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Background: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co‐occurring manic symptoms affect treatment response. Methods: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate‐Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline‐based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. Results: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co‐occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. Conclusions: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline‐based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment‐by‐indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants. [ABSTRACT FROM AUTHOR]

Background: Up to 15% of patients with major depressive disorder (MDD) attempt suicide and up to 2% complete suicide. This was a post-hoc analysis aimed to evaluate the risk of suicide ideation and behavior associated with adjunctive pimavanserin treatment in adults with MDD.Methods: CLARITY was a randomized, double-blind, placebo-controlled study in patients with MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). For this post-hoc analysis, the primary endpoint was mean change from baseline for HAMD item 3 (suicide). The incidence of suicidal ideation or behavior was also assessed from the Columbia-Suicide Severity Rating Scale (C-SSRS) and reports of adverse events.Results: During Stage 1, LS mean change for HAMD Item 3 was reduced from baseline at each week with pimavanserin with a significant difference between pimavanserin and placebo at Week 3 (p=0.012, effect size: 0.431). At any post-baseline assessment, suicidal ideation on the C-SSRS was reported in 28 (18.1%) of patients with placebo and 9 (17.3%) with pimavanserin during Stage 1 and in 7 (20.7%) with placebo and 4 (13.8%) with pimavanserin during Stage 2. No events of suicidal behavior were observed with either placebo or pimavanserin.Limitations: The post hoc nature, exclusion of patients with any history of suicide from the primary study, and the small number of patients who demonstrated evidence of suicidal ideation.Conclusions: Adjunctive pimavanserin was not associated with an increase in suicidal ideation in patients with MDD. Further study is needed to verify these results. [ABSTRACT FROM AUTHOR]

Background: Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study.Methods: Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined.Results: Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo.Conclusions: Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction. [ABSTRACT FROM AUTHOR]

Importance: Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear.Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD.Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018.Interventions: Maintenance of or withdrawal from treatment with ADM.Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases.Results: A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88).Conclusions and Relevance: Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear.Trial Registration: ClinicalTrial.gov identifier: NCT00057577. [ABSTRACT FROM AUTHOR]

Background: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. Methods: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. Results: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. Conclusions: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. Trial registration: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014. [ABSTRACT FROM AUTHOR]

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.Design, Setting, and Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.Main Outcomes and Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.Conclusions and Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.Trial Registration: ClinicalTrials.gov identifier: NCT02493868. [ABSTRACT FROM AUTHOR]

Objective: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.Methods: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.Results: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.Conclusions: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression. [ABSTRACT FROM AUTHOR]

Objective: Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association. Methods: We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression (n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression. Results: Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups. Conclusion: Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population. [ABSTRACT FROM AUTHOR]

Background: The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup.Methods: We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission.Results: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup.Conclusion: Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample. [ABSTRACT FROM AUTHOR]

Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD).Design, Setting, and Participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings.Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks.Main Outcomes and Measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy).Conclusions and Relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials.Trial Registration: clinicaltrials.gov identifier: NCT01998958. [ABSTRACT FROM AUTHOR]

Background: Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stress-related disorders such as major depression and PTSD.Methods: A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted.Results: Based on the Comprehensive Meta-Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD.Limitations: The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size.Conclusions: These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD. [ABSTRACT FROM AUTHOR]

Objective: Prior research suggests a bidirectional relationship between obesity and major depressive disorder (MDD), but the results have been heterogeneous. Differences between males and females in the association of MDD with obesity may contribute to inconsistent results. Thus, this study was designed to determine whether sex has a differential effect on the relationship between MDD and obesity, and to explore the potential mechanisms. Methods: All participants were diagnosed with MDD, and depression severity was measured using the 17-item Hamilton Depression Rating Scale. Body weight and height were measured to calculate body mass index (BMI). Body composition, including total fat, trunk fat, android fat, and visceral fat mass, was measured by dual-energy X-ray absorptiometry. Subjects provided blood samples, and serum was extracted for measuring the inflammatory factors using human immunoassay kits. results: Among all obesity measures, depressed women had greater BMI and total body fat. By contrast, depressed men had greater visceral fat mass. However, only in depressed women was depression correlated with several measures of obesity, including BMI, total body fat, and visceral fat mass. A stepwise multiple regression analysis was conducted, and only visceral fat entered the regression model and was most predictive of depression in women (β = 0.60, p = 0.007). Moreover, compared with depressed men, depressed women had higher leptin levels after controlling for BMI, total body fat, and visceral fat. conclusion: These results highlight gender differences in determining the association between obesity and depression, and elevated leptin level is a potential mechanism linking MDD to obesity in depressed women. Understanding a gender-specific relationship between obesity and MDD would allow clinicians to target and personalize therapies in the hope of improving health outcomes. [ABSTRACT FROM AUTHOR]

Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n = 20), MDD patients with (n = 14) or without serious suicidal ideation (n = 10), we studied methylation of the stress-associated genes, Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1). In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population. [ABSTRACT FROM AUTHOR]

Objective: Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.Method: In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).Results: In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.Conclusions: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days. [ABSTRACT FROM AUTHOR]

Background: Meta-analyses of placebo-controlled trials of SSRIs suggest that only a small portion of the observable change in depression may be attributed to "true" pharmacological effects. But depression is a multidimensional construct, so treatment effects may differ by symptom cluster. We tested the hypothesis that SSRIs uniquely alter psychological rather than somatic symptoms of depression and anxiety. Method: Outpatients with moderate to severe MDD were randomly assigned to receive paroxetine (n = 120) or placebo (n = 60). Results: Paroxetine significantly outperformed placebo on all psychological subscales of the syndrome measures, but not on any of the somatic subscales. The difference in score reduction between paroxetine and placebo was more than twice as great for the psychological symptoms compared to the somatic symptoms. Conclusions: Paroxetine appears to have a “true” pharmacological effect on the psychological but not on the somatic symptoms of depression and anxiety. Paroxetine's influence on somatic symptoms appears to be mostly duplicated by placebo. [ABSTRACT FROM AUTHOR]

Background: Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality.Methods: The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions-Bipolar Version) were conducted at baseline and follow-up.Results: The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs.Limitations: The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up.Conclusions: The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to test the efficacy of adjunctive ziprasidone in adults with nonpsychotic unipolar major depression experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram.Method: This was an 8-week, randomized, double-blind, parallel-group, placebo-controlled trial conducted at three academic medical centers. Participants were 139 outpatients with persistent symptoms of major depression after an 8-week open-label trial of escitalopram (phase 1), randomly assigned in a 1:1 ratio to receive adjunctive ziprasidone (escitalopram plus ziprasidone, N=71) or adjunctive placebo (escitalopram plus placebo, N=68), with 8 weekly follow-up assessments. The primary outcome measure was clinical response, defined as a reduction of at least 50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D). The Hamilton Anxiety Rating scale (HAM-A) and Visual Analog Scale for Pain were defined a priori as key secondary outcome measures.Results: Rates of clinical response (35.2% compared with 20.5%) and mean improvement in HAM-D total scores (-6.4 [SD=6.4] compared with -3.3 [SD=6.2]) were significantly greater for the escitalopram plus ziprasidone group. Several secondary measures of antidepressant efficacy also favored adjunctive ziprasidone. The escitalopram plus ziprasidone group also showed significantly greater improvement on HAM-A score but not on Visual Analog Scale for Pain score. Ten (14%) patients in the escitalopram plus ziprasidone group discontinued treatment because of intolerance, compared with none in the escitalopram plus placebo group.Conclusions: Ziprasidone as an adjunct to escitalopram demonstrated antidepressant efficacy in adult patients with major depressive disorder experiencing persistent symptoms after 8 weeks of open-label treatment with escitalopram. [ABSTRACT FROM AUTHOR]

Importance: Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone.Objective: To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD).Design, Setting, and Participants: A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved.Interventions: Antidepressant medication with or without CT.Main Outcomes and Measures: Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation.Results: Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6% vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95% CI, 1.06-1.68; number needed to treat [NNT], 10; 95% CI, 5-72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3% vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95% CI, 1.54-3.57; NNT, 3; 95% CI, 2-5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9% vs 26.8%; t451 = -2.04; P = .04; HR, 0.66; 95% CI, 0.45-0.98). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode.Conclusions and Relevance: Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression.Trial Registration: clinicaltrials.gov Identifier: NCT00057577. [ABSTRACT FROM AUTHOR]

Objective: The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). Method: In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/ day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the L-methylfolate dosage was 15 mg/day during both 30-day periods. Results: In the first trial, no significant differencewas observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolatewas well tolerated, with rates of adverse events no different from those reported with placebo. Conclusions: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs. [ABSTRACT FROM AUTHOR]

The article presents information on the study of Ziprasidone as mono therapy for Major Depressive Disorder (MDD). According to the author vivo affinity and insufficient dose of Ziprasidone with a good placebo response and remission rates are the possible reason why Ziprazidone is not better than placebo in MDD.

