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P.3.039 Peripheral indexes of central serotonergic dysfunction in panic disorder
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P.3 Anxiety disorders and anxiolytics
subaffective disorders (minor depression, disthymia) were registered. The symptoms of social phobia were isolated and usually appeared only within particular forms of social activity (fear of speaking or eating in public, etc), Social phobia was presented with fear of failure in usual activities and accompanying avoidance of particular social situations. In the clinical picture of the 2nd subtype of social phobia no comorbidity with other anxious disorders was registered. The comorbid disorders w e r e presented with more severe mood disorders (major recurrent depression, bipolar affective disorder). The symptoms of social phobia were of generalized nature and appeared within most of social situations involving exposure to unfamiliar people. Social phobia was presented with pathological shyness, fear of attracting attention, fear of making oneself's unfavorable features (mostly moral, not physical) evident in public, which often combined with suspiciousness and development of ideas of reference. Opposite to the 1st subtype phobic avoidance was generally exposed to any social contacts. The studied group included 12 patients with symptoms of social phobia. The group was selected according to the DSM-IV criteria. Moclobemide was administered in the daily doses of 600-900 mg during 12 weeks. Both the rate of reduction ot' sociophobic symptoms and the dynamics of comorbid disorders (affective disorders, other anxious disorders) were taken into account in evaluation of the therapeutical efficacy. The results of this evaluation presented a basis for social phobia' subtypes distinguishment, which proved to be significant for predicting the therapeutical efficacy of moclobemide.
•
Peripheral indexes of central serotonergic dysfunction in panic disorder
R. Stain-Malmgren 1, B. Sinner 2, j. Neuger, A. El Khoury, A./~,berg-Wistedt 1, B. Wistedt 2. 1Karolinska Institute, Institution of
Clinical Neuroscience, Dept of Psychiatry, St GOran's Hospital; 2Danderyd's Hospital, Stockholm, Sweden The involvement of a central serotonergic dysfunction in panic disorder has been implicated by the efficacy of SSRI in treatment. We determined platelet 14C-serotonin uptake and 3H-paroxetine binding, as a marker of the serotonin transporter complex, and platelet 3H-LSD- binding, as a marker of the 5-HT2-receptor, in 33 patients that forfilled the DSM III-R criteria for panic disorder. There were 25 women (age range 23-63 years, mean age 35.5 :t: 9 years) and 8 men (age range 50-22 years, mean age 34.1 4- 11 years). The degree of anxiety and depression was assessed using the BAI and BDI self assessment scales and CAS and MADRS for clinical evaluation (Keedwell and Snaith 1996). The mean values for the assessments were BAI: 31 4- 10, BDI: 17 4- 11, CAS: 13 4- 5, and MADRS: 17 4- 9 respectively. The control group consisted of 33 healthy volunteers without heridity for depressive disorders, matched for age, gender and season. There were no differences in platelet ~4C-serotonin uptake kinetics and 3H-LSD-binding to platelet membranes between patients and controls or between gender. There was a gender difference in Bmax for platelet 3H-paroxetine-binding, which was significantly higher in men compared to in women in both patients and controls. Brnax in male patients was 666 + 270 fmoles/mg protein and 1035 + 323 fmoles/mg protein in male controls (p < 0.01). Brna× in female patients was 750 fmoles/mg protein, which was significantly lower than that of 898 fmoles/mg protein in female controls (p < 0.05). There was a tendency to invers correlation between BDI ratings and Bmax for platelet paroxetine bindning; r = -0.27, p = 0.06. A bulk of platelet studies suggest a link between increased 5-HT2-receptor densities and anxiety/aggression and a low serotonin uptake may be a trait marker in depression. We found no evidence for abnormalities in 5-HT2-receptor densities or platelet serotonin uptake in the present study suggesting that the serotonergic dysfunction in panic disorders differs from that in depression and the anxiety/aggression entity in suicidal behavior. Our finding of a reduced 3H-paroxetine binding in untreated panic disorders is in concordance with the findings of Faludi et al (1994). A decreased number of 3H-paroxetine binding sites has also been denoted in posttraumatic stress disorder (Fichter et al 1995). Whether a reduced 3H-paroxetine-binding may be a state or trait marker in panic disorder remains to be settled.
