- Email: [email protected]
Modulation of serotonin 1A receptor gene expression by antidepressants
THURSDAY. MAY 18
increases in popping and hyperactivity counts compared to vehicletreated animals; LSD IP (dose range of 0.32-5.6 mg/kg) did not result in significant changes in these behaviors compared to vehicle. As the psychosis elicited by P e P in humans has been described as perhaps the best drug-induced model of schizophrenia, we pro[x)se that MK-801 or PCPelicited mouse popping and hyperactivity could serve as a useful preclinical screening paradigm for potential antipsychotic medications, and that the use of the automated system described should facilitate quantitative evaluation of the effects of pharmacological manipulations on elicited [x)pping and hyperactivity.
23. PROLONGED HALOPERIDOL INDUCES A CHRONIC AP-1 COMPLEX IN THE STRIATUM
BIOLPSYCHIATRY 599 1995;37:593-683
trations of chlorpromazine and haloperidol (125 ng/ml, 250 ng/ml, and 500 ng/ml of chlorpromazine and 5, 10, and 20 ng/ml of haloperidol), showed markedly depressed recovery of RNA synthesis at 1 and 4 hours. Complete recovery was not reached even after 24 hours. Our results suggest that neuroleptics widely used in clinical practice adversely influence cell lines that are sensitive to DNA-damaging agents.
25. INTERFERENCE WITH NITRIC OXIDE PRODUCTION A N D ACTION POTENTIATES FLURAZEPAM'S ANTISEIZURE EFFICACY S.I. Deutsch, R. Rosse, C. Morn, L. Koetzner, & J. Mastropaolo
P. Rogue & G. Vincendon L.N.M.I.C., C N R S Center for Neurochemistry, Strasbourg 67084, France A single IP injection of haloperidol (2 mg/kg) produces a transient increase in c-los andjun B mRNA in the dorsal striatum of the rat. These inductions, also found in the nucleus accumbens, are blocked by pretreatmerit with a specific D 2 agonist (1 mg/kg quinelorane). Using gel-shift assays, we studied the effect of haloperidol on the AP-1 binding activity of nuclear extracts from the striatum. A single acute injection (2 mg/kg) rapidly determines a significant increase of AP-I binding activity in both the dorsal and the ventral striatum, which is transient and returns to norreal within 24 hours. It is prevented by pretreatment with a D 2 agonist. The therapeutic effects of antipsychotic drugs are delayed. Thus, we further studied the effect of prolonged haloperidol administration (2 mg/kg for 15 days) on striatal IEG expression and AP-1 activity. Both c-fos and jun B induction were significantly desensitized, though not completely abolished. Despite this down-regulation, AP-1 binding activity remained elevated at levels comparable to those seen after acute haloperidol administration. This increase persisted, though attenuated, for at least 5 days following the last haloperidol injection. Similar results were found in the dorsal and ventral striatum. This suggests that the composition of the APl transcription factor complex is modified upon prolonged neuroleptic administration. The significance of these results for the mode of action of antipsychotics will be discussed.
24. CHLORPROMAZINE AND HALOPERIDOL EFFECTS ON DNA DAMAGE AND REPAIR OF ACTIVELY TRANSCRIBED GENES
Psychiatry Service, Department o f Veterans Affairs Medical Center, Washington, DC 20422 The effect of inhibiting the "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole (7-NI), an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue (MB), an inhibitor of the nitric oxide (NO) sensitive soluble guanylyl eyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate flurazepam's antiseizure efficacy were also examined. When administered alone, 7-N1 (10-100 mg/kg) and MB (l-100 mg/kg) did not share MK-80 l's (.01-1.0 mg/kg) ability to antagonize electrically precipitated tonic hindlimb extension; however, doses of MK-801 (0.18 mg/kg), 7-NI (100 mg/kg), and M B (10 and 100 mg/kg) that were devoid of apparent antiseizure efficacy by themselves potentiated flurazepam's antiseizure efficacy. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippoeampal CA(l) region, and precipitate psychoses in susceptible individuals. The development of NMDA receptor open-channel blockers, and inhibitors of the "downstream" consequences of NMDA receptor-gated calcium ion conduction as potential adjunctive antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.
