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Objectives: Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD.Methods: 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance.Results: Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed.Conclusions: The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD. [ABSTRACT FROM AUTHOR]

Frailty and disability are commonly found in Late Life Depression (LLD) and have been associated with increased depression severity, health comorbidities and mortality. Additionally, physical frailty has been associated with suicide in later life, independent of presence of a mood disorder. The objective of our study was to assess the associations of physical frailty and functional disability with suicidal ideation, controlling for depression severity and demographic factors, in an older depressed sample. This study used data from community-dwelling older adults with major depression. Eligible participants were ≥ 65 years old, completed measures of depression symptom severity (Hamilton Depression Rating Scale-24 item; HDRS-24), current suicidal ideation (Geriatric Suicide Ideation Scale; GSIS), and physical frailty/functional capacity measures. Participants were 88 older adults with a mean age of 71.5 (SD = 6.0) and 66% of the sample was female. Poorer performance on frailty measures of gait speed (B =.239, p =.003) and muscle weakness (B = −.218, p =.01) were significantly associated with higher levels of suicidal ideation, independent of depression severity and demographic factors. Functional disability was also significantly related to suicide ideation, specifically impairment in financial capacity (B = −.290, p =.008), social interaction (B =.408, p <.001), and communication skills (B =.373, p =.001). Our findings show that, in LLD, frailty and functional disability are significantly associated with higher levels of suicide ideation, independent of depression symptom severity. [ABSTRACT FROM AUTHOR]

Objective: The authors conducted a systematic review and meta-analysis to determine whether the risk of psychosis is higher in past or future episodes in patients with major depression with psychotic features than in patients with nonpsychotic depression.Method: PubMed, Embase, and PsycINFO were searched, and studies were selected that 1) identified patients with unipolar major depression, 2) made diagnoses of psychosis based on the presence of delusions or hallucinations, 3) characterized past or subsequent episodes as psychotic or nonpsychotic, and 4) were published in English. Two meta-analyses were then conducted using data from patients having index depressive episodes with or without psychosis at study entry to determine the risk of any prior or subsequent psychotic episode and the risk of psychosis in all episodes.Results: Twelve studies met the inclusion criteria, and altogether they included 546 psychotic and 1,583 nonpsychotic patients with unipolar depression. In seven of the studies, the risk ratio for a prior or subsequent psychotic episode in patients whose index depressive episode was psychotic compared with those whose index episode was nonpsychotic was 9.98 (95% CI=4.75, 20.94). In eight studies, the risk ratio for psychosis among all episodes of depression in the subgroups with psychotic and nonpsychotic index episodes was 7.24 (95% CI=5.03, 10.43). Differences in risk of psychosis between these subgroups remained robust when potential sources of heterogeneity were explored.Conclusions: The findings support the hypothesis that psychotic depression runs true to form, and they support the distinction between psychotic and nonpsychotic depression. Because patients with psychotic depression are at high risk for psychosis in future episodes, determination of effective preventive treatments is imperative. [ABSTRACT FROM AUTHOR]

• Predictors of response to ESK+AD and AD+PBO were identified in patients with TRD. • ESK+AD treatment, younger age, employment, and low anxiety predicted response. • Fewer failed ADs in the current episode and early response also predicted response. • Odds of achieving response were 68% higher with ESK+AD versus AD+PBO (P = 0.003). • Our findings may identify patients mostly likely to benefit from ESK+AD treatment. This exploratory post hoc analysis of two pooled 4-week, phase 3, double-blind, placebo- and active-controlled studies that compared esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD; n = 310) with a newly initiated oral AD plus placebo nasal spray (AD+PBO; n = 208) in patients with treatment-resistant depression (TRD) examined baseline patient demographic and psychiatric characteristics as potential predictors of response (≥50% reduction from baseline in Montgomery–Åsberg Depression Rating Scale [MADRS] total score) and remission (MADRS total score ≤12) at day 28. Overall, younger age, any employment, fewer failed ADs in the current depressive episode, and reduction in Clinical Global Impression-Severity (CGI-S) score at day 8 were significant positive predictors of response and remission at day 28. Treatment assignment was an important predictor of both response and remission. Patients treated with ESK+AD had 68% and 55% increased odds of achieving response and remission, respectively, versus those treated with AD+PBO. In the ESK+AD group, attainment of response and remission was more likely in patients who were employed, without significant anxiety at baseline, and who experienced a reduction in CGI-S score at day 8. Identification of predictors of response and remission may facilitate identification of those patients with TRD most likely to benefit from ESK+AD. Trial Registration: ClinicalTrials.gov: NCT02417064 (clinicaltrials.gov/ct2/show/NCT02417064) and NCT02418585 (clinicaltrials.gov/ct2/show/NCT02418585) [ABSTRACT FROM AUTHOR]

