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OBJECTIVE Posttraumatic stress disorder and prolonged grief disorder (PGD) arise following major life stressors and may share some overlapping symptomatology. This study aimed to examine the presence and response to treatment of posttraumatic stress symptoms (PTSS) in bereaved adults with a primary diagnosis of PGD. METHODS A randomized controlled trial of 395 adults with PGD (defined as an Inventory of Complicated Grief score ≥ 30 plus confirmation on structured clinical interview) randomly assigned participants to either complicated grief treatment (CGT) with citalopram, CGT plus placebo, citalopram, or placebo between March 2010 and September 2014. This secondary analysis examined the presence of PTSS (per the Davidson Trauma Scale) at baseline and change in PTSS with treatment using longitudinal mixed-effects regression and examined the role of violent compared to nonviolent deaths (loss type). RESULTS High levels of PTSS were present at baseline, regardless of loss type, and were associated with increased functional impairment (P

Objective To assess the efficacy and safety of citalopram in the acute and maintenance phases of bipolar depression in a randomized, double-blind, placebo-controlled trial. Methods Between 2007 and 2014, 119 subjects with acute major depressive episodes diagnosed with DSM-IV bipolar disorder, type I or type II, were randomized blindly to citalopram or placebo, added to standard mood stabilizers. They were followed for 6 weeks for acute efficacy (primary outcome) and up to 1 year for maintenance efficacy (secondary outcome) using scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Mania Rating Scale of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). The study was powered for a clinically meaningful effect size. Results Mean ± SD MADRS scores changed from a baseline value of 27.4 ± 9.1 to 13.1 ± 8.4 at the end of the acute phase for citalopram versus a change from 27.4 ± 7.3 to 15.2 ± 9.9 for placebo, a clinically and statistically nonsignificant difference. Maintenance efficacy also was not better with citalopram than with placebo. Acute manic/hypomanic episodes were similar in both groups, and subjects with type II illness did not have better outcomes than subjects with type I illness. In maintenance treatment, MRS-SADS scores were greater overall, especially in subjects with a rapid-cycling illness course, with citalopram versus placebo. Conclusions Citalopram, added to standard mood stabilizers, did not have clinically meaningful benefit versus placebo for either acute or maintenance treatment of bipolar depression. Acute mania did not worsen with citalopram, but maintenance treatment led to worsened manic symptoms, especially in subjects with a rapid-cycling course. Trial registration ClinicalTrials.gov identifier: NCT00562861.

OBJECTIVE There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.

Objective Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. Methods We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. Results Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P Conclusions Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. Trial registration ClinicalTrials.gov identifier: NCT01655706.

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02818751.

OBJECTIVE: Prospective studies have not identified a viable pharmacologic strategy for secondary prevention of posttraumatic stress disorder (PTSD). The authors examined whether preventive intervention via early and short-term administration of a selective serotonin reuptake inhibitor (SSRI), within 1 month of exposure to a traumatic event (before diagnosis of PTSD could be made), may reduce the severity of PTSD symptoms according to DSM-IV at 13 months' follow-up. METHODS: Over 25,000 screening calls to patients referred to an emergency department for a traumatic event performed between June 2006 and December 2008 yielded 353 participants who were recruited within the month following a traumatic event. Participants were randomly assigned in a double-blind design to escitalopram (n = 176) or placebo (n = 177). The per-protocol analysis comprised 198 participants (escitalopram, n = 102; placebo, n = 96) who received treatment for 12 to 24 weeks and were available for follow-up at week 56. RESULTS: The primary outcome measure, the Clinician Administered PTSD Scale (CAPS), revealed no prevention effect. However, a secondary outcome, the Pittsburgh Sleep Quality Inventory (PSQI), showed better results for the SSRI group than for the placebo group. For a subset of participants who experienced intentional trauma (missile attacks, rape, or physical assault; n = 50), the prevention effect was found on both primary and secondary measures (CAPS, PSQI and measures of depression and global illness severity). CONCLUSIONS: Early and short-term administration of escitalopram was not shown to prevent PTSD, although it did improve sleep quality. In a subgroup of participants who experienced intentional trauma, however, this early-treatment approach may be effective as secondary prevention. This large study is the first to investigate the preventive effect of early administration of escitalopram on PTSD. It highlights the relevance of the type of trauma (intentional vs unintentional) to the outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00300313​. Language: en

Objective An antidepressant medication switch often follows a failed initial trial with selective serotonin reuptake inhibitors (SSRIs). When, for whom, and how often second-step response and remission occur are unclear, as is preferred second-step trial duration. As more treatments are approved for use following 2 failed "adequate" trials, researchers and clinicians require an evidence-based definition of "adequate." Methods Following citalopram in the randomized Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial (which ran July 2001-September 2006), participants with score ≥ 11 on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR₁₆) were randomized to bupropion sustained release, sertraline, or venlafaxine extended release (up to 14 weeks). The QIDS-SR₁₆ defined response, remission, and no clinically meaningful benefit based on the modified intent-to-treat sample. Results About 80% of 438 participants completed ≥ 6 weeks of treatment with the switch medication. All treatments had comparable outcomes. Overall, 21% (91/438) remitted, 9% (40/438) responded without remission, and 58% (255/438) had no meaningful benefit. Half of the responses and two-thirds of remissions occurred after 6 weeks of treatment. Overall, 33% of responses (43/131) occurred after ≥ 9 weeks of treatment. No baseline features differentiated early from later responders or remitters. No early triage point was found, but those with at least 20% reduction from baseline in QIDS-SR₁₆ score around week 2 were 6 times more likely to respond or remit than those without this reduction. Conclusions Following nonefficacy with an initial SSRI, only about 20% remit and more than half achieve no meaningful benefit with a second-step switch to another monoaminergic antidepressant. A 12-week trial duration seems necessary to capture as many second-step switch responders as possible. Trial registration ClinicalTrials.gov identifier: NCT00021528.

OBJECTIVE To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole. METHODS Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2). RESULTS After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy. CONCLUSIONS This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01655706.

Objective Studies demonstrating that higher doses of citalopram (> 40 mg) and escitalopram (> 20 mg) prolong the corrected QT interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these selective serotonin reuptake inhibitors (SSRIs) to that for equivalent doses of fluoxetine, paroxetine, and sertraline. Methods The Tennessee Medicaid retrospective cohort study included 54,220 persons 30-74 years of age without cancer or other life-threatening illness who were prescribed high-dose SSRIs from 1998 through 2011. The mean age was 47 years, and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of proarrhythmic effects. Results The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% CI, 0.40-1.75), 1.24 (95% CI, 0.75-2.05), 0.75 (95% CI, 0.45-1.24), and 1.53 (95% CI, 0.91-2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥ 60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study end point. Conclusions We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline.

Objective Over 50% of outpatients with nonpsychotic major depressive disorder (MDD) do not achieve remission with any single antidepressant medication (ADM). There are currently no clinically useful pretreatment measures that inform the decision to prescribe or select ADMs. This report examines whether a biomarker based on diffusion tensor imaging (DTI) measures of brain connectivity can identify a subset of nonremitting patients with a sufficiently high degree of specificity that use of a medication that is likely to fail could be avoided. Methods MDD outpatients recruited from community and primary-care settings underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment in Depression (conducted December 2008-June 2014). DSM-IV criteria and a 17-item Hamilton Depression Rating Scale (HDRS17) score ≥ 16 confirmed the primary diagnosis of nonpsychotic MDD. Data from the first cohort of MDD patients (n = 74) were used to calculate fractional anisotropy measures of the stria terminalis and cingulate portion of the cingulate bundle (CgC). On the basis of our previous data, we hypothesized that nonremission might be predicted using a ratio of these 2 values. Remission was defined as an HDRS17 score of ≤ 7 following 8 weeks of open-label treatment with escitalopram, sertraline, or venlafaxine extended-release, randomized across participants. The second study cohort (n = 83) was used for replication. Results Thirty-four percent of all participants achieved remission. A value > 1.0 for the ratio of the fractional anisotropy of the stria terminalis over the CgC identified 38% of the nonremitting participants with an accuracy of 88% (test cohort; odds ratio [OR] = 9.6; 95% CI, 2.0-45.9); 24% with an accuracy of 83% (replication cohort; OR = 1.8; 95% CI, 0.5-6.9) and 29% with an accuracy of 86% (pooled data; OR = 4.0; 95% CI, 1.5-11.1). Treatment moderation analysis showed greater specificity for escitalopram and sertraline (χ(2) = 8.07; P = .003). Conclusions To our knowledge, this simple DTI-derived metric represents the first brain biomarker to reliably identify nonremitting patients in MDD. The test identifies a meaningful proportion of nonremitters, has high specificity, and may assist in managing the antidepressant treatment of depression. Trial registration ClinicalTrials.gov identifier: NCT00693849.