Objective: Previous research has found that therapist adherence to concrete, problem-focused cognitive therapy (CT) techniques predicts depressive symptom change (e.g., Feeley, DeRubeis, & Gelfand, 1999). More recently, Strunk, DeRubeis, Chui, and Alvarez (2007) demonstrated that in-session evidence of patients' use of CT skills was related to a lower rate of relapse in the year following CT for depression. The current investigation attempts to integrate and extend these findings within 2 separate samples of patients and therapists. Method: Drawing from the CT samples (N = 105, mean age = 40 years, female = 62%, White = 82%) of 2 published randomized clinical trials of depression treatment, we conducted analyses to examine whether therapist adherence to concrete CT techniques (Collaborative Study Psychotherapy Rating Scale) and the quality of the therapeutic alliance (Working Alliance Inventory) predict patients' use of CT skills (Performance of Cognitive Therapy Strategies) and subsequent Beck Depression Inventory symptom change. Results: Results indicated a differential pattern of prediction in the 2 samples. In one, CT techniques exhibited a stronger association with patient CT skills and symptom change than did the alliance, whereas the reverse pattern emerged in the second sample. A baseline symptom severity X CT techniques interaction indicated that between-study differences in intake depression severity might in part explain the process-outcome differences. Conclusions: The present findings suggest that the nature of the therapy sample examined may moderate process-outcome findings in psychotherapy research. The implications of these results and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Background Polymorphism of the serotonin transporter gene, 5-HTTLPR (short allele) has been associated with depression. The purpose of this study was to show the evaluated depression in patients with head and neck cancer and a possible association with the 5-HTTLPR. Methods The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID for DSM-IV) was administered to 94 patients with head and neck cancer, of which 33 patients were genotyped for 5-HTTLPR. We also evaluated the prevalence of 5-HTTLPR polymorphism in 121 patients with head and neck cancer and 97 controls. Results Forty-three percent of the patients met the criteria for a depressive diagnosis, 19% of which was new onset. In depressed patients, 85.7% ( n = 12 of 14) had at least 1 short allele versus 68.4% ( n = 13 of 19) of the patients without depressive diagnosis ( p < .04). No difference was noted in the prevalence of the short allele in head and neck cancer cases versus controls (odds ratio = 0.8; p = .490). Conclusion Despite the high rate of depressive diagnosis, patients with head and neck cancer did not demonstrate a higher prevalence of this short allele of the 5-HTTLPR compared with a control population.© 2011 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

The article discusses about the potential of lamotrigine as an antidepressant augmentation medication for patients with treatment-resistant unipolar depression. The study was conducted on unipolar depression patients aged 18 to 65 years, where patients were provided either dosages of lamotrigine or placebo. Results revealed similarities on the mental health progress of patients who were given placebo and those who had lamotrigine.

Objective: Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. Method: The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology-Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition. Results: Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%-52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41 .8%-46.6%), response rates (57.4%-59.4%), and most secondary outcomes were not significantly different. Conclusions: Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events. [ABSTRACT FROM AUTHOR]

