Association between serotonin transporter polymorphisms (5-HTTLPR) and the MADRS Dysphoria, Retardation, and Vegetative Subscale scores in the treatment of depression.

OBJECTIVE: We investigated the association between serotonin- or 5-hydroxytryptamine (5-HT)-related gene polymorphisms and response to antidepressant treatment in a specific symptom cluster of major depression by using the three-factor model of the Montgomery-Åsberg Depression Rating Scale (MADRS), ie, dysphoria (items of sadness, pessimistic thoughts, and suicidal thoughts), retardation (items of lassitude, inability to feel, apparent sadness, and concentration difficulties), and vegetative symptoms (items of reduced sleep, reduced appetite, and inner tension). METHODS: This study was an open-label and nonrandomized trial. A total of 160 patients with baseline MADRS scores of ≥21, who were treated with fluvoxamine or milnacipran for 6 weeks, were included in the statistical analysis. Polymorphisms within a 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), and 5HT2A receptor (1438G/A) were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The 5-HTTLPR polymorphisms affected the MADRS score change in dysphoria, but not in retardation, vegetative, or total symptoms. Dysphoria scores significantly decreased in patients with the S/S genotype compared to those in patients with the short (S)/long (L) + L/L genotype. However, 5-HTTVNTR and 1438G/A polymorphisms were not significantly associated with the treatment response to any cluster of depressive symptoms. When a Bonferroni correction was made, however, our results did not reach the criteria for statistical significance. CONCLUSION: The use of a single total depression rating scale may not be sufficient to accurately estimate the clinical response to antidepressants. Analyzing a subset of symptoms in psychological scales could be important when performing pharmacogenetic studies.

Bcl1 polymorphism of the glucocorticoid receptor gene and treatment response to milnacipran and fluvoxamine in Japanese patients with depression.

BACKGROUND: Polymorphisms in the glucocorticoid receptors (GRs) have been widely studied with rather less emphasis on relating their differences with possible pharmacological treatment outcomes. The purpose of this study was to investigate whether Bcl1 polymorphisms of GRs are associated with the antidepressant effect of milnacipran, a serotonin noradrenaline reuptake inhibitor (SNRI), and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in Japanese patients with depression. METHODS: Patients were prescribed either milnacipran (n = 98) or fluvoxamine (n = 95). The severity of depression was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) at 0, 1, 2, 4 and 6 weeks of treatment. RESULTS: Both agents were similarly effective in reducing MADRS scores in 6 weeks. In all subjects receiving milnacipran or fluvoxamine, our data showed no significant interaction between Bcl1 polymorphisms and therapeutic effects. However, when milnacipran- and fluvoxamine-treated subjects were analyzed independently, patients with G allele in Bcl1 polymorphism had a significantly better response to fluvoxamine than those with C/C genotype. On the other hand, no significant relationship was found between treatment response to milnacipran and Bcl1 polymorphism. CONCLUSION: Bcl1 polymorphism may be one of the genetic factors in predicting treatment response to SSRI but not SNRI in Japanese patients with depression.

Genetic polymorphisms in the serotonergic system and symptom clusters of major depressive disorder.

BACKGROUND: It has been suggested that the symptoms of major depressive disorder (MDD) are composed of some clusters, which are linked to distinct genetic mechanisms. The purpose of this study was to examine the associations of genetic polymorphisms in the serotonergic system with three factors of the Montgomery-Åsberg Depression Rating Scale (MADRS), i.e., dysphoria, retardation, and vegetative symptoms. METHODS: The subjects were 132 Japanese patients of MDD. The genotypes of tryptophan hydroxylase 218A/C, serotonin transporter gene-linked polymorphic region (5HTTLPR), and 5HT2A receptor -1438G/A polymorphisms were determined by PCR methods. Statistical analyses were performed by the multiple regression analysis. RESULTS: The A allele of 5HT2A polymorphism was associated with higher vegetative scores (p=0.001) and total MADRS scores (p=0.005), while the S allele of 5HTTLPR was related to higher dysphoric scores (p=0.012). The tryptophan hydroxylase genotype was not related to any factor scores or total MADRS scores. LIMITATIONS: The sample size was relatively small, and the subjects were composed of Japanese only. CONCLUSION: This study suggests that the genetic polymorphisms in 5HT2A receptor and serotonin transporter are linked to discrete symptom clusters of MDD.

