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Effect of bipolar disorder and Lithium treatment on inositol monophosphatase transcription and translation in lymphoid cells
l?l Aflectiue disorders and antidepressants
S186
effects of stress-induced anxiety and depression on the immune system of rodents.. Nefazodone is a recently released antidepressant drug that potently antagonizes the serotonin type 2A receptor and blocks uptake of norepinephrine and serotonin that seems to be more anxiolytic than other antidepressants. Nevertheless, there is no data about its effects of this drug on the immune system. To further elucidate this latter interaction, in this study we determine the effects of nefazodone (10 mg/kg/day s.c.) on thymus and spleen cellularity, peripheral T lymphocyte populations, the blastogenic response of spleen lymphoid cells and the in vitro and in uiuo activity of phagocytosis in mice exposed to a chronic auditory stressor. Since there is a correlation between the immunosuppressive effects of stress and the rise in plasma corticosterone levels, this hormone was also determined in this experiment. Female mice (7 to 12 weeks old) of the BALBic were randomly dealed in five groups; A) controls, B) unstimulated mice injected with placebo, C) unstimulated mice injected with nefazodone, D). stressed mice injected with placebo, E) stressed mice injected with nefazodone. Stress consisted in a broad band noise at 100 dB daily for 5 seconds every minute during 1- or 3-hour period around midnight, at the height of the diurnal activity cycle. Determinations were performed at times 4, 8 and 12 days of experiments. Thymua, spleen and blood cellularity were calculated by cytometry. T-cell proliferation was determined by measuring (3H)thymidine uptake to spleen cells cultured with the mitogen concanavalin A. The in oitm phagocytosis of peritoneal macrophages was calculated using the zymosan test. The in uiuo phagocytic activity was estimated using the carbon clearance test. Statistical analysis was performed using the Sttkdent’st-test, X2 analysis or one-way analysis of variance with grouping of means by Fisher’s least-significant difference method. Our results show that daily exposure to the auditory stressor caused a reduction of thymus, spleen and peripheral blood cellularity throughout the duration of the experiments. Stress also decreased the proliferative response spleen lymphocytes, the in oitm and the in uiuo activity of phagocytosis in comparison with unstressed mice. Treatment with nefazodone did not affect those parameters in unstressed mice but partially reversed the adverse effects of stress on T-cell populations, the proliferative response of spleen cells and the activity of phagocytosis. There was also a correlation between the immunoprotective effects of nefazodone and a decrease in the stress-induced increase in corticosterone levels. In conclusion, our data at present show that nefazodone partially reversed the adverse effects of stress on the immune system of mice.
ml441
Frequency of sleep disturbance depression
in major
J.L. Ayuso’, J. Babes*, J. Gibert3, J. Saiz-Ruiz4, J. Vallejo5, E Rico”. ‘Dept. of Psychiatry - Uniuersity Complutense of Madrid; 2Dept. of Psychiatry- University of Ouiedo; 3Dept. of Neumsciences - Universiv of Cad& 4Dept of Psychiae - University of Alcala de Henares; ‘Dept. of Psychiatry - Uniuersity Autonoma of Barcelona: 6Bristol-Myers-Squibb, Spain Objective: To determine the frequency of sleep disturbance in patients with major depression. Subjects and Method: Cross sectional, multicentric study. Patients with major depression (DSM-IV criteria), without neither antidepressive treatment nor maniac depressive disease were included. They were evaluated at outpatient psychiatric clinics, with a questionnaire including anamnesis, the Hamilton scale and the “Oviedo questionnaire of sleep quality”. Results: 1253 patients were included in the study (mean age: 45.5 SD: 13.9; 67.2% women, p < 0.001). During the previous month, 79.2% of patients referred a poor subjective satisfaction with their sleep, 13.6% medium and 7.2% were satisfied. 33.8% of the patients had difficulty falling asleep almost every day. 27.1% had difficulty staying asleep almost every day. 71.9% awakened at least half an hour earlier than usually, and 3 1.7% had fatigue, affecting their social life. 7.7% were somnolient almost every day, and 12.8% were somnolient with significative decrease of their’s work performance.
Conclusion: The majority of the patients with a major depression disorder are not subjectively satisfied with their sleep. Difficulty with staying of falling asleep, or early insomnia are frequent complaints in these patients.