References [1] Keedwell P and Snaith RP. What do anxiety scales measure. Acta Psychiatr Scand 93: 177-180, 1996. [2] Faludi G, Tekes K, Tothfalusi L. Comparative study of the platelet 3H-paroxetine and 3H-imipramine binding in panic disorder patients and healthy corttrols. J Psychiatry Neurosci 19:109-113. [31 Fichter CG, O'Connor FL, Yeoh HC, Aftra RC, Crayton JW. Hypodensity of platelet serotonin uptake sites in posttraumatic stress disorder: associated clinical features. Life Sci 57: 37~t4, 1995.
~ T h e
effect of citalopram treatment on platelet serotonin uptake and 3H-paroxetine- and 3H-LSD-binding in panic disorder
R. Stain-Malmgren 1, B. Sinner 2, J. Neuger 1, A. E1 Khoury 1, A. ]kberg-Wistedt 1, B. Wistedt 2. Karolinska Institute, Institution cf
Clinical Neuroscience, Dept of Psychiatry, St. GOran's Hospital and Danderyd's Hospital, Stockholm, Sweden We investigated the effect of citalopram after 6-8 weeks and 6 months of treatment on clinical effect and peripherial indexes for central serotonergic function in 36 patients that forfilled the DSM-III-R criteria for panic disorder. The indexes were platelet 14C-serotonin uptake and 3H-paroxetine-binding as markers for the serotonin transport complex and 3H-LSD-binding as a marker for the 5-HT2-receptor. In this p:esenration we report the results after 6-8 weeks of citalopram treatmenL. The material consisted of 25 women (age range 23-63 years, mean age 35.5 nE 9 years) and 9 men (age range 50-22 years, mean age 34.1 4- 11 years). The degree of anxiety and depression was assessed using the BAI and BDI self assessment scales and CAS and MADRS for clinical evaluation (Keedwell and Snalth 1996). Criterion for satisfactory therapeutic response was >50% reduction in BAI scores and complete remisson was 75%. The citalopram dosages varied between 15 and 60 rag/day, mean dosage was 38.5 :k l 1.1 rag/day. The plasma concentrations of citalopram was monitored continuously during the study. Three (3) patients, all men, chose to discontinue treatment. Mean basal BAI and BDI scores were 31 ± 10 (SD) and 17 + 11 and mean basal CAS and MADRS scores were 13 4- 5 and 17 ± 9 respectively. The percentage reduction in BAI and BDI scores were 35.3 4- 12.3% and 41.9 + 12.0% and the percentage reduction in CAS and MADRS scores were 41.1 ::L 9.8 and 53.8 4- 8.2% respectively. A satisfactory response was found in 69% of the patients after 6-8 weeks of treatment. The mean value for Km for the platelet t4C-serotonin uptake increased from a basal value of 0.83 + 0.53 /~M to 4.93 + 3.22 /zM (p < 0.0001). There was a significant decrease in the mean value of Vrnax from a basal value of 0.76 + 0.25 pmoles/min/106 platelets to 0.30 -~ 0.22 pmoles/min/106 platelets (p < 0.0001). Bmax for platelet 3H-LSD-binding decreased significantly from a mean basal value of 35 4- 15 fmoles/mg protein to 19 4- 8 fmoles/mg protein (p < 0.001). There was no differertce in 3H-paroxetine binding, the mean value of which was 746 ::k 300 fmoles/mg protein before and 770 + 423 fmoles/mg protein after citalopram treatment. There were no differences in the mean values of the 3H-LSD and 3H-paroxetine affinity varables (Kd) before and after treatment. There was no correlation between the decrease in anxiety or depression scores and the decrease in 3H-LSD-binding. Data for the citalopram concentrations in plasma are not yet available but will be presented. The present study shows that citalopram treatment, apart exerting an inhibitory effect on serotonin reuptake, causes a decrease in platelet 5-HT2-receptor densities. Considering the similarities between platelet 5-HT2-receptors and its counterparts in CNS is seems conceivable to assume that a similar downregulation of post-synaptic 5-HT2-receptors occurs in the brain. The conclusion is in conformity with findings of decreased 5-HT2-receptor densities in rat cerebral cortex after repeated treatment with citalopram (Klimek et al 1994). Our finding that citalo 9ram treatment had no impact on the number of serotonin transporters (Brnax for the 3H-paroxetine binding) is in adherence with results from stn]dies on rat cerebral cortex (Dewar et al 1993). Considering our finding that platelet 3H-paroxetine binding is significantly reduced in untreated panic disorder (to be published) and does not alter in responders to citalopram treatment it is possible that platelet 3H-paroxetine binding may constitute a trait marker in panic disorder.