BACKGROUND: Suicidal ideation is a frequent and difficult-to-treat clinical challenge among patients with major depressive disorder (MDD). However, little is known regarding the differential development during antidepressant treatment and whether some patients may suffer from persistent suicidal ideation.METHODS: Among 811 patients with Schedules for Clinical Assessment in Neuropsychiatry (SCAN)-verified MDD from 2004-2007 assessed weekly for 12 weeks of escitalopram or nortriptyline antidepressant treatment, we applied item response theory to integrate a suicidality score based on 3 rating scales. We performed latent growth mixture modeling analysis to empirically identify trajectories. Multinomial logistic regression analyses estimated associations with potential predictors.RESULTS: We identified 5 distinct classes of suicidal ideation. The Persistent-low class (53.7%) showed no suicidal ideation whereas the Persistent-high class (9.8%) had high suicidal ideation throughout 12 weeks. Two classes showed a fluctuating course: the Fluctuating class (5.2%) ended at a low level of suicidal ideation, whereas the Slow-response-relapse class (4.8%) initially responded slowly but then experienced a large increase to a high level of suicidal ideation after 12 weeks. The Fast-response class (26.5%) had a high baseline severity similar to the Persistent-high class but responded quickly within a few weeks and remained at a low level. Previous suicide attempts and higher mood symptom severity were associated with worse suicidal ideation trajectories, whereas living with a partner showed a trend toward better response.CONCLUSION: Approximately 1 of 5 patients with MDD showed high or fluctuating suicidal ideation despite antidepressant treatment. Studies should investigate whether suicidal ideation may persist for longer periods and more targeted treatment possibilities.TRIAL REGISTRATION: ISRCTN​​ identifier: ISRCTN03693000​​​​.

OBJECTIVE The present placebo-controlled study evaluated the efficacy and safety of 8 weeks of treatment with tianeptine 25-50 mg/d in elderly patients suffering from major depressive disorder (MDD) according to DSM-IV-TR. Escitalopram 5-10 mg/d was used as an active comparator. METHODS Elderly outpatients aged at least 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD were recruited by psychiatrists in 44 clinical centers in 10 countries from October 2013 to January 2016. Patients were randomly assigned to receive tianeptine (n = 105), placebo (n = 107), or escitalopram (n = 99) for 8 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS₁₇) total score. RESULTS Tianeptine improved depressive symptoms, as evaluated by the HDRS₁₇ total score in terms of absolute change from baseline (week 0) to week 8 (placebo-tianeptine difference [SE] of 3.84 [0.85] points, P < .001, using a last-observation-carried-forward approach) and response to treatment (tianeptine: 46.7%; placebo: 34.0%, estimate [SE] = 12.70% [6.70], P = .06). A sensitivity analysis using a mixed model for repeated measures confirmed the main results on HDRS total s​core. The placebo-tianeptine difference (SE) was 0.66 (0.15) for Clinical Global Impressions-Severity of Illness (95% CI, 0.37 to 0.96; P < .001) and 0.57 (0.14) for Clinical Global Impressions- Improvement (95% CI, 0.30 to 0.83; P < .001). Positive results were also obtained with the active control escitalopram (HDRS₁₇ total score placebo-escitalopram difference of 4.09 ± 0.86 points, P < .001), therefore validating the sensitivity of the studied population. Tianeptine was well tolerated, with only minimal differences in tolerability from placebo. CONCLUSIONS The present study provides robust evidence that an 8-week treatment period with tianeptine 25-50 mg is efficacious and well tolerated in depressed patients aged 65 years or older. TRIAL REGISTRATION EudraCT identifier: 2012-005612-26​.

OBJECTIVE To evaluate the efficacy and tolerability of dose increase compared to dose continuation of the initially prescribed antidepressant in antidepressant treatment failure (ATF). DATA SOURCES We searched CENTRAL, PubMed, Embase, and PsycINFO using generic terms for depression, dose increase, and randomized controlled trials (RCTs), without date or language restrictions. STUDY SELECTION Of 1,780 studies screened, 9 studies reporting on 1,273 patients were included for meta-analysis (PROSPERO Registration: CRD42017058389). Studies met the following predetermined inclusion criteria: randomized controlled trial, patients diagnosed with unipolar depression according to a standardized diagnostic instrument, ATF after a standard antidepressant trial (duration of ≥ 3 weeks at a standard dose), dose increase regimen, and control group of dose continuation. DATA EXTRACTION Two authors extracted data independently according to the Cochrane Handbook for Systematic Reviews. Analyses are based on random effects models. RESULTS All studies reported on selective serotonin reuptake inhibitors (SSRIs); 1 study also reported on maprotiline. Meta-analyses resulted in a statistically nonsignificant summary effect size of 0.053 standardized mean difference (95% CI, -0.143 to 0.248) in favor of antidepressant dose increase. Subgroup and sensitivity analyses and secondary outcome analyses resulted in similar effect estimates and supported the robustness of the results. CONCLUSIONS With clinically and statistically nonsignificant effect estimates, there is evidence from RCTs against increasing the dose of SSRIs (with the possible exception of citalopram) in adult patients with major depression and ATF. Dose increase with other antidepressants (eg, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors) and in other patient groups (minor depression, children and adolescents) or after long periods of first-line antidepressant therapy (ie, 8 weeks) have not been or not been sufficiently studied and, at this time, cannot be recommended in clinical practice.

BACKGROUND According to prevailing models and classical reports, abrupt responses to antidepressant medication are not true drug responses but rather transient placebo effects. By contrast, recent reports suggest that early sudden improvements have a lasting effect and appear in most patients receiving medication. Clinical guidelines influenced by these contradictory findings are mixed and confusing. OBJECTIVE To evaluate the occurrence and effects of abrupt improvements in symptoms in placebo vs antidepressant conditions in individuals with late-life depression, using a rigorous method of identifying sudden gains, developed and tested in scores of studies in psychotherapy research. METHODS We analyzed data (collected during 1999-2002) from 174 patients 75 years or older, with unipolar depression (based on DSM-IV), who were randomly assigned to citalopram or placebo. We tested differences between conditions in the prevalence of sudden gains, and their effect on outcome, using χ² analyses and linear regression models. Pretreatment predictors of sudden gains were identified using a machine learning approach. RESULTS 36.2% of patients showed stable sudden gains, without significant differences between medication and placebo conditions (χ²₁ = 0.95, P = .33). The mean reduction in the Hamilton Depression Rating Scale score was 7.2 points greater for patients who showed sudden gains (t₁₇₂ = -7.52, P < .0001). Higher levels of pretreatment symptom severity and higher processing speed increased the likelihood of showing sudden gains. CONCLUSION Even in a geriatric population, which is likely to show more sustained depression and less fluctuation, sudden gains were common. The findings may necessitate modifying current models of mechanisms of change of antidepressant medication and may affect guidelines for best clinical practice.