Objective: The therapeutic alliance has been linked to symptom change in numerous investigations. Although the alliance is commonly conceptualized as a multidimensional construct, few studies have examined its components separately. The current study explored which components of the alliance are most highly associated with depressive symptom change in cognitive therapy (CT). Method: Data were drawn from 2 published randomized, controlled clinical trials of CT for major depressive disorder (n = 105, mean age = 40 years, female = 62%, White = 82%). We examined the relations of 2 factor-analytically derived components of the Working Alliance Inventory (WAI; Horvath & Greenberg, 1986, 1989) with symptom change on the Beck Depression Inventory—II (BDI-II; Beck, Steer, & Brown, 1996) that occurred either prior to or subsequent to the examined sessions. WAI ratings were obtained at an early and a late session for each therapist-patient dyad. Results: Variation in symptom change subsequent to the early session was significantly related to the WAI factor that assesses therapist-patient agreement on the goals and tasks of therapy but not to a factor assessing the affective bond between therapist and patient. In contrast, both factors, when assessed in a late session, were significantly predicted by prior symptom change. Conclusions: These findings may reflect the importance, in CT, of therapist-patient agreement on the goals and tasks of therapy. In contrast, the bond between therapist and patient may be more of a consequence than a cause of symptom change in CT. The implications of these results and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Obesity and related metabolic conditions are of epidemic proportions in most of the world, affecting both adults and children. The accumulation of lipids in the body in the form of white adipose tissue in the abdomen is now known to activate innate immune mechanisms. Lipid accumulation causes adipocytes to directly secrete the cytokines interleukin (IL) 6 and tumor necrosis factor α (TNFα), but also monocyte chemoattractant protein 1 (MCP-1), which results in the accumulation of leukocytes in fat tissue. This sets up a chronic inflammatory state which is known to mediate the association between obesity and conditions such as cardiovascular disease, type 2 diabetes, and cancer. There is also a substantial literature linking inflammation with risk for depression. This includes the observations that: (1) people with inflammatory diseases such as multiple sclerosis, cardiovascular disease, and psoriasis have elevated rates of depression; (2) many people administered inflammatory cytokines such as interferon α develop depression that is indistinguishable from depression in non-medically ill populations; (3) a significant proportion of depressed persons show upregulation of inflammatory factors such as IL-6, C-reactive protein, and TNFα; (4) inflammatory cytokines can interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. While many factors may contribute to the association between inflammatory mediators and depression, we hypothesize that increased adiposity may be one causal pathway. Mediational analysis suggests a bi-directional association between adiposity and depression, with inflammation possibly playing an intermediary role. [Copyright &y& Elsevier]

The article focuses on a study which estimated the relative benefit of medication versus placebo across a wide range of initial symptom severity in patients diagnosed with depression using information from several databases, which include the Cochrane Library database. The study observed that as a function of baseline severity, medication and placebo differences varied substantially. It concluded that the magnitude benefit of antidepressant medication compared with placebo increases with severity of depression symptoms, but it can also be minimal or nonexistent, on average, in patients with mild or moderate symptoms.

We evaluated the efficacy, tolerability, and safety of olanzapine monotherapy in 20 adult patients with bipolar I or II disorder, depressed phase. Patients received open-label olanzapine monotherapy (mean modal dose, 15 mg/day) for 8 weeks. Assessments of psychopathology (Montgomery–Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology [QIDS-SR-16], Young Mania Rating Scale [YMRS]), clinical global state (Clinical Global Impressions [CGI] scale), and safety/tolerability were performed at baseline, and at 1, 2, 4, 6, and 8 weeks. Seventeen patients (85.0%) completed the study. Improvement in MADRS total scores was observed after the first week of treatment, and at all remaining follow-up time points (p ≤ 0.005). Parallel improvement in QIDS-SR-16 (p < 0.001) and CGI-Severity (p < 0.001) was observed between baseline and study endpoint. Nine (45%) subjects achieved positive treatment response, eight of whom (40%) also achieved symptom remission. There were significant increases in weight (+3.2 kg, p = 0.001) and body mass index (+1.1 kg/m2, p = 0.001), but not fasting glucose or lipids, with the exception of reduced triglyceride levels in the overall sample, and reduced HDL cholesterol in females. Olanzapine may be an effective, well-tolerated option for treating acute non-psychotic depression across a variety of bipolar disorder subtypes. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article offers tips on modifying treatment plan to meet the changes in the needs of depressed patients. The ultimate treatment goals for depression are highlighted. An explanation on the challenges associated with the treatment of depression is presented, including treatment resistance, residual symptoms and risk of relapse. The article also discusses the mechanisms of treatment response and the long-term efficacy of depression treatment.