Background: Patients with major depressive disorder (MDD) who do not adequately respond to antidepressant treatment (ADT) may benefit from adjunctive atypical antipsychotics; however, certain agents target specific symptoms of depression and not the full syndrome. The aim of this analysis was to examine the effects of brexpiprazole, adjunct to ADT, on the core symptoms of MDD, defined using Montgomery-Åsberg Depression Rating Scale (MADRS) items.Methods: This was a post hoc analysis of data from two 6-week, randomized, double-blind studies of adjunctive brexpiprazole in patients with MDD and inadequate response to ADTs (n = 1056). Efficacy was assessed using the MADRS core symptom subscale (MADRS6) and individual items (apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts).Results: At Week 6, adjunctive brexpiprazole showed a greater effect than adjunctive placebo on the MADRS6 (within-group Cohen's d effect sizes: brexpiprazole, 1.05; placebo, 0.71; p < 0.001 between groups) and on each of the six core symptoms (effect sizes: brexpiprazole, 0.64-0.94; placebo, 0.39-0.64; all p < 0.001). At Week 2, adjunctive brexpiprazole already showed a greater effect than adjunctive placebo on the MADRS6, and on five of the core symptoms (all p < 0.01).Limitations: This was a post hoc analysis of studies that were not designed for this purpose. Correction for multiple comparisons was not performed.Conclusions: Brexpiprazole, as adjunct to ADT, produced a statistically significant and clinically meaningful improvement on the core symptoms of MDD. Brexpiprazole is thought to exert its effects in MDD by treating the core symptoms of the disease. [ABSTRACT FROM AUTHOR]

Background: Due to the clinical challenges of treatment-resistant depression (TRD), we evaluated the efficacy of mindfulness-based cognitive therapy (MBCT) relative to a structurally equivalent active comparison condition as adjuncts to treatment-as-usual (TAU) pharmacotherapy in TRD.Methods: This single-site, randomized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program (HEP), comprising physical fitness, music therapy and nutritional education, as adjuncts to TAU pharmacotherapy for outpatient adults with TRD. The primary outcome was change in depression severity, measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D17), with secondary depression indicators of treatment response and remission.Results: We enrolled 173 adults; mean length of a current depressive episode was 6.8 years (SD = 8.9). At the end of 8 weeks of treatment, a multivariate analysis showed that relative to the HEP condition, the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 (36.6 vs. 25.3%; p = 0.01) and a significantly higher rate of treatment responders (30.3 vs. 15.3%; p = 0.03). Although numerically superior for MBCT than for HEP, the rates of remission did not significantly differ between treatments (22.4 vs. 13.9%; p = 0.15). In these models, state anxiety, perceived stress and the presence of personality disorder had adverse effects on outcomes.Conclusions: MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates. MBCT appears to be a viable adjunct in the management of TRD. [ABSTRACT FROM AUTHOR]

Background Lithium augmentation of antidepressants for treatment of unipolar major depression was one of the first adjunctive strategies based on a neuropharmacologic rationale. Randomized controlled trials supported its efficacy but most trials added lithium to tricyclic antidepressants (TCAs). Despite its efficacy, use of lithium augmentation remains infrequent. The current systematic review and meta-analysis examines the efficacy of lithium augmentation as an adjunct to second generation antidepressants as well as to TCAs and considers reasons for its infrequent use. Method A systematic search of Medline and the Cochrane Clinical Trials database was performed. Randomized, placebo-controlled trials of lithium augmentation were selected. A fixed-effects meta-analysis was performed. Odds ratios for response were calculated for each treatment-control contrast, for the trials grouped by type of initial antidepressant (TCA or second generation antidepressant), and as a meta-analytic summary for all treatments combined. Results Nine trials that included 237 patients were selected. The odds ratio for response to lithium vs. placebo in all contrasts combined was 2.89 (95% CI 1.65, 5.05, z=3.72, p=0.0002). Heterogeneity was very low, I²=0%. Adjunctive lithium was effective with TCAs (7 contrasts) and with second generation agents (3 contrasts). Discontinuation due to adverse events was infrequent and did not differ between lithium and placebo. Limitations The meta-analysis is limited by the small size and number of trials and limited data for treatment resistant patients. Conclusions Adjunctive lithium appears to be as effective for second generation antidepressants as it was for the tricyclics. [ABSTRACT FROM AUTHOR]

