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Michael E Thase,1 Emmanuelle Weiller,2 Peter Zhang,3 Catherine Weiss,4 Roger S McIntyre5 1Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA; 2Medical Affairs, H. Lundbeck A/S, Valby, Copenhagen, Denmark; 3Biostatistics Department, Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA; 4Global Medical Affairs, Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA; 5Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada Objective: Episodes of major depressive disorder (MDD) characterized by high levels of anxiety symptoms are less likely to respond to some forms of antidepressant treatment (ADT). This report examines the effects of adjunctive brexpiprazole on depressive symptoms among patients with MDD and anxiety symptoms.Materials and methods: This was a post hoc analysis of 1,171 patients from the 6-week, randomized, double-blind phases of three studies in adults with MDD and inadequate response to ADTs (NCT01360645, NCT01360632, NCT02196506). Data were pooled for brexpiprazole 2–3 mg/day and for placebo (adjunct to ADT). Montgomery–Åsberg Depression Rating Scale Total score changes were assessed in subgroups of patients with and without anxious distress (based on proxies for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria) and anxious depression (defined as a Hamilton Depression Rating Scale Anxiety/somatization factor score of ≥7). Safety was assessed by the incidence of treatment-emergent adverse events (TEAEs).Results: Benefits were seen for adjunctive brexpiprazole (compared with adjunctive placebo) in both anxiety definition subgroups. For patients with anxious distress, the least squares mean difference (95% CI) at week 6 was -3.00 (-4.29, -1.71; P

BackgroundThe efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance.ObjectiveIn rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks.MethodsForty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed.ResultsScalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response.ConclusionEEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems.

BackgroundPrecise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression.ObjectiveTo use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations.MethodsAn imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks.ResultsThe average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P

Abstract Objective: Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day. Methods: The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time. Results: Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: -3.2 [p = 0.001], RCT-1; -2.5 [p = 0.009], RCT-2). Clinical Global Impressions-Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: -0.4 [p = 0.001], RCT-1; -0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52). Conclusion: Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data. Trial registration: Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592 ; open-label, long-term study: ClinicalTrials.gov identifier: NCT00644358, http://ClinicalTrials.gov/ct2/show/NCT00644358 . [ABSTRACT FROM AUTHOR]

Although antidepressants continue to be a mainstay for clinicians who treat people suffering from depressive disorders, there have recently been articles published in both the scientific literature and the popular press that have raised questions about the utility of this class of medications. This paper briefly examines recent meta-analyses that have reported small drug versus placebo differences in randomized controlled trials and, from the perspective of a prescribing psychiatrist, discusses the clinical significance of these findings. It is concluded that antidepressants do have relatively modest effects (as compared with placebo) in contemporary randomized controlled trials, and that the contribution of placebo-expectancy factors to individual outcomes is often underestimated. Nevertheless, it is also concluded that the modest benefits of antidepressants in grouped datasets obscure large, specific, and very meaningful therapeutic effects for 10% to 20% of those treated with antidepressants. [ABSTRACT FROM AUTHOR]