OBJECTIVE To identify clinical and genetic characteristics that can be used to recognize depressed patients who are likely to respond quickly versus those who will have a more delayed response following multiple treatment trials. METHODS The data used were obtained from the National Institute of Mental Health-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted between July 2001 and September 2006. Of the 4,041 treatment-naive participants in the original study, 1,953 with DNA samples were included. Major depressive disorder (DSM-IV criteria) was defined as baseline score > 14 on the 17-item Hamilton Depression Rating Scale. Time to remission was defined from the entry point to when a score ≤ 5 on the Quick Inventory of Depressive Symptomatology, Clinician Rating was achieved, irrespective of the type or number of treatments received. A Kaplan-Meier estimator was used for data description, proportional hazard regression for model building, and logistic regression for measures of predictive accuracy. RESULTS The overall rate of remission across all levels of treatment was 65.6%, and the overall median (interquartile range) of time to remission was 11.4 (6.0-17.9) weeks. The predictors of delayed remission included unemployment (P = .004), severe medical comorbidity (P < .0001), severe baseline depression (P < .0001), more than 4 dysthymic symptoms (P = .005), more than 9 posttraumatic stress symptoms (P = .005), and serotonin receptor 1A (P = .006) and cytochrome P450 2D6 (P = .002 for C/T and P = .0004 for T/T) genetic variants. The final model had good predictive measures of accuracy of area under the curve (70%) and sensitivity (88%). CONCLUSIONS The results offer clinical tools for clinicians to identify depressed individuals who are likely to have delayed remission with multiple antidepressant treatments and therefore might be candidates for advanced care options.

OBJECTIVE: This work tested the hypothesis that patients with high negative affectivity (NA) would have a better response to a serotonergic agent (escitalopram) than to one not thought to act directly on serotonin (bupropion). METHOD: Data from a study conducted between August 2007 and July 2011 were reanalyzed retrospectively. Patients (N = 245) meeting criteria for major depressive disorder (MDD), diagnosed with DSM-IV-TR, were randomly assigned to double-blind treatment with bupropion extended-release, escitalopram, or the combination. Negative affectivity score was estimated using the guilt, hostility/irritability, and fear/anxiety items of the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptoms, and the Social Adjustment Scale. We felt that these items captured published descriptions of the NA construct. A Clinical Global Impressions-Severity of Illness (CGI-S) score ≤ 2 defined response. Because combined treatment addressed both serotonin and non-serotonin systems, patients treated with both medications did not test the hypothesis and so were excluded from the analyses. RESULTS: Analysis of covariance with treatment as a grouping variable, NA as covariate, and CGI-S as dependent variable showed a significant 2-way interaction between treatment and NA (F₁,₁₅₆ = 4.82, P < .03). In the low-NA group, response rates were similar between treatments (escitalopram: 28/42 [67%]; bupropion: 23/40 [58%]; NS), while there was a significant advantage for escitalopram in patients with high NA (escitalopram: 24/40 [60%]; bupropion = 14/41 [34%]; P = .017). CONCLUSIONS: These data suggest that patients with high negative affectivity respond preferentially to antidepressants that selectively enhance serotonin neurotransmission. Although patients with low NA appear to benefit from serotonin enhancement as well, they also improved with bupropion, an antidepressant not thought to directly affect serotonin neurotransmission. These findings come from retrospective analyses using unproven approximation of NA, so no clinical inferences should be made before independent replication utilizing accepted NA measurement. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00519428.

Objective: In this study, we assessed the efficacy of 2 pharmacodynamically different antidepressants, citalopram (a selective serotonin reuptake inhibitor) and reboxetine (a norepinephrine reuptake inhibitor), as adjunctive therapy to risperidone and olanzapine for the treatment of negative symptoms in schizophrenia. Method: We performed a 6-month, multicenter, double-blind, randomized, placebo-controlled clinical trial. The recruitment period was from November 2008 to December 2011. The sample comprised 90 patients with a diagnosis of schizophrenia (DSM-IV criteria) who exhibited negative symptoms. The patients were recruited from 10 centers in different cities of the Spanish State. The primary efficacy measure was change in score on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) between baseline and 6-month assessment. Other efficacy measures were changes in the PANSS subscales and total score, as well as the Scale for the Assessment of Negative Symptoms (SANS) subscales and total score. Results: For statistical analysis, we employed mixed-effects models. We did not find statistically significant differences between the placebo group and the 2 treatment groups at 6-month assessments for the PANSS total (P = .6511), any PANSS subscale (negative [P = .5533], positive [P = .1723], or general psychopathology [P = .2083]), or the SANS (P = .5884). Cohen d measure showed a small effect size below the 0.5 threshold for all comparisons. Conclusions: In conclusion, our results do not support adjunctive use of citalopram or reboxetine with risperidone or olanzapine for the treatment of negative symptoms in schizophrenia. (C) Copyright 2014 Physicians Postgraduate Press, Inc.

Antidepressant medications are the most commonly prescribed intervention for the treatment of major depressive disorder (MDD).1–3 Conventional wisdom is that the effects of antidepressants take at least 2–4 weeks to become clinically evident, although there is evidence that the treatment effects of selective serotonin reuptake inhibitors (SSRIs) can be observed statistically as early as 1 week after the initiation of treatment.4 Improvement with antidepressant agents continues 6, 8, and even 12 weeks following initiation of SSRI medication.4 Approximately half of patients with MDD respond (achieve a clinically meaningful reduction in symptoms) with SSRI treatment for depression.5 A much smaller proportion of MDD patients, 25%–40%, experience remission, the virtual absence of symptoms, after an acute antidepressant trial.5 A large fraction of patients do not respond or remit with SSRI treatment for MDD, which often takes several months to reach maximal benefits in reducing depressive symptoms. Therefore, identifying predictors and moderators of SSRI treatment effects is clinically important. Particularly useful, in this regard, is identifying subgroups of MDD patients with differential likelihood of improvement with SSRI pharmacotherapy. This knowledge would provide a better foundation for clinicians to make decisions at an earlier stage of treatment regarding treatment strategies for individual patients (continuation of current medication, augmenting current pharmacotherapy, or switching).6–7 Socioeconomic status (SES) plays an important role in the prevalence of mental disorders. According to a cross-national comparison of prevalences and correlates of mental disorders carried out by the World Health Organization, people with low SES show higher prevalence rates in almost all mental disorders.8 Whereas poverty and unemployment were shown to be predictive of persistence of mental disorders, financial strain was associated with both onset and future morbidity.9 As for depression in particular, a meta-analysis showed that low SES was associated with both the new onset and persistence of depression.10 Access to mental health services varies as a function of SES, to the disadvantage of those with lower SES.11 This association poses the question as to whether the relationship between SES and psychiatric disorder—MDD in particular—is mediated by the accessibility of treatment. This question can be answered by examining a large clinical trial providing standardized care to a sample of patients with large sociodemographic differences. Such a trial is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D).12,13 Logistic regression, which is usually the method of choice in treatment studies,5 is not helpful in identifying homogenous subgroups of patients with differential likelihood of responding. Its possibilities to account for potential interactions between predictor variables are strictly limited to a few a priori-defined ones. An alternative method of analysis is offered by the receiver operating characteristic (ROC) analysis, which identifies subgroups of subjects with meaningful differences in the outcome variable from a set of predictor variables. We applied ROC analysis to data from the first treatment phase of the STAR*D trial, which enrolled over 2,000 nonpsychotic MDD patients and treated them for 8–14 weeks with citalopram in real-world settings.12 We sought to empirically identify homogeneous subgroups of patients with different prognoses after citalopram treatment (both response and remission) using baseline demographic, social, and clinical characteristics. We refined these models using clinical data from weeks 2 and 4 of treatment to examine the additional predictive value of information on early response and side effects to help guide clinical decisions early in SSRI treatment. These empirically derived models should help improve the accuracy of initial prognosis for individual patients treated with SSRIs and provide additional prognostic information to guide treatment decisions early in pharmacotherapy.