P.3 Anxiety disorders and anxiolytics
subaffective disorders (minor depression, disthymia) were registered. The symptoms of social phobia were isolated and usually appeared only within particular forms of social activity (fear of speaking or eating in public, etc), Social phobia was presented with fear of failure in usual activities and accompanying avoidance of particular social situations. In the clinical picture of the 2nd subtype of social phobia no comorbidity with other anxious disorders was registered. The comorbid disorders w e r e presented with more severe mood disorders (major recurrent depression, bipolar affective disorder). The symptoms of social phobia were of generalized nature and appeared within most of social situations involving exposure to unfamiliar people. Social phobia was presented with pathological shyness, fear of attracting attention, fear of making oneself's unfavorable features (mostly moral, not physical) evident in public, which often combined with suspiciousness and development of ideas of reference. Opposite to the 1st subtype phobic avoidance was generally exposed to any social contacts. The studied group included 12 patients with symptoms of social phobia. The group was selected according to the DSM-IV criteria. Moclobemide was administered in the daily doses of 600-900 mg during 12 weeks. Both the rate of reduction ot' sociophobic symptoms and the dynamics of comorbid disorders (affective disorders, other anxious disorders) were taken into account in evaluation of the therapeutical efficacy. The results of this evaluation presented a basis for social phobia' subtypes distinguishment, which proved to be significant for predicting the therapeutical efficacy of moclobemide.
•
Peripheral indexes of central serotonergic dysfunction in panic disorder
R. Stain-Malmgren 1, B. Sinner 2, j. Neuger, A. El Khoury, A./~,berg-Wistedt 1, B. Wistedt 2. 1Karolinska Institute, Institution of
Clinical Neuroscience, Dept of Psychiatry, St GOran's Hospital; 2Danderyd's Hospital, Stockholm, Sweden The involvement of a central serotonergic dysfunction in panic disorder has been implicated by the efficacy of SSRI in treatment. We determined platelet 14C-serotonin uptake and 3H-paroxetine binding, as a marker of the serotonin transporter complex, and platelet 3H-LSD- binding, as a marker of the 5-HT2-receptor, in 33 patients that forfilled the DSM III-R criteria for panic disorder. There were 25 women (age range 23-63 years, mean age 35.5 :t: 9 years) and 8 men (age range 50-22 years, mean age 34.1 4- 11 years). The degree of anxiety and depression was assessed using the BAI and BDI self assessment scales and CAS and MADRS for clinical evaluation (Keedwell and Snaith 1996). The mean values for the assessments were BAI: 31 4- 10, BDI: 17 4- 11, CAS: 13 4- 5, and MADRS: 17 4- 9 respectively. The control group consisted of 33 healthy volunteers without heridity for depressive disorders, matched for age, gender and season. There were no differences in platelet ~4C-serotonin uptake kinetics and 3H-LSD-binding to platelet membranes between patients and controls or between gender. There was a gender difference in Bmax for platelet 3H-paroxetine-binding, which was significantly higher in men compared to in women in both patients and controls. Brnax in male patients was 666 + 270 fmoles/mg protein and 1035 + 323 fmoles/mg protein in male controls (p < 0.01). Brna× in female patients was 750 fmoles/mg protein, which was significantly lower than that of 898 fmoles/mg protein in female controls (p < 0.05). There was a tendency to invers correlation between BDI ratings and Bmax for platelet paroxetine bindning; r = -0.27, p = 0.06. A bulk of platelet studies suggest a link between increased 5-HT2-receptor densities and anxiety/aggression and a low serotonin uptake may be a trait marker in depression. We found no evidence for abnormalities in 5-HT2-receptor densities or platelet serotonin uptake in the present study suggesting that the serotonergic dysfunction in panic disorders differs from that in depression and the anxiety/aggression entity in suicidal behavior. Our finding of a reduced 3H-paroxetine binding in untreated panic disorders is in concordance with the findings of Faludi et al (1994). A decreased number of 3H-paroxetine binding sites has also been denoted in posttraumatic stress disorder (Fichter et al 1995). Whether a reduced 3H-paroxetine-binding may be a state or trait marker in panic disorder remains to be settled.