Residual symptoms of major depressive disorder ( MDD) following treatment are increasingly recognized as having a negative impact on the patient because of their association with lack of remission, poorer psychosocial functioning, and a more chronic course of depression. Although the effects of specific residual symptoms have not been as systematically studied, several symptoms, including fatigue, sleep disturbance, anxiety, and concentration difficulties, commonly occur as part of the residual state in MDD. In particular, the relatively high prevalence of residual fatigue suggests that this symptom is not being adequately addressed by standard antidepressant therapies. A review of the clinical relevance of residual fatigue was undertaken, using the published literature with respect to its assessment, neurobiology, and treatment implications. The findings of this review suggest that fatigue is highly prevalent as a residual symptom; its response to treatment is relatively poor or delayed; and the presence of residual fatigue is highly predictive of inability to achieve remission with treatment as well as impaired psychosocial functioning. Recognition of the significant consequences of residual fatigue should reinforce the need for further therapeutic interventions to help reduce the impact of this symptom of MDD. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to identify factors that moderate outcome in late-life major depression and that identify patients for whom antidepressants have clinically meaningful effects. Method: A previous systematic review identified 10 placebo-controlled trials of second-generation antidepressants in outpatients with major depressive disorder who were age 60 or older. For the present study, the authors obtained from the sponsors of the 10 trials individual patient data, including age, sex, duration of illness (current age minus age at onset), course (single episode or recurrent depression), baseline depression severity, treatment assignment, and outcomes. Logistic regression models were estimated and tested to examine the association of potential moderator variables with treatment response and the treatment group-response interaction. Results: All moderator variables were collected and documented for seven of the 10 trials (N=2,283). Univariate and multivariate analyses were restricted to these seven trials. Illness duration was the only variable significantly associated with drug-placebo differences in the multivariate model. In patients with an illness duration >10 years, baseline depression severity was also significantly associated with drug-placebo differences. In those with an illness duration >10 years and a Hamilton Depression Rating Scale score ≥21, the drug-placebo difference in response rates was relatively robust (number needed to treat=4). In the remaining patients, the drug-placebo difference in response rates was small (46.3% compared with 41.5%). Conclusions: Older patients with a long illness duration and moderate to severe depression appear to benefit from antidepressants as compared with placebo. Antidepressants do not appear to be effective for older patients with short illness duration. [ABSTRACT FROM AUTHOR]

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness. [ABSTRACT FROM AUTHOR]

The article discusses a research study on antidepressants and its efficacy for the treatment of late-life major depressive disorder (MDD). Study subjects include elderly and late-life patients with MDD in a randomized placebo-controlled trials for antidepressants including amitriptyline, imipramine and clomipramine and compared them with various studies. Conclusions indicated there is antidepressant efficacy in late-life MDD and reduced efficacy in MDD patients 65 years old and older.

Objectives: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy. Methods: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint. Results: Four hundred and nine older patients (placebo, n¼198; aripiprazole, n¼211) and 679 younger patients (placebo, n=341; aripiprazole, n=338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p<0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p<0.001) and younger (26.9% vs. 16.4%; p<0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. Conclusions: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine the efficacy of antidepressants in people with depression and dementia. DESIGN: A systematic review and meta-analysis based on a literature search of Medline and Cochrane Trials Registry for acute-phase, double-blind, placebo-controlled, parallel-design, random-assignment trials of antidepressants marketed in the United States. SETTING: Outpatient clinics, inpatient units, residential settings. PARTICIPANTS: People with criterion-based diagnoses of dementia and depression. MEASUREMENTS: Numbers of participants randomized; baseline and end point depression scale scores; and response, remission, and discontinuation rates were extracted. Random-effects meta-analyses were performed for response and remission rates, change scores using standardized mean differences, and discontinuation rates. Sensitivity analyses were planned to examine effects of depression diagnosis, severity, and trial duration. RESULTS: Seven trials with 330 participants met selection criteria. The odds ratio (OR) for six trials reporting response rates with antidepressant and placebo was 2.12 (95% confidence interval (CI)=0.95-4.70; Z=1.84, P=.07). The OR for five trials reporting remission rates was 1.97 (95% CI=0.85-4.55; Z=1.59, P=.11). Both analyses demonstrated heterogeneity. The standardized mean difference in trials was 0.29 (95% CI=0.02-0.60, Z=1.86, P=.06). This analysis did not demonstrate significant heterogeneity. Adverse event discontinuation rates (9.0%) were not significantly higher with drug than placebo (6.0%), and were low. CONCLUSION: The evidence for antidepressant treatment of people with depression and dementia, although suggestive, does not confirm efficacy. All of the trials were significantly underpowered to detect differences, resulting in inconclusive findings. Variable trial methods, comorbid conditions, and differences in antidepressants employed further confounded findings. [ABSTRACT FROM AUTHOR]

Background: Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of ''accelerated aging'' in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation. Methodology: Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex. Principal Findings: The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p<0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure (⩾9.2 years' cumulative duration) was 281 base pairs shorter than that in controls (p<0.05), corresponding to approximately seven years of ''accelerated cell aging.'' Telomere length was inversely correlated with oxidative stress in the depressed subjects (p<0.01) and in the controls (p<0.05) and with inflammation in the depressed subjects (p<0.05). Conclusions: These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure. [ABSTRACT FROM AUTHOR]