Symptom predictors of response to electroconvulsive therapy in older patients with treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) has been used for treatment-resistant depression. However, predictors of response to ECT have not been adequately studied using the Montgomery and Åsberg Depression Rating Scale, especially in older patients with treatment-resistant depression. METHODS: This study included 18 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision criteria for a diagnosis of major depressive disorder or bipolar disorder with a current major depressive episode, and met the definition of treatment-resistant depression outlined by Thase and Rush, scoring ≥21 on the Montgomery and Åsberg Depression Rating Scale. The three-factor model of the Montgomery and Åsberg Depression Rating Scale was used for analysis. Factor 1 was defined by three items, factor 2 by four items, and factor 3 by three items, representing dysphoria, retardation, and vegetative symptoms, respectively. ECT was performed twice a week for a total of six sessions using a Thymatron System IV device with the brief pulse technique. Clinical responses were defined on the basis of a ≥50% decrease in total pretreatment Montgomery and Åsberg Depression Rating Scale scores. RESULTS: The mean pretreatment factor 2 score for responders (n = 7) was significantly lower than that for nonresponders (n = 11). Furthermore, a significant difference in mean factor 3 score between responders and nonresponders was observed one week after six sessions of ECT, indicating a time lag of response. No significant differences were observed for age, number of previous episodes, and duration of the current episode between responders and nonresponders. CONCLUSION: This study suggests that a low pretreatment factor 2 score is a good predictor of response to ECT in older patients with major depression.

[Prediction of antidepressant response to milnacipran and fluvoxamine using pharmacogenetical methods].

In a milnacipran study, ninety-six patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale. The purpose of this study was to determine whether norepinephrine transporter (NET) gene and serotonin transporter (5-HTT) gene polymorphisms are associated with the antidepressant response to milnacipran, a serotonin and norepinephrine reuptake inhibitor. Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response. In contrast, no influence of 5-HTTLPR (5-HTT linked polymorphic region) on the antidepressant response to milnacipran was detected. The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran. In a fluvoxamine study, sixty-six patients with major depressive disorder were treated with fluvoxamine, 100-200 mg/day, for 6 weeks. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine, a selective serotonin reuptake inhibitor. Fifty-seven patients completed the study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones. The results suggest that fluvoxamine is not less effective in depressive patients carrying the s allele than in those carrying the long (1) allele and it is not less effective in Japanese than in Caucasians.

Efficacy of milnacipran in the treatment of chronic pain syndromes.

Abstract Eleven outpatients with chronic pain syndromes other than fibromyalgia were treated for 12 weeks with milnacipran, a novel serotonin noradrenaline reuptake inhibitor. The agent was administered at 50-150 mg/day, and the mean ± SD dose at 12 weeks or at the time drug treatment was stopped was 84.1 ± 32.2 mg/day. None of the patients met the DSM-IV criteria for a major depressive disorder. Abdominal, chest, back, arm, leg or glossal pain, or headache was involved. Pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of milnacipran treatment, or at the time drug treatment was stopped. The mean ± SD decrease in VAS scores was 42.3 ± 31.6 (50.8 ± 49.2%). One patient discontinued treatment after 4 weeks because of nausea, whereas others tolerated the agent well. These results suggest that the use of milnacipran in patients with a variety of chronic pain syndromes is beneficial.

Predictors of response to electroconvulsive therapy obtained using the three-factor structure of the Montgomery and Asberg Depression Rating Scale for treatment-resistant depressed patients.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most effective treatments for refractory major depressive disorder (MDD). Although studies have examined different predictors of a positive response to ECT, predictors based on symptoms listed on a depression rating scale have not been studied. METHODS: This study included 24 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for MDD or bipolar disorder with current major depressive episode. All subjects had a score of 21 or higher on the Montgomery and Asberg Depression Rating Scale (MADRS). The 3-factor model of MADRS was used for analysis: factor 1 (dysphoria) was defined by 3 items, factor 2 (retardation) was defined by 4 items, and factor 3 (vegetative symptoms) was defined by 3 items. Electroconvulsive therapy was performed 2 times a week for a total of 6 sessions using the Thymatron System IV device (Somatics, Inc., Lake Bluff, Ill) with the brief-pulse technique. A clinical response was defined as a 50% or greater decrease on the pretreatment total MADRS score. RESULTS: The mean factor 1 score of responders (n = 17) at pretreatment was significantly higher than that of the nonresponders (n = 7). Furthermore, a significant difference in mean factor 3 scores between responders and nonresponders was observed 1 week after the 6 ECT sessions were complete, indicating a lag in response time. No significant differences were observed in age, number of previous episodes, and duration of current episodes between the responders and nonresponders. CONCLUSIONS: This study suggests that a high factor 1 MADRS score at pretreatment was a good predictor of response to ECT in patients with treatment-resistant MDD.