OBJECTIVE To evaluate the association between selective serotonin reuptake inhibitors (SSRIs) and corrected QT interval (QTc) prolongation via meta-analysis of prospective studies. DATA SOURCES PubMed/MEDLINE database (January 1, 1975-August 15, 2012), with additional reports identified using hand searches of reference lists of relevant articles. Key words searched were QT, torsades de pointes, and sudden cardiac death, combined with antidepressants, citalopram, escitalopram, fluoxetine, sertraline, paroxetine, and fluvoxamine. English-, Spanish-, and German-language articles were included. STUDY SELECTION Two reviewers independently identified prospective controlled studies in adults that reported data related to QTc intervals prior to and following treatment with SSRIs. DATA EXTRACTION AND SYNTHESIS Three reviewers independently extracted study-level data including population characteristics, method of QTc measurement and treatment and outcome data. Two independent reviewers critiqued study quality. Publication bias was assessed visually using a funnel plot and quantitatively. Heterogeneity was measured using Cochran Q statistic. RESULTS Sixteen articles (with 25 distinct data subsets) involving 4,292 patients were included. SSRIs were associated with a dose-dependent increase in QTc interval compared to placebo (+6.10 milliseconds; 95% CI, 3.47-8.73; P < .001). Tricyclic antidepressants (TCAs) were associated with a significantly greater QTc increase than SSRIs (TCA prolongation, 7.05 milliseconds; 95% CI, 3.84-10.27 greater than SSRIs; P < .001). With respect to specific SSRI agents, citalopram was associated with significantly greater QTc prolongation than sertraline, paroxetine, and fluvoxamine. CONCLUSIONS SSRIs were associated with a modest but statistically significant increase in the QTc interval, although to a lesser extent than TCAs; this finding was not limited to any single study. Citalopram was associated with more QTc prolongation than most other SSRIs.

BACKGROUND Agomelatine was efficacious in reducing symptoms in a short-term placebo-controlled trial in generalized anxiety disorder (GAD) and in preventing relapse in a longer term placebo-controlled study. An additional short-term placebo-controlled study is required by regulatory agencies to confirm the efficacy of agomelatine in GAD. METHOD This 12-week, placebo-controlled, double-blind, randomized, parallel group, international, multicenter study was designed to confirm the efficacy of agomelatine 25-50 mg/d in the treatment of patients with a primary DSM-IV-TR diagnosis of GAD. The primary outcome measure was the Hamilton Anxiety Rating Scale (HARS) total score. Assay sensitivity was evaluated by including an escitalopram (10-20 mg/d) group. SETTINGS The study was undertaken in 45 clinical centers in Argentina, Czech Republic, Finland, South Korea, Poland, Russia, and Slovakia from April 2010 to July 2011. RESULTS One hundred thirty-nine outpatients were included in the agomelatine group, 131 in the placebo group, and 142 in the escitalopram group. Agomelatine significantly reduced mean (SD) HARS total score (agomelatine-placebo difference: 4.71 [1.03], P

Elderly patients commonly receive statin drugs for the primary or secondary prevention of cardiovascular and cerebrovascular events. Elderly patients also commonly receive antidepressant drugs, usually selective serotonin reuptake inhibitors (SSRIs), for the treatment of depression, anxiety, or other conditions. SSRIs are associated with many pharmacokinetic drug interactions related to the inhibition of the cytochrome P450 (CYP) metabolic pathways. There is concern that drugs that inhibit statin metabolism can trigger statin adverse effects, especially myopathy (which can be potentially serious, if rhabdomyolysis occurs). However, a detailed literature review of statin metabolism and of SSRI effects on CYP enzymes suggests that escitalopram, citalopram, and paroxetine are almost certain to be safe with all statins, and rosuvastatin, pitavastatin, and pravastatin are almost certain to be safe with all SSRIs. Even though other SSRI-statin combinations may theoretically be associated with risks, the magnitude of the pharmacokinetic interaction is likely to be below the threshold for clinical significance. Risk, if at all, lies in combining fluvoxamine with atorvastatin, simvastatin, or lovastatin, and even this risk can be minimized by using lower statin doses and monitoring the patient.

Objective Late-life depression frequently co-occurs with cognitive impairment. To inform clinical management of these conditions, we examined the hypotheses that, relative to cognitively normal elders meeting DSM-IV criteria for major depressive disorder, those with cognitive impairment would require greater intensity of pharmacotherapy to reach criteria for antidepressant response and would take longer to respond. Method Using data from the MTLD-3 study, we conducted a series of secondary analyses examining the implications of cognitive impairment for short-term, open-trial pharmacotherapy of late-life depression (major depressive disorder in individuals 65 years and older). The treatment algorithm consisted of 3 steps: initial treatment with a selective serotonin reuptake inhibitor (SSRI), a switch to a serotonin-norepinephrine reuptake inhibitor (SNRI) if the patient did not respond, and addition of an atypical antipsychotic if the patient did not respond to the SNRI. The first subject entered the protocol in April 2004, and the last subject exited in September 2009. We examined data for participants who completed the acute phase of MTLD-3 as responders and received a cognitive diagnosis (N = 153) based on National Alzheimer's Coordinating Center (NACC) Uniform Data Set criteria. We divided participants into 3 groups on the basis of NACC cognitive diagnosis: no cognitive disorder (n = 74), mild cognitive impairment (n = 60), and dementia (n = 19). For each group, we calculated the proportion of participants requiring first- (SSRI), second- (SNRI), or third-step (add-on atypical antipsychotic) treatment to meet criteria for response (17-Item Hamilton Depression Rating Scale score ≤ 10 for 3 consecutive weeks). We compared time to response across groups and correlates of nonresponse. Results The 3 groups did not differ in intensity of pharmacotherapy (P = .68) or time to response (P = .84). Nonresponse was more strongly correlated with longer major depressive episode duration (P = .0015), presence of recurrent depression (P = .002), and younger current age (P = .047), rather than cognitive status (P = .61). Conclusions Cognitive status does not appear to impact short-term pharmacotherapy response variability in individuals whose depression responds to treatment with open-trial antidepressants delivered in a supportive, university-based medication clinic.

Objective To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. Method A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient preanesthesia evaluation in the period 2007 until 2012. The index group included elderly users of an SSRI. The reference group of nonusers of antidepressants was matched to the index group on sex and year of scheduled surgery (ratio, 1:1). The primary outcome was the occurrence of QT interval prolongation shown on electrocardiogram. The QT interval was corrected for heart rate (QTc interval). The secondary outcome was the duration of the QTc interval. The outcomes were adjusted for confounding by using regression techniques. Results The index and reference groups included 397 users of an SSRI and 397 nonusers, respectively. QTc interval prolongation occurred in 25 (6%) and 19 (5%) index and reference patients, respectively. After adjustment for confounding, users of an SSRI did not have a higher risk for QTc interval prolongation compared to nonusers: OR = 1.1 (95% CI, 0.5 to 2.0). The adjusted mean QTc interval length in users of an SSRI and nonusers was comparable (difference of 1.5 milliseconds [95% CI, -1.8 to 4.8]). Use of the most frequently used SSRIs citalopram and paroxetine was not associated with a higher risk of QTc interval prolongation nor with lengthening of the QTc interval duration. Conclusions The use of an SSRI by elderly surgical patients was not associated with the occurrence of QT interval prolongation.

Objective Clinical trials in major depressive disorder (MDD) commonly assess remission at a single endpoint. Complementary, clinically relevant metrics include the likelihood and speed of achieving sustained remission. A neurophysiologic measure, the Antidepressant Treatment Response (ATR) index, previously predicted 8-week outcomes of pharmacotherapy. We retrospectively examined data from the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) trial to evaluate this biomarker's properties in predicting sustained remission and time to achieve sustained remission. Method In the BRITE-MD trial, 67 adults with DSM-IV MDD received escitalopram continuously for 13 weeks. The 17-item Hamilton Depression Rating Scale (HDRS17) was used to define sustained remission as achieving remission (HDRS17 score ≤ 7) at a series of consecutive assessments, including week 13. The onset of sustained remission was defined as the earliest time from which all subsequent HDRS17 assessments were ≤ 7. The ATR was evaluated by using frontal quantitative electroencephalogram recordings at baseline and week 1. Subjects were stratified based on ATR status (ie, ATR+/ATR-). Kaplan-Meier survival analysis evaluated group differences in time to sustained remission. Higher ATR was hypothesized to predict sustained remission and time to sustained remission. Subjects participated between January 2006 and July 2007. Results Of 67 subjects, 36 achieved remission by week 13, and ATR predicted this single endpoint in receiver operating characteristic analyses (P = .016; sensitivity, 52.8%; positive predictive value, 76.0%). Remitters had a higher mean (SD) ATR value than those who did not remit (57.9 [10.0] vs 51.9 [8.7], P = .012). Sixteen of the 31 individuals with sustained remission had ATR+ status, while 28 of the 36 who were not sustained remitters had ATR- status (P = .012). The mean time to reach sustained remission was significantly shorter among ATR+ subjects than ATR- individuals (38 vs 53 days, P = .038). Conclusions The ATR index predicted remission at 13 weeks as well as the speed of achieving sustained remission with antidepressant monotherapy. This finding suggests that the ATR biomarker may predict stable longer-term outcomes. Trial registration ClinicalTrials.gov identifier: NCT00289523.