Background: Uncontrolled antidepressant trials suggest that anxious patients with major depressive disorder (MDD) are less responsive to antidepressant treatment than less anxious patients. The objective of this study is to determine whether specific antidepressant effects, estimated by drug-placebo differences, are reduced in anxious depression during treatment of MDD with duloxetine. Methods: This is a retrospective secondary pooled analysis of all placebo-controlled trials of duloxetine at therapeutic doses conducted by the sponsor in outpatients with nonpsychotic unipolar MDD, using the Hamilton Depression Rating Scale (HAMD). Anxious depression was defined by ≥7 on the anxiety/somatization factor of the HAMD. Response was defined as ≥50% improvement from baseline to endpoint on the HAMD. Remission was defined as an endpoint HAMD≤7. Analyses were performed in the intent-to-treat sample with at least one post-treatment rating. Results: Eleven trials included 2,841 patients of whom 1,326 were classified as anxious and 1,515 as nonanxious. Change on the HAMD was greater with duloxetine than placebo in both anxious (9.91 versus 7.55, P<.001) and nonanxious (6.65 versus 5.23, P<.001) patients. Level of anxiety had no effect on the drug–placebo differences. Response and remission rates were significantly greater in duloxetine than placebo-treated patients and drug–placebo differences were unaffected by anxious status. Use of HAMD items psychic and somatic anxiety to define anxious subgroups had similar outcomes. Conclusions: Duloxetine was more effective than placebo in achieving response and remission in both anxious and nonanxious patients. Anxious status did not affect the magnitude of the drug effect. Depression and Anxiety, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Background: Although antipsychotic agents have a long history of use in depression, their effectiveness in treating core symptoms of depression such as loss of interest has been questioned. Adjunctive aripiprazole is beneficial for the treatment of patients with major depressive disorder but its effects on specific symptoms have not been reported. The objective of this study was to examine the effects of aripiprazole on core symptoms of depression. Methods: This is a post-hoc, pooled analysis of two trials of aripiprazole augmentation of standard antidepressants (ADT) in patients with major depression. Patients with an inadequate response to ADT received adjunctive aripiprazole (n =373) or placebo (n =368) for 6weeks. Change on four subscales of the 17-item Hamilton Depression Rating Scale (HAM-D17) that capture core depression symptoms was determined and change on individual HAM-D items also was assessed. The magnitude of within-group change for the subscales and individual items was expressed as effect size (ES) and between-group significance tested with ANCOVA. The magnitude of change was also examined comparing the response rates for aripiprazole and placebo on HAM-D17 and the four subscales. Change on three composite subscales — anxiety, insomnia and drive was also examined. Results: Within-group change on the four core subscales was substantial (ES=1.1–1.2) and similar to that for the 17-item HAM-D total score. Between-group comparisons indicated mean change and response rates were significantly greater with adjunctive aripiprazole than placebo for each core subscale (all p <0.01). Individual HAM-D17 items showing the greatest change from baseline with adjunctive aripiprazole: depressed mood (within-group ES=1.03) work and activities (ES=0.86), guilt (ES=0.77) and psychic anxiety (ES=0.67) are the same symptoms identified by each of the core subscales and each of these items differed significantly from change on that item with placebo (p <0.01). On three composite scales, adjunctive aripiprazole was significantly more effective than placebo with respect to mean change for anxiety, insomnia and drive (all p <0.001). Conclusions: Aripiprazole augmentation of standard ADT results in significant, clinically meaningful changes in the core symptoms of depression. It is also associated with significant change in anxiety, insomnia, and drive components of the 17-item HAM-D. [Copyright &y& Elsevier]

Objective: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder. Method: Searches were conducted of MEDLINE/PubMed (1966 to January 2009), the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events. Results: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo (response: odds ratio 1.69, 95% Cl=1.46-1.95, z=7.00, N=16, p<0.00001; remission: odds ratio=2.00, 95% Cl=1.69-2.37, z=8.03, N=16, p<0.00001). Mean odds ratios did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo (odds ratio=3.91, 95% CI=2.68-5.72, z=7.05, N=15, p<0.00001). Conclusions: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events. [ABSTRACT FROM AUTHOR]