References [1] Keedwell P and Snaith RP. What do anxiety scales measure. Acta Psychiatr Scand 93: 177-180, 1996. [2] Faludi G, Tekes K, Tothfalusi L. Comparative study of the platelet 3H-paroxetine and 3H-imipramine binding in panic disorder patients and healthy corttrols. J Psychiatry Neurosci 19:109-113. [31 Fichter CG, O'Connor FL, Yeoh HC, Aftra RC, Crayton JW. Hypodensity of platelet serotonin uptake sites in posttraumatic stress disorder: associated clinical features. Life Sci 57: 37~t4, 1995.
~ T h e
effect of citalopram treatment on platelet serotonin uptake and 3H-paroxetine- and 3H-LSD-binding in panic disorder
R. Stain-Malmgren 1, B. Sinner 2, J. Neuger 1, A. E1 Khoury 1, A. ]kberg-Wistedt 1, B. Wistedt 2. Karolinska Institute, Institution cf
Clinical Neuroscience, Dept of Psychiatry, St. GOran's Hospital and Danderyd's Hospital, Stockholm, Sweden We investigated the effect of citalopram after 6-8 weeks and 6 months of treatment on clinical effect and peripherial indexes for central serotonergic function in 36 patients that forfilled the DSM-III-R criteria for panic disorder. The indexes were platelet 14C-serotonin uptake and 3H-paroxetine-binding as markers for the serotonin transport complex and 3H-LSD-binding as a marker for the 5-HT2-receptor. In this p:esenration we report the results after 6-8 weeks of citalopram treatmenL. The material consisted of 25 women (age range 23-63 years, mean age 35.5 nE 9 years) and 9 men (age range 50-22 years, mean age 34.1 4- 11 years). The degree of anxiety and depression was assessed using the BAI and BDI self assessment scales and CAS and MADRS for clinical evaluation (Keedwell and Snalth 1996). Criterion for satisfactory therapeutic response was >50% reduction in BAI scores and complete remisson was 75%. The citalopram dosages varied between 15 and 60 rag/day, mean dosage was 38.5 :k l 1.1 rag/day. The plasma concentrations of citalopram was monitored continuously during the study. Three (3) patients, all men, chose to discontinue treatment. Mean basal BAI and BDI scores were 31 ± 10 (SD) and 17 + 11 and mean basal CAS and MADRS scores were 13 4- 5 and 17 ± 9 respectively. The percentage reduction in BAI and BDI scores were 35.3 4- 12.3% and 41.9 + 12.0% and the percentage reduction in CAS and MADRS scores were 41.1 ::L 9.8 and 53.8 4- 8.2% respectively. A satisfactory response was found in 69% of the patients after 6-8 weeks of treatment. The mean value for Km for the platelet t4C-serotonin uptake increased from a basal value of 0.83 + 0.53 /~M to 4.93 + 3.22 /zM (p < 0.0001). There was a significant decrease in the mean value of Vrnax from a basal value of 0.76 + 0.25 pmoles/min/106 platelets to 0.30 -~ 0.22 pmoles/min/106 platelets (p < 0.0001). Bmax for platelet 3H-LSD-binding decreased significantly from a mean basal value of 35 4- 15 fmoles/mg protein to 19 4- 8 fmoles/mg protein (p < 0.001). There was no differertce in 3H-paroxetine binding, the mean value of which was 746 ::k 300 fmoles/mg protein before and 770 + 423 fmoles/mg protein after citalopram treatment. There were no differences in the mean values of the 3H-LSD and 3H-paroxetine affinity varables (Kd) before and after treatment. There was no correlation between the decrease in anxiety or depression scores and the decrease in 3H-LSD-binding. Data for the citalopram concentrations in plasma are not yet available but will be presented. The present study shows that citalopram treatment, apart exerting an inhibitory effect on serotonin reuptake, causes a decrease in platelet 5-HT2-receptor densities. Considering the similarities between platelet 5-HT2-receptors and its counterparts in CNS is seems conceivable to assume that a similar downregulation of post-synaptic 5-HT2-receptors occurs in the brain. The conclusion is in conformity with findings of decreased 5-HT2-receptor densities in rat cerebral cortex after repeated treatment with citalopram (Klimek et al 1994). Our finding that citalo 9ram treatment had no impact on the number of serotonin transporters (Brnax for the 3H-paroxetine binding) is in adherence with results from stn]dies on rat cerebral cortex (Dewar et al 1993). Considering our finding that platelet 3H-paroxetine binding is significantly reduced in untreated panic disorder (to be published) and does not alter in responders to citalopram treatment it is possible that platelet 3H-paroxetine binding may constitute a trait marker in panic disorder.