OBJECTIVE Major depressive disorder (MDD) can substantially worsen patient-reported quality of life (QOL) and functioning. Prior studies have examined the role of age in MDD by comparing depressive symptom severity or remission rates between younger and older adults. This study examines these outcomes before and after SSRI treatment. On the basis of prior research, we hypothesized that older adults would have worse treatment outcomes in QOL, functioning, and depressive symptom severity and that nonremitters would have worse outcomes. METHODS A retrospective secondary data analysis was conducted from the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (July 2001-September 2006). We analyzed data for 2,280 nonpsychotic adults with DSM-IV-TR-defined MDD who received citalopram monotherapy. Older adults were classified as adults aged 65 years and above. All subjects completed patient-reported QOL, functioning, and depressive symptom severity measures at entry and exit. Subjects included 106 older adults and 2,174 adults < 65. MDD remission status posttreatment was also determined. RESULTS Both older adults and adults < 65 experienced significant improvements and medium to large treatment responses across QOL, functioning, and depressive symptom severity (P < .001). Older adults had smaller treatment effect sizes for all outcomes, particularly functioning. Conversely, mean change scores from entry to exit were equivalent across all outcomes. Remitters at exit had significantly better responses to treatment than nonremitters for the majority of outcomes. CONCLUSION Findings suggest that older adults and younger adults have comparable treatment responses to citalopram monotherapy, with significant improvements in patient-reported depressive symptom severity, functioning, and QOL. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.

Objective To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. Methods This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. Results Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. Conclusions In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.

Objective: The timing and rate of improvement after the initiation of an antidepressant has implications for establishing the mechanism of antidepressant action and for answering the clinically relevant question of how long an appropriate trial of antidepressant medication should be. We explore the individual trajectories of relative change in depression severity to establish what proportion of individuals experience early and late onset of improvement. Method: Longitudinal latent class analysis was applied in a secondary analysis of data obtained from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. In the GENDEP trial, conducted in 9 European academic psychiatry centers from July 2004 to June 2008, 811 treatment-seeking adult subjects with DSM-IV major depression received escitalopram or nortriptyline for 12 weeks. Montgomery- Asberg Depression Rating Scale measurements were taken weekly. The secondary analysis reported in this article was conducted in 2010. Results: A model with 9 latent classes provided a good description of the individual trajectories of symptom change over time. These classes included 3 nonresponder classes, 3 classes with varying degrees of improvement concentrated in the first 3 weeks (early improvement), and 3 classes with varying degrees of improvement that was more prominent in the second 3 weeks than in the first 3 weeks (delayed improvement). More than half of the subjects who eventually reached remission showed a pattern of delayed improvement, and their eventual outcome could not be predicted from early time points. Early marked response occurred more frequently in subjects treated with nortriptyline than in those treated with escitalopram (12.9% vs 7.5%, X 2 = 6.29, P = .01). Delayed complete remission occurred more frequently in subjects treated with escitalopram than in those treated with nortriptyline (13.6% vs 6.1%, X 2 = 11.52, P = .0007). Conclusions: Both early and delayed improvement are common. Although early changes are maintained, the eventual outcome of 12-week antidepressant treatment can be accurately predicted only after 8 weeks. Trial Registration: http://www.controlled-trials.com Identifier: ISRCTN03693000. © Copyright 2011 Physicians Postgraduate Press, Inc.

Background It is generally believed that selective serotonin reuptake inhibitor (SSRI) drugs increase the risk of abnormal bleeding and decrease the risk of ischemic heart disease events by blocking the uptake of serotonin into platelets, leading to an impairment in the platelet hemostatic response. Objective To perform a detailed qualitative review of existing literature on the association of abnormal bleeding with the use of SSRIs. Data sources We conducted a PubMed search during June 2009 using the search terms antidepressants and SSRIs (including the names of individual SSRIs: fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram) in association with bleeding, platelets, hemostasis, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, antiplatelet drugs, proton pump inhibitors, peptic ulcer, premenstrual dysphoric disorder, menstruation, pregnancy, postpartum hemorrhage, surgery, tooth extraction, dental bleeding, stroke, ischemic heart disease, and other terms related to the field. We then searched the reference lists of identified studies. Study selection We provide a qualitative discussion of all studies that would inform clinicians about the mechanisms of bleeding and bleeding risks associated with these drugs in different clinical contexts. Results Epidemiologic studies show that SSRI use is associated with roughly doubled odds of upper gastrointestinal (GI) bleeding; bleeding at other sites has been less commonly described, as has a possibly increased risk of bleeding associated with surgical procedures. The risk of SSRI-associated GI bleeding is increased with the concurrent use of NSAIDs, anticoagulants, and antiplatelet agents and is decreased by concurrent proton pump inhibitors. The risk of bleeding is increased in patients with cirrhosis of the liver or liver failure. There is, curiously, little literature on use of SSRIs and menstrual or postpartum blood loss. Selective serotonin reuptake inhibitors appear protective against ischemic heart disease events. The data are too limited to allow interpretations about influences on ischemic and hemorrhagic stroke. Conclusions On the basis of the findings of our literature search, we suggest that SSRI-induced increase in gastric acid secretion may explain the GI bleeding risk and that SSRI-related effects on platelet reactivity, endothelial reactivity, and inflammatory markers may explain the ischemic heart disease protective effect. Because the absolute risk of GI bleeds with SSRIs is low, precautions are probably necessary only in high-risk patients, such as those with acid-peptic disease and those with a history of bleeds. We discuss management issues and areas for future research.

OBJECTIVE: There are currently no clinically useful assessments that can reliably predict--early in treatment--whether a particular depressed patient will respond to a particular antidepressant. We explored the possibility of using baseline features and early symptom change to predict which patients will and which patients will not respond to treatment. METHOD: Participants were 2,280 outpatients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study who had complete 16-item Quick Inventory of Depressive Symptomatology-self-report (QIDS-SR16) records at baseline, week 2, and week 6 (primary outcome) of treatment with citalopram. Response was defined as a ≥ 50% reduction in QIDS-SR16 score by week 6. By developing a recursive subsetting algorithm, we used both baseline variables and change in QIDS-SR16 scores from baseline to week 2 to predict response/nonresponse to treatment for as many patients as possible with controlled accuracy, while reserving judgment for the rest. RESULTS: Baseline variables by themselves were not clinically useful predictors, whereas symptom change from baseline to week 2 identified 280 nonresponders, of which 227 were true nonresponders. By subsetting recursively according to both baseline features and symptom change, we were able to identify 505 nonresponders, of which 403 were true nonresponders, to achieve a clinically meaningful negative predictive value of 0.8, which was upheld in cross-validation analyses. CONCLUSIONS: Recursive subsetting based on baseline features and early symptom change allows predictions of nonresponse that are sufficiently certain for clinicians to spare identified patients from prolonged exposure to ineffective treatment, thereby personalizing depression management and saving time and cost. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528.