Influence of serotonergic/noradrenergic gene polymorphisms on nausea and sweating induced by milnacipran in the treatment of depression.

The present study was conducted to find out the predictors of side effects such as nausea and excessive sweating induced by milnacipran, a serotonin/norepinephrine reuptake inhibitor. Both clinical characteristics prior to the treatment and gene polymorphisms such as serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the second intron of the 5-HTT gene (5-HTTVNTR), 5-HT2A receptor gene (5-HT2A G-1438A), a TPH gene polymorphism in intron 7 (TPH A218C), norepinephrine transporter (NET) gene polymorphism in the promoter region (NET T-182C) and in the exon 9 (NET G1287A), a variable number of tandem repeats in the promoter region of monoamine oxidase A, were items to be assessed in this study. Ninety-six patients with major depressive disorder were treated with milnacipran. Side effects were assessed at 1, 2, 4, and 6 weeks of treatment with Udvalg for Kliniske Undersogelser side effects scale. The results showed that no gene polymorphisms included in this study affected the susceptibility of nausea and excessive sweating induced by milnacipran. Patients with older age are more likely to develop excessive sweating than others. The major limitation of this study is a small sample size. Further studies with larger populations and more kinds of gene polymorphisms should be needed to see if specific gene polymorphisms determine the susceptibility of side effects induced by milnacipran.

Differential clinical effects of fluvoxamine by the effect of age in Japanese female major depressive patients.

The effects of gender differences and age on the treatment response to fluvoxamine were investigated in major depressive Japanese patients. A total of 100 Japanese patients participated in this study. The daily dose of fluvoxamine was fixed to 100, 150 or 200 mg in the fourth week. This fixed dose was maintained until the end of the 6-week study. The patients were divided into 3 groups: younger females, older females, and males. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) at pretreatment and at 1, 2, 4, and 6 weeks after the commencement of the study. Seven of the 100 patients were excluded, and the remaining 93 patients constituted the subjects (50 females, 43 males). The number of intent-to-treat responders and non-responders was 55 and 38, respectively. There was a significant difference in the changes in the time course of the MADRS score and changes in the MADRS scores at each evaluation point between the younger and older females. Younger females demonstrated a significantly better response than older females. The results suggest that fluvoxamine is more effective in younger female patients than in older female patients.

Predictors of antidepressant response to fluvoxamine obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale for major depressive disorders in Japanese patients.

AIMS: Fluvoxamine, a selective serotonin reuptake inhibitor, is widely used to treat major depression. However, the symptomatological predictors of the response to fluvoxamine have not been studied. METHODS: This study included 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was 21 or higher. Eighty-one patients were included. Patients with a pretreatment MADRS score of >or=31 were defined as 'severe' (n = 32) and the rest were defined as 'non-severe' (n = 49). The three-factor model of MADRS was used for analysis: the first factor was defined by three items, the second factor was defined by four items, and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Fluvoxamine (100-200 mg/day) was administered twice daily for 6 weeks. RESULTS: In the non-severe patients, the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders. However, a significant difference was observed in the mean factor 3 scores from 1 week onwards between the non-severe responders and non-responders. Furthermore, the fluvoxamine response rate in the severe patients was 75% and higher than that of the non-severe patients (65.3%). CONCLUSIONS: This study suggested that a low factor 3 score at pretreatment was a good predictor of the response to fluvoxamine in non-severe patients. The marked efficacy of fluvoxamine in the treatment of severe patients was also confirmed.

No predictors of antidepressant patient response to milnacipran were obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale in Japanese patients with major depressive disorders.

