Treatment Response in Depressed Patients with Enhanced Ca
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Treatment Response in Depressed Patients with Enhanced Ca Mobilization Stimulated by Serotonin Ichiro Kusumi, M.D., Ph.D., Katsuji Suzuki, M.D., Yuki Sasaki, B.S., Kensuke Kameda, M.D., Ph.D., and Tsukasa Koyama, M.D., Ph.D. Serotonin (5-HT)-stimulated intraplatelet calcium (Ca) years. The depressed patients with enhanced Ca response to mobilization has been shown to be enhanced in 5-HT in bipolar disorders exhibited a good response to mood nonmedicated depressive patients by many studies. stabilizers but those with major depressive disorders showed However, there has not been any longitudinal follow-up a poor response to antidepressants. These findings suggest study of this parameter. We examined the relationship the possibility that the 5-HT-induced intraplatelet Ca response between treatment response and pretreatment value of the may be a good predictor of treatment response in depressed 5-HT-induced Ca response. The 5-HT(10 M)-induced patients. Longer longitudinal follow-up studies are needed intraplatelet Ca mobilization was measured in 98 in larger samples to examine if this parameter may be a nonmedicated depressive patients (24 bipolar disorders, 51 specific biological marker for unipolar-bipolar dichotomy. melancholic major depressive disorders, and 23 non- [Neuropsychopharmacology 23:690–696, 2000] © 2000 melancholic major depressive disorders). These patients American College of Neuropsychopharmacology. Published were followed up prospectively for a further period of five by Elsevier Science Inc. KEY WORDS: Calcium; Serotonin; Mood disorder; Treatment tryptophan was enhanced in nonmedicated depressed response; Platelet and manic patients (Meltzer et al. 1984). By measuring 5-HT-induced intraplatelet calcium (Ca) mobilization, A large number of studies have indicated that central we have already indicated that 5-HT receptor func- serotonin-2A (5-HT ) receptor dysfunction is an im- 2A 2A tion is enhanced in nonmedicated patients with bipolar portant factor in the etiology of mood disorders. In- disorders and melancholic major depression compared creased densities of 5-HT receptor binding sites in the 2A to normal controls (Kusumi et al. 1991b, 1994). postmortem brain of depressed patients or suicide vic- Although these findings were confirmed by several tims, and platelets of depressed patients have been re- studies (Mikuni et al. 1992; Eckert et al. 1993; Okamoto et ported by many investigators (see review: Kusumi and al. 1994; Konopka et al. 1996; Tomiyoshi et al. 1999), there Koyama 1998). An neuroendocrine study also sug- has not been any follow-up study of this parameter except gested the supersensitivity of 5-HT receptors by 2A our previous report (Kusumi et al. 1994), which suggested showing that cortisol response to oral D, L-5-hydroxy- that the enhanced Ca response is not state dependent, but trait dependent. Assuming that this parameter might be From the Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan. some predictor of treatment response in depressed pa- Address correspondence to: Ichiro Kusumi, M.D., Ph.D., Depart- tients, in this study, we examined the relationship be- ment of Psychiatry, Hokkaido University School of Medicine, North tween clinical improvement and pretreatment value of 15, West 7, Sapporo 060–8638, Japan. Received 8 February 2000; revised 18 May 2000; accepted 23 May the 5-HT-induced intraplatelet Ca response in patients 2000. with bipolar disorders and major depressive disorders. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 6 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00149-4 NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 6 Treatment Response and Ca Mobilization 691 SUBJECTS AND METHODS rich plasma was incubated with 4 M fura-2/ace- toxymethylester, a Ca sensitive fluorescent probe, for 15 Subjects min at 37ЊC. After centrifugation, the resulting platelet The study reports on a total of 98 drug-free, major de- pellet was suspended at 1 ϫ 108 cells/ml in Krebs- pressive patients and 30 normal controls. After com- Ringer HEPES buffer. The samples were prewarmed in plete description of the study, written informed consent a cuvette at 37ЊC for 4 min and then 10 M 5-HT was was obtained from all participants. The depressed pa- added to the incubation medium. Fluorescence was tients were diagnosed and subtyped using DSM-IV cri- measured on a Hitachi F-2000 fluorometer with excita- teria, which consisted of 24 bipolar disorders, 51 major tion at 340 and 380 nm, and with emission at 510 nm. depressive disorders with melancholic feature, and 23 Intracellular Ca concentrations were calculated from major depressive disorders without melancholic fea- the ratio of fluorescence intensities at two excitation ture. For at least four weeks before blood sampling, wavelengths in the platelet samples