Data were analyzed from 2 prospective, double-blind, placebo-controlled trials of escitalopram in obsessive-compulsive disorder (OCD) to characterize the baseline levels of functional disability and impairment in health-related quality of life (HRQoL) and to assess the relationship between treatment outcomes (response or relapse) and disability or HRQoL.Data from a 24-week, placebo-controlled, fixed-dose trial (N = 466) of escitalopram (10-20 mg/d) or paroxetine (40 mg/d) and from a 40-week, flexible-dose (escitalopram 10-20 mg/d), placebo-controlled relapse-prevention trial (N = 468) were analyzed. Obsessive-compulsive disorder symptoms (DSM-IV criteria) were assessed using the Yale-Brown Obsessive Compulsive Scale (YBOCS), functioning was assessed using the Sheehan Disability Scale (SDS), and HRQoL was assessed using the Medical Outcomes Study Short Form (SF-36). Baseline data were pooled for patients across both studies. For patients in the fixed-dose study, SDS and SF-36 scores were compared across treatment groups and for responders versus nonresponders. In the relapse-prevention trial, SDS and SF-36 scores were compared for relapsed versus nonrelapsed patients.Patients with more severe baseline symptoms (YBOCSor = 27) reported significantly greater impairment on the SDS (P.001) and SF-36 (except for bodily pain). Patients receiving escitalopram or paroxetine reported significant improvements on most SF-36 dimensions and on the SDS compared to placebo; however, improvements in work-related functioning were seen earlier for patients receiving escitalopram (20 mg/d). At the study endpoints, SDS and SF-36 scores were significantly better for patients who were responders (versus nonresponders) and for patients who did not relapse (versus relapsers).Obsessive-compulsive disorder is associated with significant impairment in functioning and HRQoL. Significant differences in disability and HRQoL between responders and nonresponders or relapsers and nonrelapsers suggest a relationship between symptomatic and functional outcomes.lundbecktrials.com Identifiers: 10205 and 10193.

Objective This study examines whether continuation therapy with citalopram can prevent a relapse following remission of major depression due to traumatic brain injury. Method After 65 subjects with DSM-IV-diagnosed major depression following traumatic brain injury were treated with open-label citalopram (20 mg to 50 mg/d), 25 subjects (38.5%) met criteria for remission. Of those, 21 (84.0%) were randomly assigned to either same-dose citalopram or placebo and followed monthly over 40 weeks. Remission was defined as a Hamilton Depression Rating Scale (HDRS) score of ≤ 7 or a Clinical Global Impressions-Improvement rating of "much improved" or better. The main outcome variable was the presence of relapse, as defined by meeting criteria for major depressive episode according to the DSM-IV and an HDRS score ≥ 16. Data were collected from February 16, 2005, to May 5, 2008. Results Ten subjects were randomly assigned to citalopram and 11 to placebo. There were 3 dropouts, including 1 for adverse drug effects (diarrhea). Relapse occurred in 11 subjects (52.4%), with a mean ± SD time to relapse of 23.52 ± 16.6 weeks. The groups did not differ in relapse rates (drug: 50.0% [5/10] vs placebo: 54.5% [6/11], Fisher exact test, P = .835) or time to relapse (log rank test χ² = 0.148, P = .700). Conclusions The present study suggests important limitations of continuation pharmacotherapy in the prevention of relapse of major depression following traumatic brain injury. Trial registration clinicaltrials.gov Identifier: NCT00162916.

OBJECTIVE To examine the effects of citalopram augmentation of antipsychotics on suicidal ideation in middle-aged and older people with schizophrenia and subthreshold depressive symptoms. METHOD In this placebo-controlled trial conducted from September 1, 2001, to August 31, 2007, 198 outpatients > or = 40 years old with DSM-IV-diagnosed schizophrenia or schizoaffective disorder and subthreshold depressive symptoms were randomly assigned to flexible-dose citalopram (n = 104) or placebo (n = 94) augmentation of their antipsychotic for 12 weeks. Depression was measured with the Hamilton Depression Rating Scale (HDRS) and Calgary Depression Rating Scale (CDRS). Primary suicidal ideation measures were the Clinical Global Impressions-Severity of Suicide scale (CGI-SS) and the InterSePT Scale for Suicidal Thinking (ISST); secondary outcomes were the Scale for Suicidal Ideation (SSI), Beck Hopelessness Scale (BHS), HDRS item 3, and CDRS item 8. RESULTS Compared to placebo, at the final visit, citalopram was associated with lower BHS scores (4.21 vs 4.98; P < .05) and lower likelihood of having suicidal ideation on the ISST (17.7% vs 38.7%; P < .005) and HDRS item 3 (14.4% vs 22.6%; P < .05). Among the 114 participants with no baseline suicidal ideation, there were no significant differences between citalopram and placebo regarding "emergent" ideation on either primary outcome. Among the 55 participants with baseline suicidal ideation, fewer treated with citalopram had endpoint ideation on the ISST (28.6% vs 66.7%; P < .05). Significantly more depression responders than nonresponders went from having baseline suicidal ideation to no suicidal ideation on both the ISST (75.0% vs 31.4%; P < .05) and CGI-SS (84.6% vs 31.3%; P < .05). CONCLUSIONS Treatment-emergent suicidal ideation was no more common with citalopram than placebo. In participants with baseline suicidal ideation, citalopram reduced suicidal ideation, especially in those whose depressive symptoms responded to treatment.

More data are needed to guide next-step interventions for panic disorder refractory to initial intervention.This 24-week randomized clinical trial (RCT) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases. Patients who failed to meet remission criteria were eligible for randomization in the next treatment phase. Phase 1 was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg (or escitalopram equivalent) to prospectively define treatment refractoriness (lack of remission). Phase 2 was a 6-week double-blind RCT of (1) increased-dose selective serotonin reuptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 was a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to "medication optimization" with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent-to-treat sample in each phase.In phase 1, 20.5% (8/39) of the patients achieved remission, and only baseline severity predicted endpoint PDSS score (beta [SE] = 1.04 [0.15], t = 6.76, P.001). In phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n = 2] vs increased dose 9% [n = 1]: Fisher exact test P = NS). In phase 3, remission was minimal (medication optimization = 11% [n = 1]; CBT = 10% [n = 1]), with a lack of group difference in PDSS score reduction (t(17) = 0.51, P.60) consistent with a small effect size (d = 0.24).Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ, suggesting that both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed.clinicaltrials.gov Identifier: NCT00118417.

Objective To assess the efficacy of quetiapine addition to citalopram in treatment-naive or medication-free obsessive-compulsive disorder (OCD) patients. Method Seventy-six patients who met DSM-IV criteria for OCD and who were drug-free or drug-naive at entry were randomly assigned in a 10-week, double-blind trial with citalopram (60 mg/day) plus quetiapine (300-450 mg/day) or placebo; treatment-refractory OCD patients were excluded. Of the 76 eligible patients, 66 patients completed the trial-31 in the quetiapine and 35 in the placebo group. The change from baseline to endpoint on the total Yale-Brown Obsessive Compulsive Scale (YBOCS) and the response to treatment in the quetiapine addition compared with the placebo addition group were the primary outcome measures. Response was defined as a 35% or greater reduction on the YBOCS and a Clinical Global Impressions-Improvement (CGI-I) score at endpoint of 1 or 2. The study was conducted from November 2003 to June 2005 at the University Medical Centre Utrecht, The Netherlands. Results As measured by the mean reduction in YBOCS scores following an intent-to-treat, last-observation-carried-forward analysis, quetiapine addition (11.9) was significantly superior to placebo (7.8; p = .009). Quetiapine addition was also significantly superior to placebo on the CGI-I scale, with a mean +/- SD CGI-I score of 2.1 +/- 1.3 versus 1.4 +/- 1.2, respectively (p = .023). Quetiapine addition (N = 22, 69%) was also associated with a significantly greater number of patients responding to treatment compared with placebo addition (N = 15, 41%; p = .019). More patients receiving quetiapine (N = 8) than placebo (N = 2; NS) discontinued treatment due to adverse events. Conclusions The combination of quetiapine and citalopram was more effective than citalopram alone in reducing OCD symptoms in treatment-naive or medication-free OCD patients. Trial registration www.trialregister.nl Identifier NTR116.

OBJECTIVE To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression. METHOD This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks. RESULTS Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks. CONCLUSIONS In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00177671.