Objective: Although the second-generation antipsychotic, aripiprazole (ARI), has been approved as an adjunct for treatment-resistant major depressive disorder (MDD), neither ARI nor any second-generation antipsychotic has been assessed in combination with an antidepressant at the initiation of a treatment trial for non-treatment-resistant MDD. The aim of the present study was therefore to assess the safety, tolerability, and remission rate in the treatment of MDD using the specific combination of venlafaxine-XR (VEN-XR) and ARI in a generalizable, difficult-to-treat group with chronic or recurrent MDD. Methods: Self-declared participants in primary care or psychiatric settings who had chronic or recurrent MDD and a minimum score of 14 on the 17-item Hamilton Rating Scale for Depression were included. Up to 12 weeks of open treatment with the combination of VEN-XR and ARI was provided. Participants began with VEN-XR, and ARI was added at week 2. Maximum allowable doses were 300 mg day-1 for venlafaxine-XR and 30 mg day-1 for ARI. Remission was defined as ≤ 5 on the 16-item Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR16). Results: Fifty outpatients with non-psychotic MDD were enrolled (mean age = 43±11 years; 38% male; QIDS-SR16=15±3). Mean exit dose of VEN-XR was 227±97 mg day-1, and the mean exit dose of ARI was 11±7 mg day-1. The combination was well tolerated; 16% of participants discontinued due to side-effects. Approximately 70% achieved remission at some point during the trial, and 66% achieved remission at study exit. Conclusions: To the best of the authors' knowledge this is the first study to combine an antidepressant and second-generation antipsychotic at the beginning of a treatment trial for chronic or recurrent non-treatment resistant MDD. VEN-XR and ARI combination appears to warrant further study in controlled trials. [ABSTRACT FROM AUTHOR]

A recent randomized controlled trial found nearly equivalent response rates for antidepressant medications and cognitive therapy in a sample of moderate to severely depressed outpatients. In this article, the authors seek to identify the variables that were associated with response across both treatments as well as variables that predicted superior response in one treatment over the other. The sample consisted of 180 depressed outpatients: 60 of whom were randomly assigned to cognitive therapy; 120 were assigned to antidepressant medications. Treatment was provided for 16 weeks. Chronic depression, older age, and lower intelligence each predicted relatively poor response across both treatments. Three prescriptive variables-marriage, unemployment, and having experienced a greater number of recent life eventswere identified, and each predicted superior response to cognitive therapy relative to antidepressant medications. Thus, 6 markers of treatment outcome were identified, each of which might be expected to carry considerable clinical utility. The 3 prognostic variables identify subgroups that might benefit from alternative treatment strategies; the 3 prescriptive variables identify groups who appear to respond particularly well to cognitive therapy. [ABSTRACT FROM AUTHOR]

Serotonin norepinephrine reuptake inhibitors (SNRIs) are increasingly being used as first-line treatment for major depressive disorder (MDD). This article discusses differences in the pharmacology and pharmacokinetics of the members of this class of antidepressants and compares their efficacy and tolerability to those of other agents used to treat MDD. The SNRIs have relatively short half-fives and display linear pharmacokinetics. In general, these drugs interact less with cytochrome P450 (CYP) compounds, especially the important isozyme CYP 206, than do selective serotonin reuptake inhibitors (SSRIs), suggesting a reduced potential for drug-drug interactions. Overall, SNRIs demonstrate efficacy that is comparable to or better than that of tricyclic antidepressants and SSRIs. They are also effective in treating a broad range of psychiatric illnesses associated with MDD. but additional studies are needed to determine optimal treatment for these comorbid conditions. Although SNRIs as a class exhibit many similarities, individual agents differ in their pharmacokinetic and safety profiles. Furthermore, the range of selectivity ratios observed with these agents implies that differences in serotonergic and noradrenergic levels may exist, which could have important clinical implications. These factors, along with genetic variations in individual patients and the pharmacologic profiles of concomitant medications, must be considered when selecting an SNRI for treatment of MDD. [ABSTRACT FROM AUTHOR]

This article focuses on the use of Symbax for the acute management of treatment-resistant depression (TRD). Symbax therapy is composed of olanzapine and fluoxetine. Particular focus is given to the results of Symbax studies regarding its efficacy and safety. Also included are information on Symbax's contraindications, warnings and precautions, and associated adverse events.

This article focuses on treatment-resistant unipolar depression (TRD). TRD can be described as a major depressive disorder in adults who do not respond to two separate trials of various antidepressants of adequate dose and duration. Majority of patients do not achieve remission following an initial trial of an antidepressant. Particular focus is given to the prevalence of depression in the U.S., along with factors that can inhibit a good response to antidepressive treatment.