Objective Previous studies of mixed aged and older adult samples with major depressive disorder (MDD) reported reduced depression response in anxious patients, but a systematic review and analysis has not been performed. Our aim was to determine if anxiety predicts antidepressant response in previously identified placebo-controlled trials of second generation antidepressants for late-life depression. Method From a previous systematic review that identified ten randomized, placebo-controlled trials of community dwelling patients aged 60 or older with major depression, anxious patients were identified by a score ≥7 on the anxiety/somatization factor of the Hamilton Depression Rating Scale (HDRS). Response was defined as 50% or greater improvement on the HDRS or the Montgomery Asberg Depression Rating Scale. A meta-analysis was performed using a random effects model to calculate Odds Ratios (OR). Results Data were available from eight trials having ten drug-placebo contrasts that included 2322 anxious and 1387 non-anxious patients. The odds ratio for response to drug compared to placebo in anxious patients was 1.57 (95% CI 1.15, 2.14; z = 2.86, n = 10, p < 0.001), in non-anxious patients was 1.44 (95% CI 1.15, 1.80, z = 3.21, n = 10, p < 0.001), and did not differ between groups. Pooled response rates to drug and placebo respectively were 49.4% vs 37.4% in anxious patients and 44.2 vs 35.5% in non-anxious patients. Conclusions In randomized, placebo-controlled trials, anxiety in late-life depression was not associated with decreased response to second generation antidepressants. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of adjunctive ziprasidone in treatment for major depression and adjunctive atypical antipsychotics. Information about the randomized controlled trial in patients who received adjunctive ziprasidone, is provided. An overview on the comparison of ziprasidone with other atypical antipsychotics, is also examined.

The article discusses a study which investigated the effectiveness of adjunctive aripiprazole as an antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with baseline anxious/atypical features. The study defined anxious depression using a Hamilton Rating Scale for Depression, while atypical depression was defined using a criteria on the Inventory of Depressive Symptomatology--Self-Report. Study researchers concluded that adjunctive aripiprazole is effective in patients with major depression.

Abstract: The goal of the present work was to conduct a meta-analysis comparing reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n =2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and reboxetine (59.2%)-treated groups (p =0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p =0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p =0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD. [Copyright &y& Elsevier]

Background Treatment studies of depression in residential care are limited. Reports of predictors of response are rare. In the largest nursing home prospective antidepressant trial reported, we examined predictors of response. Methods This was a 12-week open-label study of mirtazapine orally disintegrating tablets performed in 30 US nursing homes. Subjects were men and women aged ≥70, with a Mini Mental State Exam (MMSE) score ≥10, who had a depressive disorder that required antidepressant treatment. Mirtazapine was started at 15 mg at bedtime, and adjusted to 15–45 mg/day. A 16-item Hamilton Depression Rating Scale was used to assess depression at baseline, weeks 2, 4, 8, and 12 or early termination. Results One hundred and twenty-four patients received at least one dose of study drug and of these, 119 had at least one post-drug assessment. Mean age was 82.9 years and 72% were female. Response rates at 12 weeks were 47% on the HAMD and 54% on the CGI. Age, sex, MMSE score, medical burden, history of prior depression, and baseline HAMD severity were not significantly associated with HAMD response (≥50% improvement) and in most cases correlations were trivial, <0.1. Advanced age, medical burden, and cognitive impairment did not predict adverse events. Conclusions In this sample of depressed nursing home residents treated with mirtazapine orally disintegrating tablets, advanced age, medical illness, and cognitive impairment did not predict response. The findings suggest that these variables need not be viewed as obstacles to treatment. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To determine effects of sertraline on suicidal thinking and behavior in patients with late-life major depression. Methods: This was a secondary analysis of an eight-week, placebo-controlled, double-blind randomized trial of a multi- center trial at 66 clinical sites. Outpatients ≥60 years of age with major depression and a Hamilton Depression Rating (HAMD) score ≥18 were included. Intervention was sertraline 50-100 mg/day or placebo for eight weeks. Measurements were 17-item HAMD administered at baseline and two-week intervals. HAMD Item 3 used to assess suicidal ideation (SI) and behavior. Reports of serious adverse events (SAEs), adverse events (AEs) leading to discontinuation, and spontaneously reported adverse events reviewed. Results: A total of 747 patients received at least one dose of medication, and 728 had at least one posttreatment assessment. Mean age (±5D) was 69.8 ± 67 years (range: 59-97 years) and 56% were female. There were no completed suicides or suicide at- tempts during the double-blind trial. One SAE, hospitalization, was associated with SI in a patient on sertraline. No other AEs were associated with SI or behavior. HAMD Item 3 ratings progressively declined during the trial with significantly lower values for sertraline than placebo (Z= 2.41, p <0.02). In 248 patients with HAMD Item 3 of zero at baseline, the percentage of patients whose Item 3 ratings increased during treatment did not differ in the two groups (22.4% versus 25.8% for sertraline and placebo, respectively.) Conclusion: Sertraline was associated with significantly lower HAMD Item 3 scores than placebo during treatment. There was no evidence of greater emergent suicidal thinking or behavior with sertraline than placebo. [ABSTRACT FROM AUTHOR]