Background Subsyndromal symptoms of depression (SSD) in older outpatients with schizophrenia are common and clinically important. While many physicians prescribe antidepressants to patients with schizophrenia and schizoaffective disorder who have SSD, evidence for their effectiveness and safety has been meager. We describe a randomized placebo-controlled trial of citalopram in 198 patients. Method Participants in this 2-site study, conducted from September 1, 2001, to August 31, 2007, were men and women with DSM-IV schizophrenia or schizoaffective disorder who were 40 years of age or older and who met study criteria for SSD. Patients were randomly assigned to flexible-dose treatment with citalopram or placebo augmentation of their current antipsychotic medication. Analysis of covariance was used to compare improvement in scores on the Hamilton Rating Scale for Depression and Calgary Depression Rating Scale between treatment groups; secondary efficacy analyses compared improvement in several other dimensions of schizophrenia. Results Augmentation with citalopram was significantly more effective than with placebo in improving depressive (p = .002) and negative (p = .049) symptoms, mental functioning (p = .000), and quality of life (p = .046). There were no significant differences between citalopram and placebo in suicidal ideation, positive symptoms, cognition, general medical health, physical functioning, or symptoms of movement disorders. No adverse events were more frequent in participants receiving citalopram than in those receiving placebo, and only 4 participants from each treatment group terminated early because of side effects. Conclusions Subsyndromal symptoms of depression in middle aged and older patients with schizophrenia responded to treatment with citalopram with lessening of depressive symptoms and improved functioning and quality of life. It may be important for clinicians to identify and treat SSD in middle-aged and older patients with chronic schizophrenia. Trial registration clinicaltrials.gov Identifier: NCT00047450.

OBJECTIVE: It is unclear whether a positive family history of depression affects the clinical presentation or effectiveness of treatment for major depressive disorder (MDD). We aimed to determine whether depressed patients with a positive family history of depression differed from those without in terms of baseline sociodemographic and clinical characteristics, including concurrent comorbid conditions and treatment outcome with citalopram in a large, multicenter effectiveness trial. METHOD: Clinical outcome and sociodemographic information were collected on 2876 participants with DSM-IV MDD enrolled from July 2001 through April 2004 in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Participants with and without a family history of depression, as determined by self-report at initial assessment, were compared. RESULTS: Over half (55.6%) (1585/2853) of the evaluable sample reported a positive family history of depression. A positive family history of depression was associated with an earlier age at onset of MDD, a longer length of illness, and more comorbid generalized anxiety disorder and prior suicide attempts. These participants had a slightly faster onset of remission, and slightly greater side effect burden, but they did not differ overall in response or remission rates. CONCLUSIONS: A family history of depression was associated with several clinical characteristics, although its usefulness as a predictor of treatment outcome is questionable. The slightly faster remission with an SSRI despite the slightly greater side effect burden indicates the effectiveness of using an SSRI in treating depressed patients both with and without a family history of depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528. Language: en

This article aims to identify baseline sociodemographic and clinical characteristics associated with the duration of the index major depressive episode (MDE) and to assess the effect of the current MDE duration on response and remission rates with up to 14 weeks of citalopram.Eligible participants met DSM-IV criteria for nonpsychotic major depressive disorder, scoredor= 14 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and were not resistant to adequate antidepressant treatment in the current episode. The first patient was enrolled in July 2001 and the last visit for the last patient in follow-up was in March 2006. The evaluable sample (N = 2851) was divided into 4 groups based on the index MDE duration at study entry: acute (or= 6 months, N = 1324), subchronic (7-23 months, N = 807), chronic (24-41 months, N = 326), and ultrachronic (or= 42 months, N = 394). These 4 groups were compared in terms of baseline sociodemographic and clinical characteristics and treatment outcomes. Citalopram was generally begun at 20 mg/day and raised to 40 mg/day by weeks 2 through 4 and to 60 mg/day (final dose) by weeks 4 through 6. Logistic regression models with adjusted post hoc analyses were used to control for associated baseline characteristics. Response was defined asor= 50% reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores at exit. Remission was defined asor= 7 on the HAM-D-17 oror= 5 on the QIDS-SR-16.MDE duration was longer in primary care settings, blacks, Hispanics, single or widowed, unemployed, publicly insured or uninsured, older, and less educated participants and in those with lower income, less recurrence, or greater concurrent general medical or Axis I comorbidities. HAM-D-17 remission rates ranged from 31.0% (acute group) to 24.1% (ultrachronic group). HAM-D-17 remission rates were significantly related to MDE duration (p = .0010), but after adjustments for baseline differences among the 4 groups, remission rates were not different. QIDS-SR-16 response rates were lower for the subacute and chronic groups but not different for the acute and ultrachronic groups after adjustment.Longer MDE duration is associated with socioeconomic disadvantage and greater Axis I and medical comorbidity. Episode duration per se does not significantly affect the likelihood of remission.clinicaltrials.gov Identifier: NCT00021528.

Objective Little information about the disposition of individual antidepressant drugs during pregnancy has been published. We examined the dose requirements and level-to-dose (L/D) ratios of citalopram, escitalopram, and sertraline during pregnancy and after birth. Method Women aged from 32 to 43 years with major depressive disorder according to the Structured Clinical Interview for DSM-IV Axis I Disorders participated in the study. Doses were charted across each week of gestation and post-partum. Samples were collected at 20, 30, and 36 weeks' gestation; delivery; and at 2 and 12 weeks postpartum. Plasma trough levels were obtained 8 to 15 hours after dose intake. Across pregnancy and postpartum, the mean dose-corrected plasma concentrations (L/D ratios) of S- and R-citalopram and S-sertraline, and the corresponding primary chiral metabolites S- and R-desmethylcitalopram and N-desmethylsertra-line were assessed. The samples were analyzed for concentrations of stereospecific parent drug and metabolites. The study was conducted from 2003 to 2006. Results Three women received citalopram, 2 women were treated with escitalopram, and 6 women received sertraline. In 4 of 5 subjects who received citalopram or escitalopram and 5 of 6 subjects who received sertraline, the L/D ratios for the stereoisomers of the parent compound and primary metabolite decreased between 20 weeks gestation and delivery, which reflects increased drug metabolism. By 12 weeks postpartum the L/D ratios were similar to those detected at 20 weeks gestation. Conclusions Our cases illustrate that dose requirements frequently increase during the second half of pregnancy to offset increased drug turnover and maintain optimal pharmacotherapy. These findings replicate and extend earlier published data with other antidepressants. Trial registration clinicaltrials.gov Identifier: NCT00279370.

OBJECTIVE: The aim of the study was to evaluate possible new treatments for major depressive disorder in patients with comorbid alcohol dependence in a municipal alcohol treatment unit. The efficacy of memantine, a noncompetitive glutamate N-methyl-D-aspartate (NMDA)-receptor blocker used for the treatment of moderate to severe Alzheimer's disease, was compared with that of escitalopram, a selective serotonin reuptake inhibitor antidepressant. METHOD: Eighty alcohol-dependent outpatients with major depressive disorder (DSM-IV criteria) seeking treatment from municipal alcohol treatment clinics in Helsinki, Finland, were randomly assigned 1:1 to receive memantine 20 mg/day or escitalopram 20 mg/day. During the study period, patients continued their routine treatment at the clinics. Abstinence was not required. Concomitant interventions or imposed treatment goals were not offered by the study physician. The patients returned to the treatment clinics at weeks 1, 2, 4, 12, and 26 for data collection and for medication checking and dispensing. Outcome measures were the Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II for depression, Hamilton Rating Scale for Anxiety (HAM-A) and Beck Anxiety Inventory for anxiety, Consortium to Establish a Registry for Alzheimer's Disease test battery for cognitive functions, and Social and Occupational Functioning Assessment Scale for social and occupational functions and quality-of-life measures. Twenty-nine patients in each group completed the study. All primary and secondary outcome statistical analyses were performed by an independent source for intent-to-treat populations, which included all patients randomly assigned to treatment. The study was conducted from December 2004 to May 2006. RESULTS: Both treatments significantly reduced the baseline level of depression and anxiety according to MADRS and HAM-A, which were the primary measures (p < .0001). There was no significant difference between the memantine and escitalopram groups. Assessed cognitive functioning scores were primarily within the normative range and were unchanged in both groups. Quality-of-life outcomes equally improved in both treatment groups. CONCLUSIONS: These data provide new evidence for the safety and potential efficacy of memantine and escitalopram for major depressive disorder in patients with comorbid alcohol dependence. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00368862.

