resistant depressives who had failed to respond to a mean of 8 ± 5 prior treatments. A biochemical hypothesis as to why MAOIs and moclobemide (RIMA) are therapeutically more effective in the refractory depression is being proposed. In at least some patients who suffer from refractory depression we postulate that the deficiency of Noradrenaline or Serotonin can be attributed to excessive degradation by MAO due to process of "activation or induction" of MAO. This results in constant and excessive degradation of available Serotonin and Noradrenaline rendering antidepressant medication ineffective causing eventual1y recurrent refractory depression. In the absence of the substrate overload a genetic polymorphism or a sensitive negative feedback system or the antidepressants themselves may provide alternative explanations for such activation or induction. Kindling Model of Post also provides a potent explanation for this theory.
I0-19-41
Buspiron Augmentation of SSRI Therapy in Treatment-Refractory Depression
T. Fahien I, H. Agren I, A. Edstrom 2, K. Rooth 2
I Institute ofClinical Neuroscience. Goteborg University, Molndal. Sweden; 2 Bristol-Myers Squibb, Bromma, Sweden
SSRI treatment of major unipolar depression has not been proven more effective than that with tricyclics, and various augmentation strategies have been proposed. This is the first placebo-controlled protocol where 68 patients suffering from SSRl-refractory unipolar major depression have been enrolled in a double-blind randomized multi-center study of buspiron augmentation. The objective was to evaluate efficacy and safety of adding 40-60 mg of BuSpar® or placebo for 4 weeks to patients having been treated with either at least 30 mg paroxetine or 40 mg
I0-18-9\
CAG Repeat Polymorphism in Schizophrenia
H.G. Hwu, H.C. Hsu, CT. Chu, YL. Lee. Department ofPsychiatry, NTUH, Taipei, Taiwan
To elucidate the role of schizophrenia (SCH) candidate genes on the X-chromosome, we conducted an association study of 69 (male 41, female 28) SCH patients, 64 (male 36, female 28) normal first degree relatives (FDR) and 47 (male 33, female 14) normal control subjects, using polymorphism of (CAG)n repeats of exon 1 of the androgen receptor gene (Xq 11.2-q12) as a marker. Polymerase chain reaction (PCR) products longer than 434 bp were defined as allele group I, while those shorter than or equal to 434 bp were allele group II. The frequency of allele group I in the SCH patients, normal FDRs and normal controls was 56.7%, 63.0% and 68.9% respectively. Allele group II in the SCH patients, normal FDRs and normal controls were 43.3%, 37.0% and 31.1% respectively. Those subjects with allele group II were 36 (52.2%), 29 (45.3%), and 17 (36.2%) in the SCH, normal FOR and normal control subjects respectively. There was a higher frequency (X 2 '=2.89, df e I, P < 0.10) of allele group II in the schizophrenic cases. Asymmetric PCR is being performed for sequence analysis to detect variations of CAG repeat number in male SCH cases. At the present time, CAG repeat number varies from 20 to 30 and from 18 to 30 in SCH and control males. The mean of CAG repeats number in SCH males seems smaller (25.3%) than that of male controls (26.3%). Fewer CAG repeat number might be associated with some proportion of SCH patients. [I] Crow TJ. Brit J Psychiatry 159 (suppl 14) 76-82.
10-191 Depression: Clinical I0-19-1 I Acute Phase Proteins in Major Depression Michael Berk, Ahmed A. Wadee I, Alex J. O'Neill-Kerr. Department of Psychiatry. University of The Witwatersrand Medical School. 7 York Road. Parktown, Johannesburg, 2193. South Africa; I Department of Immunology. University of The Witwatersrand Medical School. 7 York Road. Parktown, Johannesburg, 2193. South Africa
Extensive evidence exists associating depression with immune changes which include an impaired lymphocyte proliferative response to mitogens, reduced lymphocyte phagocytosis and an acute phase response. Venipuncture was performed on 66 hospitalised patients who met DSM III-R diagnostic criteria for major depressive disorder as well as 50 matched controls. There was no significant difference in the mean levels of total compliment of C3 between the depressed group and the controls. The level of C4 was significantlyhigher in the depressed (0.4541 gil) than the control group (0.3552 gil; p '=0.0094, F '= 6.975, d.f. '= I, ANOVA). Levels of interleukin 6 were undetectable in 34 of the 66 depressed patients (51.5%) and 29 of the 50 controls (58%). There was a significant difference between the two groups with respect to the measurable values in the depressed (12.36, N '=28) and control (1.37, N '=21 P '=0.0007, F = 13, 143, dJ,= I). In addition, there was a significantly higher level of C reactive protein in the depressed patients (11.5, N '=38) than the controls (6.00, N '= 43) (p '= 0.0051, F'= 8.320, d.f '= I). These results suggest abnormalities in the acute phase immune response in depression.
