Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder.

BACKGROUND: Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). METHODS: This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. RESULTS: All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. CONCLUSION: These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.

A Prospective, Longitudinal Study of the Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with Treatment-Resistant Depression.

BACKGROUND: Magnetic resonance imaging studies have provided evidence of structural modifications in cortical-limbic regions in major depressive disorder. To date, however, few studies have tracked structural changes in patients during treatment. This prospective, longitudinal imaging study investigated associations between brain structure and clinical responsiveness in a sample of patients with treatment-resistant major depressive disorder during an approximate 1-year follow-up period. METHODS: FreeSurfer software was used to extract volume or cortical thickness values from 6 regions of interest (hippocampus, rostral middle frontal gyrus, orbitofrontal cortex, rostral and caudal anterior cingulate cortices, and inferior temporal gyrus) in patients (n = 26) and matched healthy controls (n = 28). Regions of interest were selected based on previous evidence of potential associations between morphometric characteristics in these regions and treatment response or remission. Analyses were conducted to compare volume and cortical thickness in patients and controls at baseline imaging, determine whether patients' brain structure at treatment initiation was associated with response over follow-up, and compare longitudinal changes in volume and cortical thickness in patients who achieved sustained 6-month remission (Montgomery-Åsberg Depression Rating Scale Score ≤12) with nonremitters. RESULTS: Patients and controls showed no structural differences at baseline. Among patients, thicker right caudal anterior cingulate cortex at baseline was associated with greater symptom improvement over follow-up. Remitters and nonremitters showed subtle changes in volume and thickness over time in opposing directions, with increased hippocampal volume and cortical thickness in the rostral middle frontal gyrus, orbitofrontal cortex, and inferior temporal gyrus in remitters, and decreased volume or thickness in these regions in nonremitters. CONCLUSIONS: The results suggest that longitudinal structural trajectories may differ in major depressive disorder patients according to their clinical response to treatment.

Impact of monoamine-related gene polymorphisms on hippocampal volume in treatment-resistant depression.

OBJECTIVE: In major depressive disorder (MDD), single nucleotide polymorphisms (SNPs) in monoaminergic genes may impact disease susceptibility, treatment response, and brain volume. The objective of this study was to examine the effect of such polymorphisms on hippocampal volume in patients with treatment-resistant MDD and healthy controls. Candidate gene risk alleles were hypothesised to be associated with reductions in hippocampal volume. METHODS: A total of 26 outpatients with treatment-resistant MDD and 27 matched healthy controls underwent magnetic resonance imaging and genotyping for six SNPs in monoaminergic genes [serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), serotonin 1A and 2A receptors (HTR1A and HTR2A), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF)]. Hippocampal volume was estimated using an automated segmentation algorithm (FreeSurfer). RESULTS: Hippocampal volume did not differ between patients and controls. Within the entire study sample irrespective of diagnosis, C allele-carriers for both the NET-182 T/C [rs2242446] and 5-HT1A-1019C/G [rs6295] polymorphisms had smaller hippocampal volumes relative to other genotypes. For the 5-HTTLPR (rs25531) polymorphism, there was a significant diagnosis by genotype interaction effect on hippocampal volume. Among patients only, homozygosity for the 5-HTTLPR short (S) allele was associated with smaller hippocampal volume. There was no association between the 5-HT2A, COMT, and BDNF SNPs and hippocampal volume. CONCLUSION: The results indicate that the volume of the hippocampus may be influenced by serotonin- and norepinephrine-related gene polymorphisms. The NET and 5-HT1A polymorphisms appear to have similar effects on hippocampal volume in patients and controls while the 5-HTTLPR polymorphism differentially affects hippocampal volume in the presence of depression.

A multifaith spiritually based intervention for generalized anxiety disorder: a pilot randomized trial.

This pilot trial evaluated the efficacy of a multifaith spiritually based intervention (SBI) for generalized anxiety disorder (GAD). Patients meeting DSM-IV criteria for GAD of at least moderate severity were randomized to either 12 sessions of the SBI (n=11) delivered by a spiritual care counselor or 12 sessions of psychologist-administered cognitive-behavioral therapy (CBT; n=11). Outcome measures were completed at baseline, post-treatment, and 3-month and 6-month follow-ups. Primary efficacy measures included the Hamilton Anxiety Rating Scale, Beck Anxiety Inventory, and Penn State Worry Questionnaire. Data analysis was performed on the intent-to-treat sample using the Last Observation Carried Forward method. Eighteen patients (82%) completed the study. The SBI produced robust and clinically significant reductions from baseline in psychic and somatic symptoms of GAD and was comparable in efficacy to CBT. A reduction in depressive symptoms and improvement in social adjustment was also observed. Treatment response occurred in 63.6% of SBI-treated and 72.3% of CBT-treated patients. Gains were maintained at 3-month and 6-month follow-ups. These preliminary findings are encouraging and suggest that a multifaith SBI may be an effective treatment option for GAD. Further randomized controlled trials are needed to establish the efficacy of this intervention.