AIMS: Milnacipran, a new specific serotonin and norepinephrine re-uptake inhibitor, is as effective as tricyclic antidepressants. Symptomatological predictors of antidepressant response to milnacipran have not been studied until now. METHODS: This study included 101 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was > or =21. Eighty-three patients were finally included. Patients with a pretreatment MADRS score > or =31 points were defined as severe (n = 28), and the rest as non-severe (n = 55). The three-factor model of MADRS was used for analysis; the first factor was defined by three items, the second factor was defined by four items and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Milnacipran was administered twice daily for 6 weeks. The initial dose was 50 mg/day; after a week it was increased to 100 mg/day. RESULTS: No significant difference was observed in the mean score of first factor, second factor and third factor at pretreatment time between responders and non-responders in both severe and non-severe patients. CONCLUSIONS: No predictor of antidepressant response to milnacipran was obtained using the three-factor structures of the MADRS in Japanese patients with major depressive disorders.

Augmentation with olanzapine in TCA-refractory depression with melancholic features: a consecutive case series.

Using an 8-week, open label study design, we report the effect of augmentation strategy with olanzapine in hospitalized depressive patients with melancholic features who had insufficient response to a tricyclic antidepressant (TCA), amitriptyline. Subjects were hospitalized patients meeting the criteria of DSM-IV major depressive disorder with melancholic features who had been suffering from residual symptoms after treatment of amitriptyline. After study entry, olanzapine was added to amitriptyline and the dose was adjusted according to patients' clinical condition. Data were analyzed using an intent-to-treat methodology, with last observation carried forward. Paired t-test was adopted to assess the data from baseline to endpoint. Of 26 patients who enrolled in this study, 23 patients completed the trial and 3 patients dropped out. The mean dose of olanzapine was 6.5 (SD = 2.4) mg/day. The mean score of Montgomery-Asberg Depression Rating Scale (MADRS) was significantly decreased from 33.6 (SD = 3.5) to 20.8 (SD = 9.1) during this study (37.9% from baseline) (p < 0.001). Ten patients (38.5%) were considered as responders (50% or greater reduction in MADRS scores from baseline). These results suggest that augmentation with olanzapine in TCAs-resistant melancholia may be effective and well tolerated. We cannot draw any conclusion with certainty from the open-label, uncontrolled clinical trial. Double blind, controlled trial is needed to confirm this preliminary finding.

Influence of the tyrosine hydroxylase val81met polymorphism and catechol-O-methyltransferase val158met polymorphism on the antidepressant effect of milnacipran.

OBJECTIVE: Genetic polymorphisms of the noradrenergic pathway can be factors to predict the effect of antidepressants when their pharmacological mechanisms of action include the noradrenergic system. The purpose of the present study was to determine whether the tyrosine hydroxylase (TH) val81met and catechol-O-methyltransferase (COMT) val158met polymorphisms are associated with the antidepressant effect of milnacipran, a serotonin/noradrenaline reuptake inhibitor. METHOD: Eighty-one Japanese patients with major depressive disorder were treated with milnacipran for 6 weeks. Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. RESULTS: The met/met genotype of the COMT val158met polymorphism was associated with a significantly faster therapeutic effect of milnacipran in the MADRS score during this study. No influence of the TH val81met polymorphism on the antidepressant effect of milnacipran was detected. CONCLUSION: These results suggest that the COMT val158met polymorphism in part determines the antidepressant effect of milnacipran.

No association of the G1287A polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a Japanese population.

Norepinephrinergic neurotransmission in the central nervous system have a major impact on the symptomatology in major depressive disorder (MDD), and genetic polymorphisms of norepinephrine transporter (NET) have a possibility to be involved in susceptibility to MDD. We investigated the association of the G1287A (rs5569) polymorphism of the NET gene and susceptibility to MDD by comparing 145 major depressive patients with 164 healthy individuals first in a Japanese population. The genotype frequencies in depressed patients and health volunteers of the NET G1287A polymorphism were 52.4% (G/G), 39.3% (G/A) and 8.3% (A/A) in depressed patients, 61.6% (G/G), 29.9% (G/A allele) and 8.5% (A/A) in healthy volunteers, respectively. The allele frequencies in depressed patients and health volunteers of the NET G1287A polymorphism were 72.1% (G allele) and 27.9% (A allele) in depressed patients, 76.5% (G allele) and 23.5% (A allele) in healthy volunteers, respectively. The genotype distribution and allele frequencies were not significantly different between major depressive patients and healthy volunteers. NET G1287A polymorphism appears not to be an important factor in susceptibility to MDD in a Japanese population.

Gender differences in the clinical effects of fluvoxamine and milnacipran in Japanese major depressive patients.