Ip.1.1451
Effect of bipolar disorder and Lithium treatment on inositol monophosphatase transcription and translation in lymphoid cells
G. Agam’, A. Shamir ’, R.H. Belmaker’, L. Nemanov*, RX’.Ebstein*. ‘Faculty of Health Sciences, Ben Gurion University of the Negeo, Beersheua; 2Herzog Memorial Hospital, Jerusalem, Ismel
Intensive research has focused on the mechanism of Li’s pharmacological actions and particularly on the phosphoinositide (PI) cycle as the molecular substrate underlying this ion’s clinical usefulness. Following the demonstration that therapeutic concentrations of Li uncompetitively inhibit inositol monophosphataae (IMPase) activity Berridge first proposed that this ubiquitous enzyme which regenerates intracellular free inositol is a principal therapeutic target of Li. These considerations spurred us to examine the activity of IMPase in the etiology of BPD. Patients were characterized by therapeutic response to Li allowing correlation with IMPase activity. IMPase activity was assessed as a potential trait marker in lymphoblastoid cells grown for several generations in uniform tissue culture conditions. IMPase activity measured as net Pi liberation from inositol-1-P in the absence and in the presence of 30 mM Li was determined in 108 lymphoblastoid cell lines derived from 29 control subjects and 79 BPD patients (67 positive responders to Li therapy and 12 poor responders). Counter intuitively, cell lines from BPD patients showed a significant 2-fold reduction in IMPase activity compared to cell lines derived from control subjects, especially for patients exhibiting a good clinical response to Li. These results prompted us to test the notion that chronic Li treatment at therapeutic concentration may up-regulate IMPase activity at the transcriptional level. Two genes, one on chromosome 18 (IMp.18~) and one on chromosome 8 (IMPA), have recently been shown to code for homologous IMPase sequences. mRNA levels were measured by reversetranscriptase. As predicted, five days of 1 mM Li treatment in vitro significantly raised by 40% IMPase relative mRNA levels of the IMPA chr 8 gene coding for the predominant brain form of this enzyme. The results above corroborate with our previous study in which five drug-free BPD patients exhibited -2/3 reduction in lymphocyte IMPase mRNA levels compared to 36 control subjects. Approximately two-fold elevation of these levels toward control values was found for patients treated with Li and/or other mood stabilizers (n = 31). Patients on Li only (n = 11) exhibited a correlation between Li plasma concentration and lymphocyte mRNA levels. Because inositol reversal of Li’s effect supports inositol depletion as a mechanism of the ion’s action, the effect of inositol in one upregulated cell line was studied. The effect of Li was partially reversed by co-administration of 30 mM inositol, but inositol itself also significantly raised IMPase mRNA levels. A significant interaction (two way ANOVA) between the effect of Li and inositol was obtained. The results suggest the possible importance of IMPase in the mediation of Li’s therapeutic efficacy and in the etiology of BPD as well as the possibility that IMPase activity is an endophenotype of this disorder.
Ip.1.146J
Experience of antidepressant drug/fluoxetine/therapy of colitis ulcerosa patfents suffering from depression
G. Ostorharics, J. Radics * Petz Aladar County Hospital, Gy& Hungary Our psychiatric ward in a cooperation of medical-gastroenterological ward of our hospital examined the relative incidence of depression among colitis ulcerosa patients. We found the relative incidence high. The revealed patients have paraticipated ndash; besides their medical therapy - in an antidepressive therapy/fluoxetine/. Our aim was double: from one part how the patients with gastroenterologic problems tolerate
S186
effects of stress-induced anxiety and depression on the immune system of rodents.. Nefazodone is a recently released antidepressant drug that potently antagonizes the serotonin type 2A receptor and blocks uptake of norepinephrine and serotonin that seems to be more anxiolytic than other antidepressants. Nevertheless, there is no data about its effects of this drug on the immune system. To further elucidate this latter interaction, in this study we determine the effects of nefazodone (10 mg/kg/day s.c.) on thymus and spleen cellularity, peripheral T lymphocyte populations, the blastogenic response of spleen lymphoid cells and the in vitro and in uiuo activity of phagocytosis in mice exposed to a chronic auditory stressor. Since there is a correlation between the immunosuppressive effects of stress and the rise in plasma corticosterone levels, this hormone was also determined in this experiment. Female mice (7 to 12 weeks old) of the BALBic were randomly dealed in five groups; A) controls, B) unstimulated mice injected with placebo, C) unstimulated mice injected with nefazodone, D). stressed mice injected with placebo, E) stressed mice injected with nefazodone. Stress consisted in a broad band noise at 100 dB daily for 5 seconds every minute during 1- or 3-hour period around midnight, at the height of the diurnal activity cycle. Determinations were performed at times 4, 8 and 12 days of experiments. Thymua, spleen and blood cellularity were calculated by cytometry. T-cell proliferation was determined by measuring (3H)thymidine uptake to spleen cells cultured with the mitogen concanavalin A. The in oitm phagocytosis of peritoneal macrophages was calculated using the zymosan test. The in uiuo phagocytic activity was estimated using the carbon clearance test. Statistical analysis was performed using the Sttkdent’st-test, X2 analysis or one-way analysis of variance with grouping of means by Fisher’s least-significant difference method. Our results show that daily exposure to the auditory stressor caused a reduction of thymus, spleen and peripheral blood cellularity throughout the duration of the experiments. Stress also decreased the proliferative response spleen lymphocytes, the in oitm and the in uiuo activity of phagocytosis in comparison with unstressed mice. Treatment with nefazodone did not affect those parameters in unstressed mice but partially reversed the adverse effects of stress on T-cell populations, the proliferative response of spleen cells and the activity of phagocytosis. There was also a correlation between the immunoprotective effects of nefazodone and a decrease in the stress-induced increase in corticosterone levels. In conclusion, our data at present show that nefazodone partially reversed the adverse effects of stress on the immune system of mice.