Objective: To conduct a systematic examination of the relationship between depression and crying by reviewing all relevant theory and empirical data including the performance of crying items in measures of depression. Method: Review of the extant literature on depression and crying using PubMed, PsychInfo and Google Scholar databases. Results: Scores on crying items of depression inventories correlate moderately with overall depression severity. Otherwise, there is surprisingly little evidence for the widespread claim that depression leads to more frequent and/or easier crying. There is also little empirical support for the competing claim that severely depressed individuals lose their capacity to cry. Conclusion: Current claims about the relationship between depression and crying lack a robust empirical foundation. Assessment instruments and diagnostic systems for mood disorders are inconsistent in how they handle crying as a symptom. Further work to investigate the causes and the context of crying in depressed patients is needed. [ABSTRACT FROM AUTHOR]

Background: We examined two previously published studies comparing a norepinephrine (NE) selective agent, reboxetine, and a serotonin (5-HT) selective agent, fluoxetine, to determine if these agents have different effects on individual depressive symptoms. Methods: Both studies were 8-week, double-blind, comparison studies of men and women with DSM III-R major depression. Within-group effect sizes for individual symptom change on the Hamilton Depression Rating Scale (HAMD) were determined in the observed case samples and in patients for whom the symptom was relatively severe at baseline. We required that any significant differences in one sample be cross-validated in the second. Results: Two hundred fifty-three subjects in study I and 168 subjects in study II were randomized to reboxetine or fluoxetine. In both samples, depressed mood, decreased interest, and psychic anxiety had the greatest change. Effect sizes for all HAMD symptoms were similar for the two drugs. No difference between groups in one sample was replicated in the second. Among subjects with severe symptoms, no significant differences were cross-validated. Conclusions: Reboxetine and fluoxetine appear to have similar effects on depressive symptoms. These data suggest that NE and 5-HT selective antidepressant drugs act through the same final common pathway and challenge the belief that symptom differences are useful for antidepressant selection. [Copyright &y& Elsevier]

: BackgroundAlthough several antidepressants are now available, all have limited efficacy and a delayed onset of action. The current study was undertaken as a proof of the concept that combining norepinephrine and serotonin reuptake inhibition would be more effective and act more rapidly than either drug alone.: MethodsInpatients with nonpsychotic unipolar major depression and a Hamilton Depression Rating Scale (HAMD) score of at least 18 after 1 week of hospitalization without antidepressant medication were randomized to 6 weeks of treatment with fluoxetine (FLX) 20 mg/day, desipramine (DMI) adjusted to an adequate plasma level, or the combination of FLX 20 mg/day and DMI, given under double-blind conditions. Twenty-four-hour DMI levels were used to rapidly adjust DMI dose to achieve a therapeutic level and to anticipate the enzyme-inhibiting effects of FLX. Treatment-resistant patients were stratified. Patients were rated with the HAMD and the Montgomery-Asberg Depression Rating Scale (MADRS).: ResultsThirty-nine patients began treatment. One patient withdrew consent. The DMI–FLX combination was significantly more likely to result in remission on the MADRS than either FLX or DMI alone [53.8% vs. 7.1% and 0%, respectively; χ2(2) = 13.49, p = .001]. The advantage for combined treatment was not explained by history of treatment resistance or by drug plasma concentrations. Rapid response, at 1 or 2 weeks, was neither statistically nor meaningfully greater with combined treatment.: ConclusionsThis study supports the hypothesis that the combination of a noradrenergic and serotonergic agent is more likely to result in remission than either selective agent alone during a 6-week treatment period. [Copyright &y& Elsevier]

Objective: There have been few placebo-controlled trials of selective serotonin reuptake inhibitors for depressed elderly patients. This placebo-controlled study of sertraline was designed to confirm the results of non-placebo-controlled trials. Method: The subjects were outpatients age 60 years or older who had a DSM-IV diagnosis of major depressive disorder and a total score on the 17-item Hamilton Depression Rating Scale of 18 or higher. The patients were randomly assigned to 8 weeks of double-blind treatment with placebo or a flexible daily dose of 50 or 100 mg of sertraline. The primary outcome variables were the Hamilton scale and Clinical Global Impression (CGI) scales for severity and improvement. Results: A total of 371 patients assigned to sertraline and 376 assigned to placebo took at least one dose. At endpoint, the patients receiving sertraline evidenced significantly greater improvements than those receiving placebo on the Hamilton depression scale and CGI severity and improvement scales. The mean changes from baseline to endpoint in Hamilton score were -7.4 points (SD=6.3) for sertraline and -6.6 points (SD=6.4) for placebo. The rate of CGI-defined response at endpoint was significantly higher for sertraline (45%) than for placebo (35%), and the time to sustained response was significantly shorter for sertraline (median, 57 versus 61 days). There were few discontinuations due to treatment-related adverse events, 8% for sertraline and 2% for placebo. Conclusions: Sertraline was effective and well tolerated by older adults with major depression, although the drug-placebo difference was not large in this 8-week trial. [ABSTRACT FROM AUTHOR]

Compares the efficacy, tolerability, and safety of paroxetineand nortriptyline in depressed patients with ischemic heart disease. Characteristics of depressed patients with heart disease; Completion or discontinuation of paroxetine or nortriptyline treatment; Hamilton Depression Rating Scale scores.