according to the they had not received any psychotropic medication or method of Grynkiewicz et al. (1985). any other drugs such as aspirin that might interfere We examined both resting Ca concentration and with platelet aggregation. They were all free of physical maximum Ca response (% increase ϭ initial peak (nM) / illness including hypertension. The severity of depres- resting level (nM) ϫ 100) induced by 10 M of 5-HT. sive symptoms was assessed by the 17-item Hamilton Since data expressed by percent increase is more stable Rating Scale for Depression (HRSD) at the time of sam- (lower inter- or intra-assay) than those by Ca increase pling. (initial peak minus resting Ca level) as suggested in the Family history was investigated whether or not there previous report (Kusumi et al. 1991a), we analysed data was any patient with mood disorders within a first- or with percent increase in this longitudinal follow-up second-degree relative. The clinical data for subgroups study. of nonmedicated patients and normal controls are shown in Table 1. Statistical Analysis Results are expressed as means Ϯ SD. Statistical analy- Treatment Response sis was performed using Student’s t-test, Mann-Whitt- All patients were observed by the psychiatrists to check ney’s U test, or one-way analysis of variance (ANOVA) the responsiveness to the treatment at least monthly for for multiple comparison followed by Scheffe’s test. a period of five years after blood sampling. Medications Analysis by 2 was used to assess the relationship be- at follow-up were prescribed based on clinical judg- tween pretreatment Ca mobilization and clinical re- ment rather than by random assignment to a particular sponse. P-values less than .05 were considered statisti- medication protocol. Responders were defined as pa- cally significant. tients with absence of DSM-IV (hypo)manic or major depressive episodes during at least two years of effec- tive treatment despite a reasonably high risk of recur- RESULTS rence (history of at least one affective episode during Clinical Characteristics of Depressive Patients the one year preceding the current episode) for bipolar disorders, and as a reduction to five or less of total Comparing the demographic data for subgroups of HRSD score for major depressive disorders. nonmedicated depressive patients, there were no sig- On the other hand, nonresponders were patients nificant differences in sex ratio, age, family history, or who experienced at least one affective episode for a pe- total HRSD score among three groups (Table 1). The riod of less than two years with onset after trials of var- maximal Ca response induced by 10 M of 5-HT was ious combination with adequate dose of mood stabiliz- significantly higher in patients with bipolar disorders ers for bipolar disorders, and those who did not than in normal controls, whereas no significant differ- respond to an adequate period (more than four weeks) ence in basal Ca concentration was observed among of treatment with at least two different antidepressants four groups (Table 1). at optimal dosage (a minimum of the equivalent of 150 We did not find any difference in both basal Ca level mg imipramine per day) for major depressive dis- and 5-HT-stimulated Ca response between male and fe- orders. male when examining for total or each subgroup of de- pressed patients (data not shown). Thus, further analy- ses were performed with male and female patients 5-HT-Stimulated Ca Response together. No significant correlation was observed be- The isolation of platelets and the measurement of intra- tween total HRSD score and the 5-HT-induced Ca mo- platelet Ca concentration were performed as described bilization in the entire group or each subgroup of pa- previously (Kusumi et al. 1991a, 1994). Briefly, platelet- tients (data not shown). 692 I. Kusumi et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 6 Table 1. Clinical Data for Subgroups of Nonmedicated Depressive Patients and Normal Controls Major depressive Major depressive disorder disorder Bipolar with melancholic without melancholic disorders features features Controls N24512330 Male/Female 10/14 21/30 12/11 14/16 Age (year) 36.8 Ϯ 14.6 42.1 Ϯ 16.3 39.1 Ϯ 15.2 42.8 Ϯ 11.0 Family historya 4 (17%) 9 (18%) 5 (22%) HRSDb 21.3 Ϯ 6.1 23.4 Ϯ 7.6 20.3 Ϯ 5.6 Resting Ca level (nM) 68.5 Ϯ 17.3 69.1 Ϯ 15.9 69.9 Ϯ 20.9 76.2 Ϯ 13.1 5-HT-induced Ca response (%) 272.1 Ϯ 58.3** 247.6 Ϯ 50.5 221.9 Ϯ 32.7 225.5 Ϯ 27.8 aFamily history of mood disorders in a first- or second degree relative. bHamilton rating scale for depression. **p Ͻ .005 vs. controls. Treatment Response in Depressed Patients according to their pretreatment value of the 5-HT- induced Ca response. The cut-off value chosen was First, we examined clinical characteristics and the 5-HT- 280% of basal, since it corresponded to the value of the stimulated Ca mobilization for responder and nonre- mean ϩ 2SD for normal controls (Table 1).