Improvement of psychic and somatic symptoms in adult patients with generalized anxiety disorder: examination from a duloxetine, venlafaxine extended-release and placebo-controlled trial.

BACKGROUND: This study examined the efficacy and tolerability of duloxetine and venlafaxine extended-release (XR) treatment for generalized anxiety disorder (GAD), with a secondary focus on psychic and somatic symptoms within GAD. METHOD: The design was a 10-week, multi-center, double-blind placebo-controlled study of duloxetine (20 mg or 60-120 mg once daily) and venlafaxine XR (75-225 mg once daily) treatment. Efficacy was measured using the Hamilton Anxiety Rating Scale (HAMA), which includes psychic and somatic factor scores. Tolerability was measured by occurrence of treatment-emergent adverse events (TEAEs) and discontinuation rates. RESULTS: Adult out-patients (mean age 42.8 years; 57.1% women) with DSM-IV-defined GAD were randomly assigned to placebo (n=170), duloxetine 20 mg (n=84), duloxetine 60-120 mg (n=158) or venlafaxine XR 75-225 mg (n=169) treatment. Each of the three active treatment groups had significantly greater improvements on HAMA total score from baseline to endpoint compared with placebo (p=0.01-0.001). For the HAMA psychic factor score, both duloxetine treatment arms and venlafaxine XR demonstrated significantly greater improvement compared with placebo (p=0.01-0.001). For the HAMA somatic factor score, the mean improvement in the duloxetine 60-120 mg and venlafaxine XR groups was significantly greater than placebo (p0.05 and p0.01 respectively), whose mean improvement did not differ from the duloxetine 20 mg group (p=0.07). Groups did not differ in study discontinuation rate due to adverse events. CONCLUSIONS: Duloxetine and venlafaxine treatment were each efficacious for improvement of core psychic anxiety symptoms and associated somatic symptoms for adults with GAD.

Serotonergic genes and suicidality.

Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of depressive illness and suicidal behavior. Studies have shown that the number of brain and platelet serotonin transporter binding sites are reduced in patients with depression and in suicide victims, and that the density of 5-HT2A receptors is increased in brain regions of depressed in suicide victims and in platelets of depressed suicidal patients. Genes that code for proteins, such as tryptophan hydroxylase, 5-HT transporter, and 5-HT2A receptor, involved in regulating serotonergic neurotransmission, have thus been major candidate genes for association studies of suicide and suicidal behavior. Recent studies by our group and by others have shown that genetic variations in the serotonin-system-related genes might be associated with suicidal ideation and completed suicide. We have shown that the 102 C allele in 5-HT2A receptor gene was significantly associated with suicidal ideation (chi2 = 8.5. p < .005) in depressed patients. Patients with a 102 C/C genotype had a significantly higher mean HAMD item #3 score (indication of suicidal ideation) than T/C or T/7 genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression and not with depression itself. We also found that the 5-HT transporter gene S/L polymorphism was 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 was 2.1 (95% CI 1.2-3.7). The association between polymorphism in serotonergic genes and suicidality supports the hypothesis that genetic factors can modulate suicide risk by influencing serotonergic activity.

Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder.

BACKGROUND: Abnormalities in functioning of the central serotonergic system have been implicated in the pathogenesis of depressive illness and suicidal behavior. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, therefore, it may play an important role in regulation or control of serotonin functions. The aim of the present investigation was to determine whether there is an association between TPH gene polymorphism and major depression. particularly in patients with suicidal ideation. METHODS: A total of 135 unrelated patients suffering from major depressive disorder and 196 normal unrelated controls were included in the study. All controls and patients were Caucasian. A biallelic polymorphism at the tryptophan hydroxylase locus was genotyped. RESULTS: No significant difference between controls and depressed subjects in TPH gene polymorphism was detected. There was no association between TPH gene polymorphism and suicidal ideation. Total HAMD scores were not different between the genotypes or alleles in patients. However, among the HAMD clusters, somatic anxiety was significantly associated with TPH genotypes and alleles in that patients with 218A/A genotype had a significantly higher somatic anxiety scores compared to other genotypes. LIMITATION: Potential confounding effect of population stratification can not be excluded. The functional relevance of the TPH gene 218A/C polymorphism is, at present, uncertain. CONCLUSION: The polymorphism in serotonergic system related genes may be associated with depressive symptoms in major depressive disorder. The results suggest that analysis of clusters that narrow down the phenotype may be more suitable in genetic studies of major depressive illness.

New standard of depression treatment: remission and full recovery.

Major depressive disorder (MDD) is a chronic disorder that substantially impairs a patient's psychosocial and occupational functioning. Lifetime prevalence rates for MDD vary widely, ranging from 4.4% to approximately 20%, and it is predicted to become the second leading cause of disability by the year 2020. The magnitude of this public health problem, with its associated decreased quality of life, increased risk of suicide, loss of productivity, and increased health care use, underscores the importance of treating depressed patients to full remission. The presence of residual depressive symptoms due to partial or incomplete remission is associated with significant morbidity and mortality. Hence, complete remission should be the goal in the treatment of patients with MDD because it leads to a symptom-free state and a return to premorbid levels of functioning. Full remission and improved long-term prognosis can be achieved with long-term antidepressant therapy with newer agents that work through multireceptor mechanisms, especially through the serotonergic and noradrenergic systems (i.e., dual action). Robust efficacy and greater remission rates have been associated with dual-action agents.