Background Isolated reports suggest that escitalopram may be effective for impulsive-compulsive Internet usage disorder (IC-IUD), an impulse-control disorder characterized by excessive time spent on the Internet at the expense of occupational, relationship, and social activities. To assess the safety and efficacy of escitalopram in IC-IUD, we conducted a 10-week, open-label trial followed by a 9-week, double-blind, placebo-controlled discontinuation phase. Method From December 2002 to October 2004, 19 adult subjects with IC-IUD (defined as time consuming, uncontrollable, distressing, and resulting in social, occupational, or financial difficulties) were enrolled. Escitalopram was started at 10 mg/day, then increased and maintained at 20 mg/day for 10 weeks at the end of which completers were randomly assigned to placebo or escitalopram for 9 additional weeks. Two key outcome measures were used: hours spent weekly in nonessential Internet use and overall clinical response (subjects rated "much improved" or "very much improved" on the Clinical Global Impressions-Improvement scale [CGI-I]). Results Fourteen subjects completed the entire study. At the end of the 10th week of open-label esci-talopram, Internet usage decreased significantly from a mean of 36.8 hours/week at baseline to 16.5 hours/week (paired t test: t = 3.58; p = .002). In addition, 64.7% of the sample (N = 11) were considered CGI-I responders. At the end of the double-blind phase, there were no significant differences in outcome measures between patients taking placebo compared to escitalopram (analysis of variance with repeated measures, p > .05). Conclusion Patients showed a significant improvement of IC-IUD symptoms during the open-label escitalopram phase. There was no significant difference between the escitalopram and placebo groups at the end of the subsequent double-blind phase; both groups maintained the gains made in the initial open-label treatment. Larger controlled trials are needed to investigate the efficacy of this and other pharmacologic agents in the treatment of IC-IUD. Trial registration clinicaltrials.gov Identifier: NCT00565422.

Background Negative symptoms are among the most chronic symptoms of schizophrenia. Even with the advent of atypical antipsychotic drugs, negative symptoms remain mostly refractory to treatment. It has been proposed that selective serotonin reuptake inhibitor (SSRI) augmentation therapy in schizophrenia could provide a greater relief of these symptoms. Published studies, however promising, have produced conflicting results. Objective To overcome this discrepancy in results, we performed a meta-analysis of studies assessing SSRI add-on therapy for the negative symptoms of schizophrenia. Data sources and study selection A search was performed using the computerized search engines PsycINFO, PubMed (MEDLINE), and Current Contents. Keywords used were schizophrenia and (for SSRI) sertraline, citalopram, paroxetine, fluoxetine, and fluvoxamine. Hand search of published review articles as well as cross-referencing were carried out, too. Pharmaceutical companies were also contacted. Studies were retained if (1) SSRI add-on therapy was compared with antipsychotic monotherapy among schizophrenia-spectrum disorder patients; (2) the clinical trial was randomized, double-blind, placebo-controlled with parallel-arm design; (3) negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms or the Positive and Negative Syndrome Scale-negative subscale. Data extraction With a consensus, authors (A.A.S. and S.P.) extracted and checked the data independently on the basis of predetermined exclusion and inclusion criteria. Effect size estimates were calculated using Comprehensive Meta-Analysis software. Data synthesis Eleven studies responded to our inclusion criteria. Within a random-effects model, a nonsignificant composite effect size estimate for (end point) negative symptoms was obtained (N = 393; adjusted Hedges' g = 0.178; p = .191). However, when studies were divided according to severity of illness, a moderate and significant effect size emerged for the studies involving so-called "chronic patients" (N = 274; adjusted Hedges' g = 0.386; p = .014). Conclusion The current meta-analysis provides no global support for an improvement in negative symptoms with SSRI augmentation therapy in schizophrenia.

BACKGROUND: Kleptomania has no definitive treatment. Mixed reports of benefit from openly prescribed selective serotonin reuptake inhibitors led us to design a double-blind, placebo-controlled discontinuation trial of escitalopram. METHOD: Between December 2002 and March 2005, we recruited 24 subjects aged >or=20 years with DSM-IV kleptomania of >or=1 year's duration. We excluded subjects with organic mental disorders, psychoses, substance or alcohol abuse, suicidal risk, bipolar I or II disorder, anorexia nervosa, or antisocial personality disorder and subjects requiring other psychotropic medications. Our primary outcome measure was theft episodes per week. A responder was defined as a subject having a > 50% decrease in theft episodes per week and a Clinical Global Impressions-Improvement scale score of "much improved" or "very much improved." Escitalopram was started at 10 mg/day and increased as necessary and tolerated after week 4 to 20 mg/day. At the end of week 7, responders were randomly assigned to a 1-week taper followed by 16 weeks of placebo or to continuation of treatment for 17 weeks at their week 7 escitalopram dose. RESULTS: Nineteen subjects (79%) were week 7 responders and 15 were randomly assigned. Five subjects (4 responders) withdrew early: 1 for unrelated illness, 1 for protocol deviation, 2 for side effects, and 1 for withdrawn consent. Three (43%) of 7 escitalopram subjects relapsed compared with 4 (50%) of 8 placebo subjects (Fisher exact test p = .38). CONCLUSION: The high response rate during open-label escitalopram treatment was not better maintained by double-blind escitalopram than by placebo. Kleptomania may be a heterogeneous pathological behavior better treated with pharma-cotherapy in some cases and psychologically or with combined treatment in others.

Objective To examine motoric, cardiovascular, endocrine, and metabolic effects of adjunctive ziprasidone in adults with major depressive disorder (MDD) and prior nonresponse to 8 weeks of open-label escitalopram. Methods A multicenter, parallel, randomized, double-blind, placebo-controlled trial was conducted at 3 US academic medical centers from July 2008 to October 2013. Recruited were 139 outpatients with persistent DSM-IV MDD following an 8-week open-label trial of escitalopram. Subjects were then randomized to adjunctive ziprasidone (escitalopram + ziprasidone, n = 71) or placebo (escitalopram + placebo, n = 68) for 8 additional weeks. Cardiac and metabolic measures were obtained at each treatment visit. Barnes Akathisia Scale and Abnormal Involuntary Movement Scale (AIMS) scores were also obtained. Changes in outcome measures for each treatment group were compared by independent-samples t test. Results A trend toward significance (P = .06) in corrected QT interval (QTc) increase was observed for ziprasidone (mean [SD] = 8.8 [20.2] milliseconds) versus placebo (-0.02 [25.5] milliseconds). Ziprasidone-treated patients had a significantly greater increase in global akathisia scores (P = .01) and significant weight increase (mean [SD] = 3.5 [11.8] kg, or 7.7 [26.1] lb) compared to placebo (1.0 [6.4] kg, or 2.2 [14.1] lb) (P = .03). No significant changes in AIMS scores were observed for either treatment group. Conclusions Adjunctive ziprasidone, added to escitalopram, led to a greater weight gain and greater but modest akathisia compared to placebo. The effect of ziprasidone on QTc showed a trend toward significance, and therefore caution should be used in the administration of ziprasidone. While ziprasidone augmentation in patients with MDD appears safe, precautions should be taken in practice, specifically regular monitoring of electrocardiogram, weight, extrapyramidal symptoms, and involuntary movements. Trial registration ClinicalTrials.gov identifier: NCT00633399​​.

Cognitive functioning is a symptom of major depressive disorder (MDD) that deserves particular attention by clinicians and researchers. Despite the fact that cognitive dysfunction represents a symptom of MDD as well as a functional outcome measure, cognition has been insufficiently investigated in antidepressant trials. While, until recently, few placebo-controlled trials have measured cognition in MDD, those examples which did have consisted of older adults. Of agents tested thus far in placebo-controlled trials (citalopram, duloxetine, vortioxetine), only the latter has been studied in patients aged 18-65, and only the latter has been shown to be superior to placebo in improving measures of executive functioning and to do so across adult age groups. Both duloxetine and vortioxetine appear to result in greater improvements than placebo in immediate and delayed memory. Clinicians who wish to improve the psychosocial recovery of patients with MDD should be familiar with studies of new options for treatment.