26. MODULATION OF SEROTONIN 1A RECEPTOR GENE EXPRESSION BY ANTIDEPRESSANTS J.F. Lopez 1,2, D.T. Chalmers 2, & S.J. Watson 1,2
P. Sirota l , Y. Barak l, I. Ron 2, T. Sobe -s, & H. Slor 3 1Abarbanel Mental Health Center, Bat-Yam, Israel; 2Department of Oncology, Tel Aviv Sourasky Medical Center and Sackler School o f Medicine, Tel Aviv University, Israel; 3Department o f Human Genetics, Sackler School of Medicine, Tel Aviv University, Israel The ability of human cells to repair DNA damage can be indirectly expressed by measuring transcriptional activity relating to active genes, namely, RNA synthesis. Chlorpromazine and halopefidol effects on damage and repair of actively transcribed genes (using cultured human fibroblasts) are the target of this study. Three cultured human fibroblast lines were used: two were "normal" in previous RNA recovery testings, and one was abnormally sensitive to UV irradiation. In the "normal" lines, recovery of RNA synthesis after exposure to various concentrations of chlorpromazine and haloperidol following UV irradiation was within 1 hour. The UV-sensitive cell line, after treatment with the above concen-
~Department o f Psychiatry and 2Mental Health Research Institute, University o f Michigan, A n n Arbor, MI 48104-0720 The serotonin l A receptor (5-HTIA) has been identified both as an inhibitory somatodendritic receptor in raphe serotonergie cells and a postsynaptic receptor in selective serotonergic terminal fields. Its abundance in the limbic system, as well as evidence from animal and clinical studies, strongly suggest that the 5-HTLA receptor plays an important role in the pathophysiology of mood disorders. A number of antidepressant drugs have been found to regulate hippocampal 5-HTIA receptor physiological responsiveness, suggesting that this receptor subtype may be important in relation to the therapeutic actions of these compounds. In humans, selective 5-HT~A agonists, such as gepirone and buspirone, can effectively treat generalized anxiety disorder as well as major depression, including the melancholic subtype. The hippocampus is a central component of the limbic system and has been implicated in controlling aspects of cognitive and behavioral function. It therefore provides an ideal anatomical environ-
600
BIOL PSYCHIATRY 1995;37:593-683
ment to study the molecular regulation of 5-HTnA by antidepressants. We report a series of experiments in which rats were administered different antidepressant medications, for two and four weeks. Chronic administration of a specific serotonin reuptake inhibitor (Zimelidine) as well as buspirone significantly increased the levels of 5-HTIA mRNA in selective hippocampal subfields. These changes in gene expression showed some specificity, since no significant changes were observed in the gene expression of other hippocampal receptors. Very small or no changes were observed in 5-HTIA receptor binding. The potential implicatiuns of our resuits for the pathophysiology and treatment of mood disorders will be discussed.
27. CORRELATIONS OF DRUG ACTION BETWEEN HUMAN PLATELET AND HUMAN BRAIN 5-HTT
THURSDAY,, MAY 18
should be superior to oral d, 1 fenfluramine: 1) d-fenfluramine is more serotonin specific; 2) the IV form has less serum level variability; and 3) less metabolite formation should occur as IV administration bypasses the liver. Five normal female subjects, aged 21-28, were given IV d-fen on day 10-14 of their menstrual cycle. Assessments of subjective behavior state were made before and after drug administration using an activationeuphoria-dysphoria-physical symptoms scale. 60 mCI of [150]H~O was given 25 and 10 minutes before, and 20 and 35 minutes after IV d-fen administration. Each time, subjects were scanned for one minute using a brain PET camera. During scanning, subjects did a simple visual-motor task. Subjects reported significantly increased euphoria and decreased fatigue (p < 0.05). Comparison of PET images (using a satistical parametric mapping technique that corrects for differences in global activity and then conducts a paired-t comparison of the relative [150]H20 amount at each pixel in the brain) revealed an increase bilaterally in the frontal-parietal cortex (p < 0.01). This study demonstrates that the intravenous d-fenfluramine challenge produces behavioral state and regional cerebral blood flow responses which can be applied as a measure of serotonergic brain function.