An examination of the sensitivity of the six-item Hamilton Rating Scale for Depression in a sample of patients suffering from major depressive disorder.

OBJECTIVES: To compare the sensitivity of the 6-item Hamilton Rating Scale for Depression (HRSD6) with the more widely used 17-item Hamilton Rating Scale for Depression (HRSD17) in patients suffering from major depressive disorder, with or without melancholia and/or dysthymic disorder. A secondary objective was to compare the sensitivity of the HRSD6 to the Montgomery-Asberg Depression Rating Scale (MADRS). DESIGN: Retrospective analysis of 4 clinical trials that tested antidepressant therapies. SETTING: Outpatient treatment in a major psychiatric hospital. PARTICIPANTS: One hundred and forty-three male and female outpatients meeting the criteria of the DSM-III-R or DSM-IV for major depressive disorder. OUTCOME MEASURES: HRSD17, HRSD6 and MADRS. RESULTS: The HRSD6 correlated strongly with the HRSD17, both at baseline and termination of treatment, and for the subgroups of double depression and melancholia. The HRSD6 was also correlated significantly with the MADRS at both measurement times, and for the subgroups. Paired t-tests with the HRSD6, HRSD17 and MADRS demonstrated equal sensitivity to change over the course of treatment, both in the full sample and in the dysthymic and melancholic subgroups. CONCLUSIONS: The HRSD6 appears to be as sensitive to change over treatment as the HRSD17 and the MADRS. A shorter, less time-consuming measure of depression may have utility in clinical practice and research.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Gender differences in association between serotonin transporter gene polymorphism and personality traits.

Since Lesch and colleagues reported an association between anxiety-related traits (Neuroticism) and a functional polymorphism in the serotonin transporter gene regulatory region (5-HTTLPR), there have been several reports on 5-HTTLPR and personality traits with both positive and negative results. The present study was a further attempt to replicate the original findings of Lesch et al. in a population of well-defined normal healthy subjects. In addition, a variable number tandem repeat polymorphism in the second intron was included in this study because it has recently been shown to act as a transcriptional regulator. Personality traits were evaluated in 186 unrelated normal subjects by the NEO Five Factor Inventory. The most important and novel finding of this study was a significant association of mean Neuroticism scores with the short allele of 5-HTTLPR in male subjects (t = 2.4, P = 0.018). We were thus able to replicate the finding of Lesch et al. of an association between serotonin transporter gene polymorphism (5-HTTLPR) and Neuroticism, but only in a male population. We also found a significant effect of gender on mean scores of Neuroticism [F = 3.9, degrees of freedom (df) = 1, 180, P = 0.05] and Agreeableness (F = 6.8, df = 1, 180, P = 0.01), but no significant effect of 5-HTTLPR genotype on Neuroticism (F = 0.87, df= 2, 180, P = 0.42) or Agreeableness (F = 0.35, df = 2, 180, P = 0.7). These findings suggest that gender differences exist in contribution of genetic factors to behavioural phenotypes. They may also explain the inconsistencies in previous reports on association of Neuroticism with 5-HTTLPR from studies using different proportions of male and female subjects.

Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression.

The monoamine neurotransmitters serotonin, norepinephrine and dopamine have been implicated in the pathogenesis of depression, schizophrenia and mood disorders. The mechanism of action of certain antidepressant drugs, particularly the tricyclics and the newly available norepinephrine and serotonin reuptake inhibitors (NSRIs) drugs, venlafaxine and nefazodone, suggest that the norepinephrine transporter, which is a target for these antidepressant drugs, and its malfunction may be involved in major depression. In this association study, we tested the hypothesis that variants of the human norepinephrine transporter (NET) gene confer susceptibility to major depression. One hundred and five patients with major depression and 74 unrelated matched controls were analyzed for a silent 1287G/A polymorphism (NET-8) in exon 9 of the NET gene. No significant differences in genotype or allele frequencies were found between controls and patients, nor between subgroups of depressed patients classified by suicidal ideation. In addition, 60 controls and 60 patients were genotyped for a missense substitution Thr99Ile in exon 2 of the NET gene (NET-1), but only one control was heterozygous for this variant. These results suggest that the NET gene is unlikely to be involved in the susceptibility to major depression.

Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial.

This was an 8-week, multicenter, open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada. Inpatients or outpatients aged 18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression (HAM-D-21) score of 2 > or = 18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant. Treatment with venlafaxine was started at 37.5 mg twice daily, and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator's assessment of clinical response and tolerability. Of the 159 patients enrolled, 152 were evaluable for efficacy. The mean daily venlafaxine dose was 260 mg/day. The mean HAM-D-21 score decreased by 52%, and the mean Montgomery-Asberg Depression Rating Scale score decreased by 50% from baseline to day 56. A response (50% improvement from baseline) was achieved by 58% of patients on the HAM-D-21, and a remission (> or = 75% improvement in the HAM-D-21) was observed in 28% at day 56. By day 56, 88% of patients had improved from baseline on the Clinical Global Impression Improvement scale. Only 8% of the patients discontinued for adverse events. The most common adverse events were headache, insomnia, nausea, constipation, diaphoresis, and xerostomia. In conclusion, these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression.

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.