Treatment of refractory depression is a common challenge for mental health professionals. To assure optimal treatment, the clinician should first determine that adequate dosage has been employed for an adequate duration. Next there are a variety of augmentation strategies or alternative antidepressants that could be considered. This report reviews the evidence supporting these strategies, describes their implementation, compares their effectiveness, and offers suggestions for approaching the array of treatments available. Depression and Anxiety 5:165–174, 1997. © 1997 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The authors examined the value of the dexamethasone suppression test (DST) for predicting response of patients with unipolar, non psychotic major depression to 1 week of hospitalization without antidepressant drugs and to a 4-week trial of desipramine at a fixed plasma level. The rates of response to hospitalization without drug treatment (defined as a score of 12 or less on the Hamilton Rating Scale for Depression) were not significantly different for the patients with a positive DST and those with a negative DST. This finding differs from those of prior studies of the DST and response to placebo. The responses of the DST-positive and DST-negative patients to desipramine also did not differ, a finding that replicates those in some prior reports. [ABSTRACT FROM AUTHOR]

The article discusses research on the effectiveness of antidepressant treatment in elderly patients with long duration of illness. It references a study by J. C. Nelson et al published in an issue of the "American Journal of Psychiatry." The place-controlled trials assessed several factors associated with the disease including cognitive impairment and baseline depression in patients aged 60 and older. Result showed that the second-generation antidepressant treatment was better than the placebo.

The author reflects on a study which demonstrates the successful use of adjunctive L-methylfolate as treatment for patients with major depressive disorder. He says that study involved two trials, the comparison of L-methylfolate and placebo in 148 patients with nonpsychotic unipolar depression and the use of 15 milligrams per day (mg/day) L-methylfolate or placebo in 75 patients. He is interested on the impact of L-methylfolate's long-term administration in depressed individuals.

El autor ofrece sus opiniones sobre el tratamiento de la depresión ansiosa. El autor cuestiona los resultados del estudio "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D). Se discute el significado del termino "ansiosa" según los médicos y los autores de estudios que abordan el trastorno.

This article presents an overview of the study regarding anxious depression. The study demonstrates that among 2,876 patients with major depression, those who were more anxious were more likely to experience adverse events and were less likely to respond and remit during citalopram treatment. The difference in response rates between anxious and nonanxious groups in the Sequenced Treatment Alternative to Relieve Depression sample is 41.7 percent and 52.8 percent, respectively, considering the magnitude of differences observed in recent placebo-controlled trials in depression and antidepressant comparison studies.

The article comments the study on the sequential series of treatments for depression. The author stresses the aspects which made this study differs from typical clinical trials. An overview of the reasons behind the decline of remission rates in patients is offered. He asserts that the study provides an interesting information about relapse but it limits in offering comparisons between treatment strategies.

Objective: Major depressive disorder is associated with elevated mortality rates that increase with the severity of depression. The authors hypothesized that patients with psychotic depression would have higher mortality rates than patients with nonpsychotic depression. Method: Survival analytic techniques were used to compare the vital status of 61 patients with psychotic major depression with that of 59 patients with nonpsychotic major depression up to 15 years after hospital admission. Medical status was assessed ,with the Cumulative Illness Rating Scale. Dexamethasone suppression test (DST) data were available for 101 patients. Results: The mortality rate for subjects with psychotic depression was significantly greater than that for those with nonpsychotic depression, with 41% versus 20%, respectively, dying within 15 years after hospital admission. A proportional hazards model with age and medical status entered as covariates confirmed a significantly higher mortality rate in patients with psychotic depression (hazards ratio=2.31). A positive DST result was associated with psychotic depression but was not related to vital status. Conclusions: Patients with psychotic depression have a twofold greater risk of death than do patients with severe, nonpsychotic major depression. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various topics within the issue including high rates of suicide in Korea and Japan, and underreporting of depression in Asia.

Deals with the use of selective serotonin reuptake inhibitors in the treatment of depression. Studies which demonstrated that interruption of the synthesis of 5-HT or norepinephrine compromised the antidepressant effect of drugs; Effectiveness of antidepressants that combine noradrenergic and serotonergic mechanisms; Mechanism of action of the mirtazapine drug.