J. Rausch, J. Hutcheson, & X. Li A u g u s t a VA and T h e Medical College of Georgia, A u g u s t a , G A 30809-3810 Evidence now suggests that the sequence for the human platelet 5-HT transporter and the brain 5-HT transporter are the same. Both proteins are encoded by the same single-copy gene, which has been assigned to the human chromosome 17. Using cross-species amplification of human 5HT transperter partial cDNA by polymerase chain reaction (PCR) and the RACE-PCR procedure, it has been previously reported that the 5-HT transporter encc~ing for the human dorsal raphe nucleus cDNA is identical with the human platelet 5-HT uptake site, and approximately 92% homologous to the rat protein. Despite the advent of this information, it has been uncertain whether human platelet would model human brain with respect to inferences about antidepressant drug action at the site(s) of the transporter. Also uncertain was the extent to which studies of the rat transporter would apply to human, recognizing that multiple hybridizing RNAs are observed in the human transporter, unlike that of the rat. Recently we have compared platelet serotonin uptake with that of human brain from neurosurgery pathology specimens and determined that the Ki between the two tissues correlates (r = 0.87, p < 0.05) across a variety of antidepressant drugs studied to date. Combined with recognition of the common genetic coding for the serotonin transporter in brain and platelet, these functional studies indicate that the two tissues react similarly to various degrees of serotonin uptake inhibition across drug potencies, strengthening the case for the human platelet as a model for pharmacologic uptake inhibition in human brain.
28. PET AND BEHAVIORAL RESPONSES TO IV D-FENFLURAMINE IN HUMANS J. Meyer, S. Kapur, A.A. Wilson, D. Hussey, S. Houle, & G.M. Brown Clarke Institute o f Psychiatry, Toronto, Ontario, C a n a d a The purpose of this study was to develop a means to assess serotonergic function using positron emission tomography (PET) and behavioral state measures. In a previous study we had used oral d,1 fenfluramine in 11 males and found increased activation and euphoria with increased bilateral uptake of 18-FDG in prefrontal lobe and decreased uptake in occipital-parietal cortex bilaterally. Intravenous d-fenfluramine (IV d-fen)
29. PRETREATMENT PLASMA FREE MHPG LEVELS AS PREDICTORS OF FLUOXETINE RESPONSE R-B. Lu l, H-C. Ko 2, I-S. Shiah l, & C-C. Hwang I aD e p a r t m e n t o f P s y c h i a t r y , Tri-Service General Hospital, National D e f e n s e M e d i c a l Center; 2Department o f Public Health and Psychiatry, National C h e n g - K u n g University This study was designed to examine whether depressed patients with high pretreatment plasma MHPG and/or low platelet 5-HT levels will respond better to fluoxetine, a specific serotonin reuptake blocker, than do those with low plasma MHPG and/or high platelet 5-HT levels. Fifty-two patients, meeting the criterion for DSM-III-R major depressive episode, were studied. After 10 ml of venous blood was drawn, 20 mg/day of fluoxetine was given orally for 6 weeks. Raters blind to the patients' status rated the patient's depression state weekly using the HDRS. After 6 weeks of treatment, patients who had a 60% or greater decrease in their baseline HDRS scores were defined as responders and those with less than 60% reduction of their HDRS as nonresponders. Following 6 weeks of treatment, a blood sample was drawn to determine the plasma free MHPG and platelet 5-HT concentrations. Twenty-five patients were classified into the fluoxetine responding group and 27 patients the fluoxetine nonres[xmding group. The fluoxetine responding group had significantly higher plasma free MHPG levels than the fluoxetine nonresponding group (5.63 + 2.26 vs. 4.16 + 1.75 ng/ml; t = 2.33; p ~ 0.03), and there was no significant difference in the platelet 5-HT levels. After the treatment, there were no intergroup differences in the platelet 5-HT and plasma free MHPG concentrations. Regarding the change of the platelet 5-HT preceding and following the treatment, the values decreased significantly in both the responding (paired t ~ 3.70; p = 0.02) and nonresponding (paired t = 5.60, p = 0.02) groups. As to the plasma free MHPG values, we found a slightly increased trend in the nonresponding group (paired t = 2.01 p = 0.06), but no change in the values of MHPG in the responding group before and after treatment. These results suggest that high pretreatment plasma MHPG levels predict a favorable treatment response with fluoxetine and that platelet 5-HT levels might reflect the effect of serotonin reuptake.