Objective: Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment-resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD. Method: Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross-referencing the term ‘depression’ with each of the six AAPs. Results: After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia. Conclusion: The existing research provides some support for the beneficial effects of AAPs when combined with SSRI’s in TRD. These medications pose significant risks that must be considered in their use. [ABSTRACT FROM AUTHOR]

Background: There is conflicting evidence about comorbid personality pathology in depression treatments.Aims: To test the effects of antidepressant drugs and cognitive therapy in people with depression distinguished by the presence or absence of personality disorder.Method: Random assignment of 180 out-patients with depression to 16 weeks of antidepressant medication or cognitive therapy. Random assignment of medication responders to continued medication or placebo, and comparison with cognitive therapy responders over a 12-month period.Results: Personality disorder status led to differential response at 16 weeks; 66% v. 44% (antidepressants v. cognitive therapy respectively) for people with personality disorder, and 49% v. 70% (antidepressants v. cognitive therapy respectively) for people without personality disorder. For people with personality disorder, sustained response rates over the 12-month follow-up were nearly identical (38%) in the prior cognitive therapy and continuation-medication treatment arms. People with personality disorder withdrawn from medication evidenced the lowest sustained response rate (6%). Despite the poor response of people with personality disorder to cognitive therapy, nearly all those who did respond sustained their response.Conclusions: Comorbid personality disorder was associated with differential initial response rates and sustained response rates for two well-validated treatments for depression. [ABSTRACT FROM AUTHOR]

Research suggests that depressed patients’ beliefs about the causes of their depression affect the course and outcomes of treatment. However, changes in such beliefs during treatment have not been investigated. Before and after treatment, participants in a randomized control trial comparing cognitive therapy (CT) with antidepressant medication (ADM) in the treatment of depression were asked about their beliefs concerning the reasons for their depression. The reason clusters of interest were: Characterological, conceptually related to CT; and Biological, conceptually related to ADM. Contrary to predictions, endorsement of treatment-relevant reasons did not increase after a successful treatment. Rather, endorsement of treatment-irrelevant reasons decreased significantly. Thus, successful treatment may preserve people’s beliefs in causes of depression most closely related to the treatment, and diminish beliefs in unrelated causes. [ABSTRACT FROM AUTHOR]

Recent research suggests that there may be a reduction in therapeutic response after multiple administrations of antidepressant drug (AD) therapy in patients with major depressive disorder. This study assessed the response to AD therapy and cognitive therapy (CT) of patients with a history of prior AD exposures. A sample of 240 patients with moderate-to-severe major depressive disorder entered a randomized controlled trial comparing pharmacotherapy with paroxetine to CT. Treatment was administered for 16 weeks. History of prior AD exposure was assessed with structured interviews, self-report, and medical records. Analyses were conducted using hierarchical linear models on the intent-to-treat sample. After controlling for various demographic and clinical factors, more prior AD exposures predicted poor response to paroxetine therapy but not to CT, as measured by the Hamilton Rating Scale for Depression (Hamilton, 1960; Williams, 1988). Whereas CT outcome was not significantly related to the number of prior AD exposures, a higher number of prior AD exposures was significantly associated with a lower response to paroxetine. If these findings are replicated in methodologically rigorous studies of paroxetine and other antidepressants, CT should be recommended, in preference to AD, for patients with multiple prior AD exposures. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Recurrent depression predicts risk for subsequent episodes, but it is unclear how it relates to demographic features, course of illness, and clinical presentation. Methods: We report on the baseline data for the first 1500 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org). Patients were required to have a DSM-IV diagnosis of nonpsychotic major depression and to score⩾14 on the 17-item Hamilton rating scale for depression. Status with respect to recurrent depression and other aspects of illness course and demographic features were ascertained at intake, along with measures of depression and concurrent general medical illness. Results: Patients with recurrent depression were older, had an earlier age of onset, and were more likely to have a positive family history of depression than first episode patients. However, recurrent patients were less likely to be chronic and reported shorter current episodes than first episode patients, something that was largely confined to females. Recurrent patients were more likely than first episode patients to report non-essential aspects of mood, cognition, and somatic symptoms, although largely as a consequence of greater overall depressive symptom severity. Conclusions: As compared to single episode depressions, recurrent depression was associated with greater symptom severity and illness characteristics suggestive of greater underlying risk, but not other demographic characteristics than age. Risk for recurrence appeared to be distinct from chronic depression. A subset of chronic first episode patients may lack the capacity to remit and may therefore be distinct from those with recurrent episodes. [Copyright &y& Elsevier]