Gender differences in the treatment response to fluvoxamine (selective serotonin re-uptake inhibitor) and milnacipran (serotonin/norepinephrine re-uptake inhibitor) were investigated in Japanese major depressive patients. A total of 125 Japanese patients was included in the present study. Sixty-six patients received fluvoxamine treatment. The daily dose was 50 mg/day for the first week and increased to 100 mg after 1 week, up to 200 mg after another week. Fifty-nine patients were given milnacipran. The daily dose was 50 mg/day for the first week, and up to 100 mg/day thereafter. Patients were divided into three groups: younger women (<44 years of age), older women (> or =44 years of age) and men. Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS) before treatment and at 1, 2, 4 and 6 weeks after the beginning of the study. In comparison with other groups, younger women treated with fluvoxamine demonstrated a significant difference in the time course of MADRS score change. However, these gender/age-related differences of antidepressant response were not observed in the patients treated with milnacipran. The results suggest that fluvoxamine is more effective in younger female patients than older female patients and male patients, while milnacipran is generally effective irrespective of gender or age.

The G196A polymorphism of the brain-derived neurotrophic factor gene and the antidepressant effect of milnacipran and fluvoxamine.

Prediction of the response to different classes of antidepressants has been an important matter of concern in the field of psychopharmacology. The purpose of the present study was to investigate whether the G196A polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with the antidepressant effect of milnacipran, a serotonin norepinephrine reuptake inhibitor, and fluvoxamine, a selective serotonin reuptake inhibitor. The subjects of our previous study of milnacipran (n = 80) and fluvoxamine (n = 54) were included in the present study. Severity of depression was assessed with the Montgomery Asberg depression rating scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. Polymerase chain reaction was used to determine allelic variants. In all subjects receiving milnacipran or fluvoxamine, the G/A genotype of the BDNF G196A polymorphism was associated with a significantly better therapeutic effect in the MADRS scores during this study. When milnacipran and fluvoxamine-treated subjects were analysed independently, the G/A genotype group showed greater reduction of MADRS scores than other genotype groups, irrespective of which antidepressant was administered. These results suggest that the BDNF G196A polymorphism in part determines the antidepressant effect of both milnacipran and fluvoxamine.

Switching to olanzapine after unsuccessful treatment with risperidone during the first episode of schizophrenia: an open-label trial.

BACKGROUND: The efficacy and safety of switching to olanzapine were investigated in patients with first-episode schizophrenia who failed to attain an adequate clinical response to an initial therapeutic trial of risperidone (2-6 mg/day for 12 weeks). METHOD: A total of 58 first-episode patients with DSM-IV schizophrenia who had residual symptoms following treatment with risperidone were enrolled in an open-label, 12-week study of olanzapine. Dosing was determined by clinical judgment. The main efficacy measure was the Brief Psychiatric Rating Scale (BPRS). Patients with a 20% or greater decrease in BPRS total score plus a final Clinical Global Impressions-Severity of Illness scale score of or= 7%) from baseline. CONCLUSION: Although we cannot draw any conclusion from a study without a control group, favorable outcomes and good tolerance were observed after switching to olanzapine from risperidone in our population. In addition, factors that predicted a good overall response included a relative absence of positive symptoms at baseline and the percentage reduction in total BPRS score at 4 weeks of treatment. Double-blind, crossover trials are needed to confirm these observations.

Switching to risperidone after unsuccessful treatment of olanzapine in the first-episode schizophrenia: an open trial.

The purpose of this study was to assess the effect of switching to risperidone in the treatment of first-episode schizophrenia who had failed to respond to an initial-prescribed antipsychotic, olanzapine. Fifty-one patients with first-episode schizophrenia after unsuccessful treatment of olanzapine (the mean (S.D.) dosage: 16.4 (4.4) mg/day) were included in this switching study. Of the 51 patients, 43 (84.3%) completed the full 12-week trial and 8 (15.7%) dropped out. The mean dosage of risperidone at the endpoint (last observation) was 3.1 (2.0) mg/day. The total scores of Brief Psychiatric Rating Scales (BPRS) were significantly reduced from baseline to endpoint, especially in the positive and excitement factors (p<0.001). Responder rate (at least 20% decrease in BPRS total score plus final Clinical Global Impression score of 3 or less) was 35.3%. These findings indicate that the switching to risperidone could be one of the useful treatment options in this population.