Mean age at onset was not significantly different in 39 delusional and 70 nondelusional unipolar depressed patients over 60 years of age. The finding was unchanged when sex, concurrent dementia, and medical illness were examined. [ABSTRACT FROM AUTHOR]

Three patients suffering from major depressive disorder with melancholia and unresponsive to a three-week trial of adequate dosage of phenelzine, received lithium. Each responded within a five-day period. The similarity to lithium augmentation of tricyclic treatment is noted and discussed. [ABSTRACT FROM AUTHOR]

The article reports on a clinical trial which showed that mirtazapine orally disintegrating tablets were well tolerated and effective in reducing depression in nursing home residents 85 years of age or older. The study reported a mean increase in weight among treated subjects of 1.1 lbs by day 28 and 1.32 lbs by day 84.

Background: Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response.Methods: Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale.Results: Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders.Limitations: The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain.Conclusions: The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed. [ABSTRACT FROM AUTHOR]

Background Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes. Methods GBM was applied to pooled data from 12 randomised clinical trials of 4987 participants experiencing an acute depressive episode who were treated with duloxetine, an SSRI or placebo to predict treatment remission. Additional analyses were conducted on the same dataset using the logistic regression model for comparison between these two methods. Results With GBM, there were noticeable differences between treatments when identifying which and to what extent variables were associated with remission. A single logistic regression only revealed a decreasing or increasing relationship between predictors and remission while GBM was able to reveal a complex relationship between predictors and remission. Limitations These analyses were conducted post-hoc utilising clinical trials databases. The criteria for constructing the analyses data were based on the characteristics of the clinical trials. Conclusions GBM can be used to identify and quantify patient variables that predict remission with specific treatments and has greater flexibility than the logistic regression model. GBM may provide new insights into inter-individual differences in treatment response that may be useful for selecting individualised treatments. Trial registration IMPACT clinical trial number 3327; IMPACT clinical trial number 4091; IMPACT clinical trial number 4689; IMPACT clinical trial number 4298; NCT00071695; NCT00062673; NCT00036335; NCT00067912; NCT00073411; NCT00489775; NCT00536471; NCT00666757 (note that trials with IMPACT numbers predate mandatory clinical trial registration requirements) [ABSTRACT FROM AUTHOR]

Abstract: Background: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. Methods: Data from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25–30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. Results: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, −2.5 [−4.0 to −1.1]; moderate, −3.2 [−4.9 to −1.6]; severe, −4.5 [−6.8 to −2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. Limitations: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. Conclusions: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. Clinical trial registration: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758. [Copyright &y& Elsevier]

Abstract: Objective: We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment. Method: After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6mg/24h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse. Results: For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis. Conclusions: While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD. [Copyright &y& Elsevier]

Abstract: Objectives: The “neurotrophin hypothesis” of depression posits a role of brain-derived neurotrophic factor (BDNF) in depression, although it is unknown whether BDNF is more involved in the etiology of depression or in the mechanism of action of antidepressants. It is also unknown whether pre-treatment serum BDNF levels predict antidepressant response. Methods: Thirty un-medicated depressed subjects were treated with escitalopram (N=16) or sertraline (N=14) for 8weeks. Twenty-five of the depressed subjects completed 8weeks of antidepressant treatment and had analyzable data. Twenty-eight healthy controls were also studied. Serum for BDNF assay was obtained at baseline in all subjects and after 8weeks of treatment in the depressed subjects. Depression ratings were obtained at baseline and after 8weeks of treatment in the depressed subjects. Results: Pre-treatment BDNF levels were lower in the depressed subjects than the controls (p=0.001) but were not significantly correlated with pre-treatment depression severity. Depression ratings improved with SSRI treatment (p<0.001), and BDNF levels increased with treatment (p=0.005). Changes in BDNF levels were not significantly correlated with changes in depression ratings. However, pre-treatment BDNF levels were directly correlated with antidepressant responses (p<0.01), and “Responders” to treatment (≥50% improvement in depression ratings) had higher pre-treatment BDNF levels than did “Non-responders” (p<0.05). Conclusions: These results confirm low serum BDNF levels in un-medicated depressed subjects and confirm antidepressant-induced increases in BDNF levels, but they suggest that antidepressants do not work simply by correcting BDNF insufficiency. Rather, these findings are consistent with a permissive or facilitatory role of BDNF in the mechanism of action of antidepressants. [Copyright &y& Elsevier]

Background: Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. Methods: Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Results: Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019–1.101). Conclusions: Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom’s National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of depressed patients treated with SSRI /serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms. [Copyright &y& Elsevier]

Depression is a common disorder that impacts on all aspects of a person’s life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data. [Copyright &y& Elsevier]