Background Antidepressant medication prevents the return of depressive symptoms, but only as long as treatment is continued. Objectives To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication. Design Patients who responded to CT in a randomized controlled trial were withdrawn from treatment and compared during a 12-month period with medication responders who had been randomly assigned to either continuation medication or placebo withdrawal. Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a subsequent 12-month naturalistic follow-up. Setting Outpatient clinics at the University of Pennsylvania and Vanderbilt University. Patients A total of 104 patients responded to treatment (57.8% of those initially assigned) and were enrolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to severe depression. Interventions Patients withdrawn from CT were allowed no more than 3 booster sessions during continuation; patients assigned to continuation medication were kept at full dosage levels. Main Outcome Measures Relapse was defined as a return, for at least 2 weeks, of symptoms sufficient to meet the criteria for major depression or Hamilton Depression Rating Scale scores of 14 or higher during the continuation phase. Recurrence was defined in a comparable fashion during the subsequent naturalistic follow-up. Results Patients withdrawn from CT were significantly less likely to relapse during continuation than patients withdrawn from medications (30.8% vs 76.2%; P = .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%; P = .20). There were also indications that the effect of CT extends to the prevention of recurrence. Conclusions Cognitive therapy has an enduring effect that extends beyond the end of treatment. It seems to be as effective as keeping patients on medication. [ABSTRACT FROM AUTHOR]

Background There is substantial evidence that antidepressant medications treat moderate to severe depression effectively, but there is less data on cognitive therapy’s effects in this population. Objective To compare the efficacy in moderate to severe depression of antidepressant medications with cognitive therapy in a placebo-controlled trial. Design Random assignment to one of the following: 16 weeks of medications (n = 120), 16 weeks of cognitive therapy (n = 60), or 8 weeks of pill placebo (n = 60). Setting Research clinics at the University of Pennsylvania, Philadelphia, and Vanderbilt University, Nashville, Tenn. Patients Two hundred forty outpatients, aged 18 to 70 years, with moderate to severe major depressive disorder. Interventions Some study subjects received paroxetine, up to 50 mg daily, augmented by lithium carbonate or desipramine hydrochloride if necessary; others received individual cognitive therapy. Main Outcome Measure The Hamilton Depression Rating Scale provided continuous severity scores and allowed for designations of response and remission. Results At 8 weeks, response rates in medications (50%) and cognitive therapy (43%) groups were both superior to the placebo (25%) group. Analyses based on continuous scores at 8 weeks indicated an advantage for each of the active treatments over placebo, each with a medium effect size. The advantage was significant for medication relative to placebo, and at the level of a nonsignificant trend for cognitive therapy relative to placebo. At 16 weeks, response rates were 58% in each of the active conditions; remission rates were 46% for medication, 40% for cognitive therapy. Follow-up tests of a site × treatment interaction indicated a significant difference only at Vanderbilt University, where medications were superior to cognitive therapy. Site differences in patient characteristics and in the relative experience levels of the cognitive therapists each appear to have contributed to this interaction. Conclusion Cognitive therapy can be as effective as medications for the initial treatment of moderate to severe major depression, but this degree of effectiveness may depend on a high level of therapist experience or expertise. [ABSTRACT FROM AUTHOR]

Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradylcinin and 1-α-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [125I]LSD binding for 5-HT2A also was conducted. Finally, Western blot analysis was performed for phospholipase CΒ1 (PLCΒ1) and Gαq11proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradylcinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [125I]LSD binding, PLCΒ1, and Gαq11 protein levels did not differ between groups. The data raise the possibility that the reduced 5-HT2A receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT2A receptor, Gq or PLC. [ABSTRACT FROM AUTHOR]

