Levomilnacipran ER 40 mg and 80 mg in patients with major depressive disorder: a phase III, randomized, double-blind, fixed-dose, placebo-controlled study.

BACKGROUND: Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an antidepressant approved for the treatment of MDD in adults. METHODS: This 10-week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Åsberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated-measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. RESULTS: The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/day group. Study completion rates were similar among the groups (76%-83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (-3.3 [-5.5 to -1.1], p = 0.003) and 80 mg/day (-3.1, [-5.3 to -1.0], p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (-1.8, 95% [-3.6 to 0], p = 0.046) and 80 mg/day (-2.7 [-4.5 to -0.9], p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (≥ 5% and ≥ double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction. LIMITATIONS: Limitations to our study included short treatment duration and lack of an active control arm. CONCLUSION: Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population. CLINICAL TRIAL REGISTRATION: NCT01377194.

Cutoff score of the sexual interest and desire inventory-female for diagnosis of hypoactive sexual desire disorder.

OBJECTIVE: To determine the most appropriate cutoff value for the Sexual Interest and Desire Inventory-Female (SIDI-F) score to discriminate between women with hypoactive sexual desire disorder (HSDD) and those with no female sexual dysfunction (FSD). The SIDI-F is a clinician-rated instrument consisting of 13 items designed to assess HSDD severity in women. The total score ranges from 0 to 51, with higher scores indicating better sexual function. METHODS: Data from patients enrolled in a North American nontreatment study and a European nontreatment study were analyzed. Both studies were 4-week, prospective, multicenter trials designed to assess the reliability and validity of the SIDI-F. Only patients with HSDD or no FSD were included in this analysis. Receiver operating characteristics (ROC) analysis was used to determine the ability of the SIDI-F to differentiate between patients with HSDD and those with no FSD at baseline. RESULTS: A total of 428 women were included in this analysis: 174 from North America (HSDD 113, no FSD 61) and 254 from Europe (HSDD 130, no FSD 124). In the North American study, a SIDI-F cutoff score of 33 minimized the difference between sensitivity (94.7%) and specificity (93.4%). In the European study, SIDI-F cutoff scores of both 33 and 34 minimized the difference between sensitivity (95.2%) and specificity (94.4%). CONCLUSIONS: In appropriately screened women, a SIDI-F score of ≤33 indicates the presence of HSDD.

Measuring the severity of depression and remission in primary care: validation of the HAMD-7 scale.

BACKGROUND: Symptomatic remission is the optimal outcome in depression. A brief, validated tool for symptom measurement that can indicate when remission has occurred in mental health and primary care settings is unavailable. We evaluated a 7-item abbreviated version (HAMD-7) of the 17-item Hamilton Depression Rating Scale (HAMD-17) in a randomized controlled clinical trial of patients with major depressive disorder being cared for in primary care settings. METHODS: We enrolled 454 patients across 47 primary care settings who met DSM-IV-TR criteria for a major depressive disorder. Of these, 410 patients requiring antidepressant medication were randomized to have their symptoms rated with either HAMD-7 (n = 205) or HAMD-17 (n = 205) as the primary measurement tool. The primary outcome was the proportion of patients who achieved a-priori defined responses to 8 weeks of therapy using each instrument. RESULTS: Of the 205 participants per group, 67% of those evaluated with HAMD-7 were classified as having responded to therapy (defined as a > or = 50% reduction from the pretreatment score), compared with 74% of those evaluated with HAMD-17 (p = 0.43). The difference between the groups' changes in scores from baseline (pretreatment) to endpoint was significant (p < 0.001), without a main effect of group (p = 0.84) or group-by-time (p = 0.83) interaction. The HAMD-7 test was brief to administer (e.g., 3-4 min for 85% of the primary care physicians evaluated), which facilitated the efficient and structured evaluation of salient depressive symptoms. INTERPRETATION: The abbreviated HAMD-7 depression scale is equivalent to the HAMD-17 in assessing remission in patients with a major depressive disorder undergoing drug therapy.

MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males.

We investigated whether the genetic variants of the MAO-A gene were associated with major depression and/or the clusters of depressive symptoms. The EcoRV and the uVNTR polymorphisms were studied in a population of 191 patients with major depression and 233 control subjects. The EcoRV polymorphism was found to be associated with depression in males but not in females. Haplotype analysis revealed that one of the haplotypes (EcoRV2-uVNTR1) was significantly more frequent among male patients than male controls. Among the HAMD symptom clusters, insomnia scores were significantly higher in male patients carrying allele 2 of the EcoRV polymorphism. These data suggest that the EcoRV and uVNTR polymorphisms may be involved in the pathogenesis of major depression and associated with insomnia in depressed patients.

Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response.

Antidepressants, such as serotonin or noradrenaline reuptake inhibitors (e.g. fluoxetine, nefadozone) or 5-HT1A agonists (flibanserin), desensitize the 5-HT1A autoreceptor, which may contribute to their clinical efficacy. The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide. Depressed patients (n=118) were treated with antidepressants including fluoxetine or nefadozone combined with pindolol or flibanserin alone. The severity of depression was assesssed using the Hamilton Rating Scale for Depression. Although patients had similar severity initially, those with the homozygous G(-1019) genotype responded significantly less to flibanserin (p=0.039) and in pooled antidepressant treatment groups (p=0.0497) and were approximately twice as likely to be non-responders as those with the C(-1019)C genotype. These results implicate the C(-1019)G 5-HT1A gene polymorphism as a potential marker for antidepressant response, suggesting a role for repression of the 5-HT1A gene.

Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide.

Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.

Assessing full remission.