ml441
Frequency of sleep disturbance depression
in major
J.L. Ayuso’, J. Babes*, J. Gibert3, J. Saiz-Ruiz4, J. Vallejo5, E Rico”. ‘Dept. of Psychiatry - Uniuersity Complutense of Madrid; 2Dept. of Psychiatry- University of Ouiedo; 3Dept. of Neumsciences - Universiv of Cad& 4Dept of Psychiae - University of Alcala de Henares; ‘Dept. of Psychiatry - Uniuersity Autonoma of Barcelona: 6Bristol-Myers-Squibb, Spain Objective: To determine the frequency of sleep disturbance in patients with major depression. Subjects and Method: Cross sectional, multicentric study. Patients with major depression (DSM-IV criteria), without neither antidepressive treatment nor maniac depressive disease were included. They were evaluated at outpatient psychiatric clinics, with a questionnaire including anamnesis, the Hamilton scale and the “Oviedo questionnaire of sleep quality”. Results: 1253 patients were included in the study (mean age: 45.5 SD: 13.9; 67.2% women, p < 0.001). During the previous month, 79.2% of patients referred a poor subjective satisfaction with their sleep, 13.6% medium and 7.2% were satisfied. 33.8% of the patients had difficulty falling asleep almost every day. 27.1% had difficulty staying asleep almost every day. 71.9% awakened at least half an hour earlier than usually, and 3 1.7% had fatigue, affecting their social life. 7.7% were somnolient almost every day, and 12.8% were somnolient with significative decrease of their’s work performance.
Conclusion: The majority of the patients with a major depression disorder are not subjectively satisfied with their sleep. Difficulty with staying of falling asleep, or early insomnia are frequent complaints in these patients.
Ip.1.1451
Effect of bipolar disorder and Lithium treatment on inositol monophosphatase transcription and translation in lymphoid cells
G. Agam’, A. Shamir ’, R.H. Belmaker’, L. Nemanov*, RX’.Ebstein*. ‘Faculty of Health Sciences, Ben Gurion University of the Negeo, Beersheua; 2Herzog Memorial Hospital, Jerusalem, Ismel
Intensive research has focused on the mechanism of Li’s pharmacological actions and particularly on the phosphoinositide (PI) cycle as the molecular substrate underlying this ion’s clinical usefulness. Following the demonstration that therapeutic concentrations of Li uncompetitively inhibit inositol monophosphataae (IMPase) activity Berridge first proposed that this ubiquitous enzyme which regenerates intracellular free inositol is a principal therapeutic target of Li. These considerations spurred us to examine the activity of IMPase in the etiology of BPD. Patients were characterized by therapeutic response to Li allowing correlation with IMPase activity. IMPase activity was assessed as a potential trait marker in lymphoblastoid cells grown for several generations in uniform tissue culture conditions. IMPase activity measured as net Pi liberation from inositol-1-P in the absence and in the presence of 30 mM Li was determined in 108 lymphoblastoid cell lines derived from 29 control subjects and 79 BPD patients (67 positive responders to Li therapy and 12 poor responders). Counter intuitively, cell lines from BPD patients showed a significant 2-fold reduction in IMPase activity compared to cell lines derived from control subjects, especially for patients exhibiting a good clinical response to Li. These results prompted us to test the notion that chronic Li treatment at therapeutic concentration may up-regulate IMPase activity at the transcriptional level. Two genes, one on chromosome 18 (IMp.18~) and one on chromosome 8 (IMPA), have recently been shown to code for homologous IMPase sequences. mRNA levels were measured by reversetranscriptase. As predicted, five days of 1 mM Li treatment in vitro significantly raised by 40% IMPase relative mRNA levels of the IMPA chr 8 gene coding for the predominant brain form of this enzyme. The results above corroborate with our previous study in which five drug-free BPD patients exhibited -2/3 reduction in lymphocyte IMPase mRNA levels compared to 36 control subjects. Approximately two-fold elevation of these levels toward control values was found for patients treated with Li and/or other mood stabilizers (n = 31). Patients on Li only (n = 11) exhibited a correlation between Li plasma concentration and lymphocyte mRNA levels. Because inositol reversal of Li’s effect supports inositol depletion as a mechanism of the ion’s action, the effect of inositol in one upregulated cell line was studied. The effect of Li was partially reversed by co-administration of 30 mM inositol, but inositol itself also significantly raised IMPase mRNA levels. A significant interaction (two way ANOVA) between the effect of Li and inositol was obtained. The results suggest the possible importance of IMPase in the mediation of Li’s therapeutic efficacy and in the etiology of BPD as well as the possibility that IMPase activity is an endophenotype of this disorder.
Ip.1.146J
Experience of antidepressant drug/fluoxetine/therapy of colitis ulcerosa patfents suffering from depression
G. Ostorharics, J. Radics * Petz Aladar County Hospital, Gy& Hungary Our psychiatric ward in a cooperation of medical-gastroenterological ward of our hospital examined the relative incidence of depression among colitis ulcerosa patients. We found the relative incidence high. The revealed patients have paraticipated ndash; besides their medical therapy - in an antidepressive therapy/fluoxetine/. Our aim was double: from one part how the patients with gastroenterologic problems tolerate