In two experimental sessions, we assessed early- and late-onset acoustic startle eyeblink modulation and subjective ratings of emotional pictures by nondepressed participants and by unipolar depressed participants. Depressed participants were assessed before and after treatment with the antidepressant medication Bupropion SR. Both depressed and nondepressed participants exhibited arousal-dependent startle modulation to early probes occurring 300 ms after picture onset. Nondepressed participants demonstrated the expected valence-dependent startle modulation to late probes (3,500–4,500 ms post-onset). In contrast, the late-probe blink magnitudes of depressed patients were unrelated to picture valence. This pattern of group differences was not moderated by treatment. There were no between-group differences in self-report ratings to pictures. These results suggest that depression may be characterized by anomalous responses to affective stimuli and that startle modulation can be a more sensitive index of affective response deficits linked to depression than self-report measures. [ABSTRACT FROM AUTHOR]

In this study, differential display technology was used to compare gene expression in cultured fibroblasts from patients with major depression, melancholic subtype vs nonmelancholic depressives and normal volunteer controls. Genes differentially expressed in depressives and normals included an overexpressed 269 bp sequence tag showing ∼95% identity with the Homo sapiens long pentraxin 3 (PTX3) gene sequence in the 3' noncoding region. The 269 bp complimentary DNA probe hybridized with the 1.9 kb PTX3 mRNA. The densitometric analysis of slot blots showed that the mean steady-state mRNA level of PTX3 was 3.5-fold higher in the melancholic group as compared to that in normal controls and in nonmelancholic depressives (n = 8, all groups). Incubation experiments were then conducted: confluent fibroblasts from melancholics and normal volunteers were incubated with isoproterenol 1 µM, dexamethasone (DEX) 500nM, and interteukin 1Β (IL-1Β) 50 ng/ml, for 0, 0.5, 1, 4, and 24h. mRNA was isolated and quantitated using Northern blot analysis. Isoproterenol produced no significant change in PTX3 expression; DEX produced a significant increase at 4 and 24 h; IL-1Β induced an increase in both the groups that peaked at 4 h, declining to near basal levels at 24 h. There were no differences between melancholics or controls in mean change or maximum response with either DEX or IL- 1Β. The results are consistent with the reported effects of IL-1Β on PTX3 expression in mouse brain. The results are of potential importance because PTX3 is a member of the long pentraxin subfamily of acute-phase proteins, which is inducible by IL-1Β, and may play roles in neuroimmunity and neuroprotection. [ABSTRACT FROM AUTHOR]

Presents letters to the editor on medical topics as of July 4, 2001. St. John's Wort and major depression; Prenatal cocaine exposure as a risk factor for later developmental outcomes; Informed consent for public automated external defibrillation; More.

Presents a study to compare the efficacy and safety of a standardized extract of St. John's wort with placebo in outpatients with major depression. Design and setting; Participants; Intervention; Main outcome measures; Results; Conclusion that in this study, St. John's wort was not an effective treatment of major depression.

Discusses the treatment guidelines for major depressive disorder revised by the American Psychiatric Association as of 2001. Reasons for recommending the use of medications in the treatment of severely depressed patients; Effects of psychotherapy not found with medications; Combined treatment for depressed patients.

Objective: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression.Method: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine.Results: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions.Conclusions: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone. [ABSTRACT FROM AUTHOR]

Background: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. Methods: We studied 18 patients with major depressive disorder and 10 normal volunteers. Weassessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypo-thalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern Results: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in non-responders was significantly greater than in responders (F[sub1,8.99;=7.52; P=.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. Conclusions: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity. [ABSTRACT FROM AUTHOR]

The action of antidepressant drugs on monoamines such as norepinephrine and serotonin has been described for three decades. However, more-recent research has looked beyond cell surface receptors to transductional cascades and gene expression. Antidepressant drug therapies seem to share several mechanisms involved in either activating the adenylyl cyclase-protein kinase A cascade or inhibiting the phospholipase C-protein kinase C mechanisms. These effects, ultimately, combine to regulate the expression of target genes. Several specific genes are known to be activated or inhibited by antidepressant therapies. Steady-state levels of mRNA for glucocorticoid and mineralocorticoid receptors, brain-derived neurotrophic factor and its receptor trkB, and preproenkephalin are enhanced, whereas those for corticotropin-releasing hormone, c-fos,N-methyl-D-aspartate receptor subunits, and nerve-growth factor 1A are reduced. New molecular genetic methods for identifying differentially expressed genes will aid in the development of targets for wholly new generations of antidepressant drug therapies. [ABSTRACT FROM AUTHOR]