increases in popping and hyperactivity counts compared to vehicletreated animals; LSD IP (dose range of 0.32-5.6 mg/kg) did not result in significant changes in these behaviors compared to vehicle. As the psychosis elicited by P e P in humans has been described as perhaps the best drug-induced model of schizophrenia, we pro[x)se that MK-801 or PCPelicited mouse popping and hyperactivity could serve as a useful preclinical screening paradigm for potential antipsychotic medications, and that the use of the automated system described should facilitate quantitative evaluation of the effects of pharmacological manipulations on elicited [x)pping and hyperactivity.
23. PROLONGED HALOPERIDOL INDUCES A CHRONIC AP-1 COMPLEX IN THE STRIATUM
BIOLPSYCHIATRY 599 1995;37:593-683
trations of chlorpromazine and haloperidol (125 ng/ml, 250 ng/ml, and 500 ng/ml of chlorpromazine and 5, 10, and 20 ng/ml of haloperidol), showed markedly depressed recovery of RNA synthesis at 1 and 4 hours. Complete recovery was not reached even after 24 hours. Our results suggest that neuroleptics widely used in clinical practice adversely influence cell lines that are sensitive to DNA-damaging agents.
25. INTERFERENCE WITH NITRIC OXIDE PRODUCTION A N D ACTION POTENTIATES FLURAZEPAM'S ANTISEIZURE EFFICACY S.I. Deutsch, R. Rosse, C. Morn, L. Koetzner, & J. Mastropaolo
P. Rogue & G. Vincendon L.N.M.I.C., C N R S Center for Neurochemistry, Strasbourg 67084, France A single IP injection of haloperidol (2 mg/kg) produces a transient increase in c-los andjun B mRNA in the dorsal striatum of the rat. These inductions, also found in the nucleus accumbens, are blocked by pretreatmerit with a specific D 2 agonist (1 mg/kg quinelorane). Using gel-shift assays, we studied the effect of haloperidol on the AP-1 binding activity of nuclear extracts from the striatum. A single acute injection (2 mg/kg) rapidly determines a significant increase of AP-I binding activity in both the dorsal and the ventral striatum, which is transient and returns to norreal within 24 hours. It is prevented by pretreatment with a D 2 agonist. The therapeutic effects of antipsychotic drugs are delayed. Thus, we further studied the effect of prolonged haloperidol administration (2 mg/kg for 15 days) on striatal IEG expression and AP-1 activity. Both c-fos and jun B induction were significantly desensitized, though not completely abolished. Despite this down-regulation, AP-1 binding activity remained elevated at levels comparable to those seen after acute haloperidol administration. This increase persisted, though attenuated, for at least 5 days following the last haloperidol injection. Similar results were found in the dorsal and ventral striatum. This suggests that the composition of the APl transcription factor complex is modified upon prolonged neuroleptic administration. The significance of these results for the mode of action of antipsychotics will be discussed.
24. CHLORPROMAZINE AND HALOPERIDOL EFFECTS ON DNA DAMAGE AND REPAIR OF ACTIVELY TRANSCRIBED GENES
Psychiatry Service, Department o f Veterans Affairs Medical Center, Washington, DC 20422 The effect of inhibiting the "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole (7-NI), an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue (MB), an inhibitor of the nitric oxide (NO) sensitive soluble guanylyl eyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate flurazepam's antiseizure efficacy were also examined. When administered alone, 7-N1 (10-100 mg/kg) and MB (l-100 mg/kg) did not share MK-80 l's (.01-1.0 mg/kg) ability to antagonize electrically precipitated tonic hindlimb extension; however, doses of MK-801 (0.18 mg/kg), 7-NI (100 mg/kg), and M B (10 and 100 mg/kg) that were devoid of apparent antiseizure efficacy by themselves potentiated flurazepam's antiseizure efficacy. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippoeampal CA(l) region, and precipitate psychoses in susceptible individuals. The development of NMDA receptor open-channel blockers, and inhibitors of the "downstream" consequences of NMDA receptor-gated calcium ion conduction as potential adjunctive antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.