A Hospital-based Study of the Prevalence and Usage of Complementary and Alternative Medicine Among Saudi Psychiatric Patients.

Introduction Complementary and alternative medicine (CAM) therapies, used singularly or in combination with more conventional therapies, are routinely used by citizens of the Kingdom of Saudi Arabia (KSA) for medical care or seeking wellness. However, the prevalence of CAM therapies among Saudi psychiatric patients is not yet documented. To better understand the importance of CAM in today's medical field, particularly within the KSA and for psychiatric patients, this descriptive study aims to characterize the use of CAM therapies by a sample of psychiatric patients in the KSA. Methods This cross-sectional hospital-based study describes the use of CAM therapies by Saudi psychiatric patients being treated at one of the largest government hospitals in the KSA. Using a pretested questionnaire, adult psychiatric patients waiting for their appointment or during their stay at a government hospital in Riyadh were interviewed regarding the use of CAM therapies after agreeing to participate. Results Forty-five adult psychiatric patients agreed to participate in this study. The average age of the participants in the study was 35. Of the participants, 62% were females, 91.1% were outpatients, and 44.4% were diagnosed with depression. Moreover, 82.2% of the participants reported using one or more types of CAM therapies within the past year to address mental illness. Of those who used CAM therapies, 62.2% did so to improve their quality of life; 59.5% did so for treatment, supportive treatment, or both, and 54.1% used CAM therapies to help control symptoms. The most frequent CAM therapies used by psychiatric patients were spiritual therapies such as Quran recitation; body therapies, mainly exercise; and mind therapies, mainly relaxation techniques. These CAM therapies were used mainly as treatments or supportive treatments for depression. Most of the participants who used CAM therapies were satisfied with the use of these therapies (75.7%). Finally, 45.9% of the participants had not discussed the use of CAM therapies with their doctors, primarily because of their reluctance to share private information, especially spiritual matters, with the treating physicians. Conclusions The study results suggest a high prevalence of CAM therapy use among Saudi adult psychiatric patients, as well as a high level of satisfaction with such therapies. However, since about half of the patients had not discussed the use of CAM therapies with their physicians, and since some of the CAM therapies may cause unfavorable interactions when used alongside certain medications or medical interventions, healthcare providers should be diligent about inquiring of their psychiatric patients any use of CAM therapies, not only during the initial visit but also during the follow-up visits as well.

Brain-volume increase with sustained remission in patients with treatment-resistant unipolar depression.

OBJECTIVE: Previous magnetic resonance imaging (MRI) studies have demonstrated brain-volume reductions in unipolar major depressive disorder (MDD). It is not clear whether these atrophic changes can be stabilized with antidepressant treatment and/or reversed with remission. The objective of this study was to prospectively examine brain-volume changes in patients with treatment-resistant depression, comparing those who achieved sustained remission with those who did not remit. METHOD: This prospective observational cohort study investigated the roles of clinical responsiveness and antidepressant treatment in lessening brain atrophy in depression. Data were collected between October 2004 and December 2008. Baseline MRI scans were obtained from 28 outpatients with treatment-resistant MDD (diagnosed according to DSM-IV criteria) who were recruited from the Mood Disorders Research Unit at the Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada. Twenty-seven patients underwent follow-up scanning after either 6 months of sustained remission (Montgomery-Asberg Depression Rating Scale score ≤ 12) or 12 months of failure to remit. Longitudinal whole-brain and voxel-based gray- and white-matter volume changes were estimated. RESULTS: Twelve patients (mean age at baseline = 47.5 years) achieved sustained 6-month remission. In contrast to nonremitters (n = 15; mean age at baseline = 44.3 years), remitted patients demonstrated a significant mean increase in whole-brain volume during follow-up (F(1,27) = 9.51, P = .005). Within-subject voxel-based morphometry analyses identified increased gray-matter volume in remitters in the right orbitofrontal cortex (t(11) = 7.61, P = .006) and the right inferior temporal gyrus (t(11) = 6.65, P = .004). Nonremitters showed decreased white-matter volume in the left anterior limb of the internal capsule (t(13) = 3.86, P = .04). CONCLUSIONS: Given that remitters exhibited a mean increase in brain volume while nonremitters lost volume, pharmacotherapy in the absence of sustained remission is most likely insufficient to elicit brain-volume increase in MDD. The findings suggest that clinical remission rather than pharmacotherapy may be the key factor involved in driving volumetric recovery in treatment-resistant depression.