141
[0-19-21 Plasma andPlatelet Amino Acids in Major Depressed Patients Treated with Fluvoxamine M.C. Mauri, A. Ferrara, L. Boscati, F. Zamberlan, M. Alecci, G. Invernizzi. Department ofClinical Psychiatry, University ofMilan. Italy; Department ofNeurology, Vicenza. Italy
Plasma and platelet levels of amino acids were measured in 26 outpatients, 14 M and 12 F, age ranging from 24 to 65 yrs, affected by Major Depression according to DSM IV. at TO (basal time) and after 8 weeks (T3).
Patients were treated with fluvoxamine 100-300 mg/day for 8 weeks. Clinical evaluation was performed at TOand after 4 (T2) and 8 weeks (T3) by using BPRS, HRS-D, HRS-A, COl and ACS (check list for anticholinergic side effects). Plasma and platelets levels of amino acids were higher in depressed patients than in healthy controls, in particular plasma glutamate concentrations were 100.05 nmollml in depressed patients vs 15.33 nmollml in healthy controls (p < 0.01). TryptophanelLNAA ratio showed a trend to be lower in depressed patients vs controls (0.07 ± 0.04 SD vs 0.13 ± 0.15 SD, p '= 0.06) while tyrosinelLNAA ratio showed a trend to be higher in depressed patients vs controls (0.16 ± 0.07 SD vs 0.13 ± 0.03 SD, p '=0.06). Platelet concentrations of glutamine, alanine, lysine were correlated with the severity of depression evaluated at HRS-D total score at TO (p < 0.05). Plasma and platelet concentrations of glutamate, glutamine, glycine, alanine, taurine, methionine. tryptophane, phenilalanine, isoleucine and tyrosine reduced after fluvoxamine treatment.
I0-19-31
Refractory Depression a Biochemical Hypothesis
R.K. Gupta I, T.R. Norman 2, G.D. Burrows 2. Canberra, Australia; Victoria, Australia
2 Dept.
I Woden Valley Hospital; Psychiatry, Austin Hospital, Heidelberg.
The current literature though sparse, on treatment resistant depression is reviewed. Nolan et al concluded Monoamine Oxidase Inhibitors (MAOIs) provide effective alternate therapy for those patients with treatment resistant major depression who do not respond to tricyclic antidepressants or such related compounds as the SSRls. In another study Thase et al found strong evidence of utility of MAOIs in tricyclic resistant depression. Amsterdam and Berwish using high doses of Tranylcypromine successfully treated 5 of 7 treatment resistant depressives who had failed to respond to a mean of 8 ± 5 prior treatments. A biochemical hypothesis as to why MAOIs and moclobemide (RIMA) are therapeutically more effective in the refractory depression is being proposed. In at least some patients who suffer from refractory depression we postulate that the deficiency of Noradrenaline or Serotonin can be attributed to excessive degradation by MAO due to process of "activation or induction" of MAO. This results in constant and excessive degradation of available Serotonin and Noradrenaline rendering antidepressant medication ineffective causing eventual1y recurrent refractory depression. In the absence of the substrate overload a genetic polymorphism or a sensitive negative feedback system or the antidepressants themselves may provide alternative explanations for such activation or induction. Kindling Model of Post also provides a potent explanation for this theory.
I0-19-41
Buspiron Augmentation of SSRI Therapy in Treatment-Refractory Depression
T. Fahien I, H. Agren I, A. Edstrom 2, K. Rooth 2
I Institute ofClinical Neuroscience. Goteborg University, Molndal. Sweden; 2 Bristol-Myers Squibb, Bromma, Sweden
SSRI treatment of major unipolar depression has not been proven more effective than that with tricyclics, and various augmentation strategies have been proposed. This is the first placebo-controlled protocol where 68 patients suffering from SSRl-refractory unipolar major depression have been enrolled in a double-blind randomized multi-center study of buspiron augmentation. The objective was to evaluate efficacy and safety of adding 40-60 mg of BuSpar® or placebo for 4 weeks to patients having been treated with either at least 30 mg paroxetine or 40 mg