26. MODULATION OF SEROTONIN 1A RECEPTOR GENE EXPRESSION BY ANTIDEPRESSANTS J.F. Lopez 1,2, D.T. Chalmers 2, & S.J. Watson 1,2
P. Sirota l , Y. Barak l, I. Ron 2, T. Sobe -s, & H. Slor 3 1Abarbanel Mental Health Center, Bat-Yam, Israel; 2Department of Oncology, Tel Aviv Sourasky Medical Center and Sackler School o f Medicine, Tel Aviv University, Israel; 3Department o f Human Genetics, Sackler School of Medicine, Tel Aviv University, Israel The ability of human cells to repair DNA damage can be indirectly expressed by measuring transcriptional activity relating to active genes, namely, RNA synthesis. Chlorpromazine and halopefidol effects on damage and repair of actively transcribed genes (using cultured human fibroblasts) are the target of this study. Three cultured human fibroblast lines were used: two were "normal" in previous RNA recovery testings, and one was abnormally sensitive to UV irradiation. In the "normal" lines, recovery of RNA synthesis after exposure to various concentrations of chlorpromazine and haloperidol following UV irradiation was within 1 hour. The UV-sensitive cell line, after treatment with the above concen-
~Department o f Psychiatry and 2Mental Health Research Institute, University o f Michigan, A n n Arbor, MI 48104-0720 The serotonin l A receptor (5-HTIA) has been identified both as an inhibitory somatodendritic receptor in raphe serotonergie cells and a postsynaptic receptor in selective serotonergic terminal fields. Its abundance in the limbic system, as well as evidence from animal and clinical studies, strongly suggest that the 5-HTLA receptor plays an important role in the pathophysiology of mood disorders. A number of antidepressant drugs have been found to regulate hippocampal 5-HTIA receptor physiological responsiveness, suggesting that this receptor subtype may be important in relation to the therapeutic actions of these compounds. In humans, selective 5-HT~A agonists, such as gepirone and buspirone, can effectively treat generalized anxiety disorder as well as major depression, including the melancholic subtype. The hippocampus is a central component of the limbic system and has been implicated in controlling aspects of cognitive and behavioral function. It therefore provides an ideal anatomical environ-
600
BIOL PSYCHIATRY 1995;37:593-683
ment to study the molecular regulation of 5-HTnA by antidepressants. We report a series of experiments in which rats were administered different antidepressant medications, for two and four weeks. Chronic administration of a specific serotonin reuptake inhibitor (Zimelidine) as well as buspirone significantly increased the levels of 5-HTIA mRNA in selective hippocampal subfields. These changes in gene expression showed some specificity, since no significant changes were observed in the gene expression of other hippocampal receptors. Very small or no changes were observed in 5-HTIA receptor binding. The potential implicatiuns of our resuits for the pathophysiology and treatment of mood disorders will be discussed.
27. CORRELATIONS OF DRUG ACTION BETWEEN HUMAN PLATELET AND HUMAN BRAIN 5-HTT
THURSDAY,, MAY 18
should be superior to oral d, 1 fenfluramine: 1) d-fenfluramine is more serotonin specific; 2) the IV form has less serum level variability; and 3) less metabolite formation should occur as IV administration bypasses the liver. Five normal female subjects, aged 21-28, were given IV d-fen on day 10-14 of their menstrual cycle. Assessments of subjective behavior state were made before and after drug administration using an activationeuphoria-dysphoria-physical symptoms scale. 60 mCI of [150]H~O was given 25 and 10 minutes before, and 20 and 35 minutes after IV d-fen administration. Each time, subjects were scanned for one minute using a brain PET camera. During scanning, subjects did a simple visual-motor task. Subjects reported significantly increased euphoria and decreased fatigue (p < 0.05). Comparison of PET images (using a satistical parametric mapping technique that corrects for differences in global activity and then conducts a paired-t comparison of the relative [150]H20 amount at each pixel in the brain) revealed an increase bilaterally in the frontal-parietal cortex (p < 0.01). This study demonstrates that the intravenous d-fenfluramine challenge produces behavioral state and regional cerebral blood flow responses which can be applied as a measure of serotonergic brain function.