The 17-item Hamilton Rating Scale for Depression (HAM-D17) has been used for 4 decades as the "gold standard" instrument to assess the severity of depression and response to therapy in clinical research. The clinical utility of the HAM-D17 is hampered, in part, by the length of time required to administer the interview and by concern about a lack of inter-rater reliability. Several groups have developed shorter versions of the HAM-D17 for use in clinical practice. However, despite extensive research highlighting the importance of achieving full remission in minimizing the risk of relapse and recurrence, these shortened questionnaires have not been validated for the task of distinguishing between remission and response. A shortened form of the HAM-D17 with cut-off scores for full remission would offer a useful tool that physicians could readily employ in clinical practice. On the basis of the responses of a sample of 292 patients with major depression who received standard clinical treatment at a tertiary university affiliated hospital (Depression Clinic, Centre for Addiction and Mental Health, Toronto Ont.) we derived a shortened version of the HAM-D. Seven items with the greatest frequency of occurrence and sensitivity to change with treatment were identified and designated as the Toronto HAM-D7. A score of 3 or less on the Toronto HAM-D7 was found to correlate with the 17-item HAM-D definition of full remission (i.e., score of 7 or less).

The neurobiology of treatment response to antidepressants and mood stabilizing medications.

As the neurobiology of mood disorders and the mechanisms of action of antidepressant drugs continue to be elucidated, there has been a shift in emphasis from changes in neurotransmitter release and metabolism to regulation of gene expression and neuroprotection. Evidence from animal studies suggests that drug therapy may act on specific transcription factors and target genes that regulate processes such as neuroprotection and neuronal survival. Clinical studies consistently identify changes in prefrontal cortex, hippocampus and amygdala that may be related to the course of illness and may be prevented with successful treatment. Together, these findings suggest that clinically relevant neurobiological correlations may ultimately be identified in patients who respond and remit to treatment. With these and future advances in the neuroscience of psychiatry, it may be possible to identify biological markers that will help in decisions about specific treatments for an individual patient.

High activity-related allele of MAO-A gene associated with depressed suicide in males.

Abnormalities in brain monoamine oxidase A activity have been implicated in the pathogenesis of depressive illness and suicidal behavior. The present investigation was to determine whether there is an association between MAO-A gene polymorphism and depressed suicide. The EcoRV polymorphism in MAO-A gene with alleles associated with enzyme activity was studied in postmortem brain samples from 44 depressed suicide victims and 92 control subjects of the same ethnic background. We have found significant differences in genotype/allele distribution between depressed suicide victims and controls in males (p = 0.012) but not in females or the total sample. The odds ratio (OR) for the high activity-related allele of the MAO-A gene associated with depressed suicide in males was 3.1. Our finding suggests that MAO-A may be a susceptibility gene in depressed male suicide victims. The results thus provide further evidence that genetic factors can modulate risk for depression, suicide or both by influencing monoaminergic activity in sexually dimorphic manner.

Does fluoxetine influence major depression by modifying five-factor personality traits?

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression, though response to them is difficult to predict. The aims of this study were two-fold: (1) to determine the differences in personality profile between patients with major depression and healthy control subjects and (2) to assess the effect of treatment with fluoxetine on personality domain scores and determine whether any of the personality traits can predict the outcome of antidepressant treatment. METHODS: The study included 53 patients with major depression and 53 healthy controls. The NEO-Five-Factor Inventory (NEO-FFI) was administered to all subjects before and after 24 weeks of treatment with fluoxetine. RESULTS: The patients in an episode of major depression had a significantly different personality profile compared to healthy controls at baseline and the severity of their illness correlated with higher scores in the Neuroticism domain. Treatment with fluoxetine was associated with a reversal of high Neuroticism scores and low Extraversion scores in the whole sample and in a subgroup of responders but not in non-responders. Among the FFI personality domains, Agreeableness was a better predictor of treatment outcome than baseline HAMD-17 scores. LIMITATIONS: There was no placebo group, which would have permitted the evaluation of the effect of non-drug factors in treatment outcome and changes in personality domain scores. The sample size was only moderate. CONCLUSIONS: The results suggest that (a) significant differences exist between the personality profiles of depressed patients and healthy control subjects and (b) responders to treatment with fluoxetine show significant changes in personality profile. These changes may be attributed to improvement of depressive symptoms.

Tryptophan hydroxylase gene 218A/C polymorphism is not associated with depressed suicide.

Abnormalities in functioning of the central serotonergic system are believed to be involved in the pathogenesis of depressive illness and suicidal behaviour. Recently, polymorphism in the tryptophan hydroxylase (TPH) gene has been studied for association with aggression, anger-related traits and suicidal behaviour, but the results are inconclusive. The present investigation was to determine whether there are differences in genotype and allele distribution of the TPH gene 218A/C polymorphism in post-mortem brain samples from 35 depressed suicide victims and 84 control subjects of the same ethnic background. A functional polymorphism in the promoter region of 5-HT transporter gene was also re-examined in this increased sample size. No significant difference in TPH gene 218A/C polymorphism between controls and depressed suicide victims was detected. This may suggest that the TPH gene has no significant effect on suicidality in depressed subjects. In a previous study on a smaller sample we found the frequency of the long allele of 5-HT transporter gene to be higher in depressed suicide victims. In this increased sample size, both the genotype and alleles of the 5-HT transporter gene were significantly associated with completed suicide. The frequency of the L/L genotype in depressed suicide victims was almost double of that found in control group (48.6 vs. 26.2%). The odds ratio for the L allele associated with depressed suicide was 2.1 (95% CI, 1.2-3.7). The relatively small sample size does not exclude the possibility of false-positive results and the finding needs replication.