J. Rausch, J. Hutcheson, & X. Li A u g u s t a VA and T h e Medical College of Georgia, A u g u s t a , G A 30809-3810 Evidence now suggests that the sequence for the human platelet 5-HT transporter and the brain 5-HT transporter are the same. Both proteins are encoded by the same single-copy gene, which has been assigned to the human chromosome 17. Using cross-species amplification of human 5HT transperter partial cDNA by polymerase chain reaction (PCR) and the RACE-PCR procedure, it has been previously reported that the 5-HT transporter encc~ing for the human dorsal raphe nucleus cDNA is identical with the human platelet 5-HT uptake site, and approximately 92% homologous to the rat protein. Despite the advent of this information, it has been uncertain whether human platelet would model human brain with respect to inferences about antidepressant drug action at the site(s) of the transporter. Also uncertain was the extent to which studies of the rat transporter would apply to human, recognizing that multiple hybridizing RNAs are observed in the human transporter, unlike that of the rat. Recently we have compared platelet serotonin uptake with that of human brain from neurosurgery pathology specimens and determined that the Ki between the two tissues correlates (r = 0.87, p < 0.05) across a variety of antidepressant drugs studied to date. Combined with recognition of the common genetic coding for the serotonin transporter in brain and platelet, these functional studies indicate that the two tissues react similarly to various degrees of serotonin uptake inhibition across drug potencies, strengthening the case for the human platelet as a model for pharmacologic uptake inhibition in human brain.
28. PET AND BEHAVIORAL RESPONSES TO IV D-FENFLURAMINE IN HUMANS J. Meyer, S. Kapur, A.A. Wilson, D. Hussey, S. Houle, & G.M. Brown Clarke Institute o f Psychiatry, Toronto, Ontario, C a n a d a The purpose of this study was to develop a means to assess serotonergic function using positron emission tomography (PET) and behavioral state measures. In a previous study we had used oral d,1 fenfluramine in 11 males and found increased activation and euphoria with increased bilateral uptake of 18-FDG in prefrontal lobe and decreased uptake in occipital-parietal cortex bilaterally. Intravenous d-fenfluramine (IV d-fen)
29. PRETREATMENT PLASMA FREE MHPG LEVELS AS PREDICTORS OF FLUOXETINE RESPONSE R-B. Lu l, H-C. Ko 2, I-S. Shiah l, & C-C. Hwang I aD e p a r t m e n t o f P s y c h i a t r y , Tri-Service General Hospital, National D e f e n s e M e d i c a l Center; 2Department o f Public Health and Psychiatry, National C h e n g - K u n g University This study was designed to examine whether depressed patients with high pretreatment plasma MHPG and/or low platelet 5-HT levels will respond better to fluoxetine, a specific serotonin reuptake blocker, than do those with low plasma MHPG and/or high platelet 5-HT levels. Fifty-two patients, meeting the criterion for DSM-III-R major depressive episode, were studied. After 10 ml of venous blood was drawn, 20 mg/day of fluoxetine was given orally for 6 weeks. Raters blind to the patients' status rated the patient's depression state weekly using the HDRS. After 6 weeks of treatment, patients who had a 60% or greater decrease in their baseline HDRS scores were defined as responders and those with less than 60% reduction of their HDRS as nonresponders. Following 6 weeks of treatment, a blood sample was drawn to determine the plasma free MHPG and platelet 5-HT concentrations. Twenty-five patients were classified into the fluoxetine responding group and 27 patients the fluoxetine nonres[xmding group. The fluoxetine responding group had significantly higher plasma free MHPG levels than the fluoxetine nonresponding group (5.63 + 2.26 vs. 4.16 + 1.75 ng/ml; t = 2.33; p ~ 0.03), and there was no significant difference in the platelet 5-HT levels. After the treatment, there were no intergroup differences in the platelet 5-HT and plasma free MHPG concentrations. Regarding the change of the platelet 5-HT preceding and following the treatment, the values decreased significantly in both the responding (paired t ~ 3.70; p = 0.02) and nonresponding (paired t = 5.60, p = 0.02) groups. As to the plasma free MHPG values, we found a slightly increased trend in the nonresponding group (paired t = 2.01 p = 0.06), but no change in the values of MHPG in the responding group before and after treatment. These results suggest that high pretreatment plasma MHPG levels predict a favorable treatment response with fluoxetine and that platelet 5-HT levels might reflect the effect of serotonin reuptake.