This paper reviews the evidence on combining antidepressants (ADs) for treatment of major depressive disorder. Although widely used and usually safe, the efficacy of even the most widely prescribed combinations of ADs has not been established by properly controlled, adequately powered, clinical trials. This stands in contrast to several adjunctive strategies for AD nonresponders, including adjunctive lithium, thyroid hormone, or newer-generation antipsychotics. The wide use of AD combinations no doubt reflects the limited efficacy of commonly used ADs and the unmet need for effective strategies for patients with treatment-resistant depression. Although of unproven efficacy, potential merits of combining selected ADs include: (1) avoiding discontinuation-emergent symptoms and cross-titration schedules, (2) at worst, the second AD should be as effective in combination as it would be as a monotherapy following a switch, and (3) the possibility of complementary neuropharmacologic effects that may enhance efficacy or improve tolerability. The dearth of controlled studies of such a commonly used strategy for such a highly prevalent condition is symptomatic of shortcomings in the way clinically relevant research is funded, points to the need for industry-academic-federal collaborations, and underscores the need for large, practice-based, research groups that can efficiently complete publicly funded studies of high public health impact. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is one of the leading causes of disability worldwide and, although many treatment options are avail-able, the percentage of patients brought to remission remains low Newer antidepressants, including serotonin norepinephrine reuptake inhibitors (SNRIs), have been developed to address this unmet need. Extrapolating from studies of older 'dual reuptake inhibitors' such as the tricyclic antidepressant (TCA) clomipramine, it was hoped that therapy with SNRIs would result in high rates of response and remission and relieve a broad array of associated symptoms, yet have a more favorable safety profile than the TCAs. The SNRI class now includes four medications: venlafaxine, duloxetine, milnacipran, and desvenlafaxine. Among these medications, milnacipran is not United States Food and Drug Administration-approved for the treatment of MDD and desvenlafaxine, which is the succinate salt of O-desmethylvenlafaxine (ie, 0DV, the principal active metabolite of venlafaxine), was introduced in early 2008. All four SNRIs have established efficacy in MDD, and several members of the class also have been shown to reduce symptoms commonly associated with MDD, including anxiety and pain. When the first SNRI, venlafaxine, was introduced in 1994, it was widely considered a second-line treatment option (ie, used after selective serotonin reuptake inhibitor failure); this ranking was mainly based on dosing and tolerability issues. Introduction of the extended-release formulation of venlafaxine and duloxetine (in 1997 and 2004, respectively, in the US) have addressed some, but not all, of these concerns. Although the four drugs are grouped together as a class, there are important differences among the SNRIs in terms of pharmacologic and pharmacokinetic characteristics. Thus, SNRIs are not interchangeable and vary in their safety and tolerability profiles and, in all likelihood, utility for particular patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients. METHOD: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. RESULTS: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. CONCLUSIONS: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events. [ABSTRACT FROM AUTHOR]

Although antidepressants represent the cornerstone of medical management of major depressive disorder, several widely publicized recent developments have called into question the safety and effectiveness of the antidepressant medications. This article reviews the methods used to conduct studies of antidepressant efficacy, with particular focus on the research conducted by the pharmaceutical industry. It is concluded that the specific efficacy of antidepressant medications in contemporary, industry-sponsored, randomized, controlled trials is modest compared with that of medications in double-blind, placebo trials. Sources of bias and artifact that detract from these studies' validity and limit their interpretability are reviewed. It is also argued that these studies--which are primarily conducted to obtain regulatory approval, to introduce new medications, or to showcase particular advantages of newer drugs after regulatory approval--form an inadequate basis for an evidence-based medicine assessment of antidepressant effectiveness. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The authors compared the effectiveness of cognitive therapy and pharmacotherapy as second-step strategies for outpatients with major depressive disorder who had received inadequate benefit from an initial trial of citalopram. Cognitive therapy was compared with medication augmentation and switch strategies.METHOD: An equipoise-stratified randomization strategy was used to assign participants to either augmentation of citalopram with cognitive therapy (N=65) or medication (N=117; either sustained-release bupropion [N=56] or buspirone [N=61]) or switch to cognitive therapy (N=36) or another antidepressant (N=86; sertraline [N=27], sustained-release bupropion [N=28], or extended-release venlafaxine [N=31]). Treatment outcomes and the frequency of adverse events were compared.RESULTS: Less than one-third of participants consented to randomization strata that permitted comparison of cognitive therapy and pharmacotherapy. Among participants who were assigned to second-step treatment, those who received cognitive therapy (either alone or in combination with citalopram) had similar response and remission rates to those assigned to medication strategies. For those who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with cognitive therapy. Among those who discontinued citalopram, there were no significant differences in outcome, although those who switched to a different antidepressant reported significantly more side effects than those who received cognitive therapy alone.CONCLUSIONS: After an unsatisfactory response to citalopram, patients who consented to random assignment to either cognitive therapy or alternative pharmacologic strategies had generally comparable outcomes. Pharmacologic augmentation was more rapidly effective than cognitive therapy augmentation of citalopram, whereas switching to cognitive therapy was better tolerated than switching to a different antidepressant. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. METHOD: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. RESULTS: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. CONCLUSIONS: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of /=11 (HRSD(17)>/=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. METHOD: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score

OBJECTIVE: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T(3)) augmentation as a third-step treatment for patients with major depressive disorder. METHOD: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T(3) (up to 50 microg/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score

Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder.Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of /=50% reduction in score from baseline).Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR(16) response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events.Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study assessed patterns of psychopharmacological treatment for bipolar disorder. METHOD: Intake treatment data were examined for the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1998 to 1999). Diagnoses were assessed by using the Structured Clinical Interview for DSM-IV mood modules. Data on treatments were obtained by interviewing patients during the initial psychiatric examination. RESULTS: Of the 500 participants, 73.6 percent had bipolar I disorder, 23.0 percent had bipolar II disorder, and 3.4 percent had bipolar disorder not otherwise specified. Upon examination, 63.4 percent were euthymic, 24.6 percent were depressed, and 12.0 percent were experiencing manic, hypomanic, or mixed states. Standard mood stabilizers (lithium, valproate, or carbamazepine) were the most commonly prescribed class of drugs that participants were taking at intake (71.9 percent). The next most common class of agents was antidepressants (40.6 percent), followed by novel anticonvulsants (31.8 percent), second-generation neuroleptics (27.2 percent), and benzodiazepines (25.0 percent). Eleven percent of patients were treated with standard mood stabilizer monotherapy. These prescribing patterns were further analyzed by subtype of illness and compared with patterns in other clinical and community settings. CONCLUSION: In a large, well-characterized cross-sectional analysis of prescription patterns in the U.S. psychiatric academic setting, patients with bipolar disorder were primarily treated with standard mood stabilizers, followed by moderate use of antidepressants, novel anticonvulsants, and second-generation neuroleptics. Results can be useful in understanding the current clinical standard of care, as well as in guiding research studies toward areas in which there is a relative absence of evidence to inform clinical practice. Studies of longitudinal prescribing patterns in bipolar disorder are also needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone. METHOD: Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks. RESULTS: No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone. CONCLUSIONS: No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence. METHOD: The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression. RESULTS: Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence. CONCLUSIONS: Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence. [ABSTRACT FROM AUTHOR]

Background: Adherence to medication is unacceptably low in both medical and psychiatric disorders. Explanatory models of illness beliefs and behaviors suggest that an individual's beliefs about a disorder and its treatment will influence their adherence. Given that beliefs about medications may influence adherence to antidepressants, we examined beliefs about medications in relation to antidepressant adherence in a primary care sample.Objective: The purpose of this report is to 1) describe beliefs about medication in primary care patients prescribed antidepressants for depression; 2) examine the factor structure of the Beliefs about Medicines Questionnaire (BMQ) and compare it with the previously reported factor structure of the BMQ in medical conditions; and 3) examine the association of medication beliefs with self-reported medication adherence.Results: Factor analysis indicates that the BMQ is valid in a sample of primary care patients receiving treatment for depression and has a similar factor structure to that obtained in samples of patients with chronic medical conditions. Beliefs about medications are significantly associated with self-reported adherence. Severity of depressive symptoms and specific concerns about antidepressants are significantly associated with self-reported medication-taking behavior. Findings suggest that in addition to telling patients how to take their medications, primary care physicians should also educate patients about the short- and long-term effects of the medication, how the medication works, and that antidepressants are not addictive. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. METHOD: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. RESULTS: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30-item clinician-rated Inventory of Depressive Symptomatology, the 17-item and 21-item Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. CONCLUSIONS: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks. [ABSTRACT FROM AUTHOR]

Context: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation.Objective: 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: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States.Participants: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20.Intervention: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks.Main Outcome Measures: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I).Results: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively).Conclusion: In this study, St John's wort was not effective for treatment of major depression. [ABSTRACT FROM AUTHOR]

Context: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT.Objective: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse.Design: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode.Setting: Two university-based hospitals and 1 private psychiatric hospital.Patients: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study.Interventions: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28).Main Outcome Measure: Relapse of major depressive episode, compared among the 3 continuation groups.Results: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse.Conclusions: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy. [ABSTRACT FROM AUTHOR]

Context: The chronic form of major depression is associated with a high rate of prevalence and disability, but no controlled research has examined the impact of long-term treatment on the course and burden of illness.Objective: To determine if maintenance therapy with sertraline hydrochloride can effectively prevent recurrence of depression in the high-risk group of patients experiencing chronic major depression or major depression with antecedent dysthymic disorder ("double depression").Design: A 76-week randomized, double-blind, parallel-group study, conducted from September 1993 to November 1996.Setting: Outpatient psychiatric clinics at 10 academic medical centers and 2 clinical research centers.Intervention: Maintenance treatment with either sertraline hydrochloride (n = 77) in flexible doses up to 200 mg or placebo (n = 84).Patients: A total of 161 outpatients with chronic major or double depression who responded to sertraline in a 12-week, double-blind, acute-phase treatment trial and continued to have a satisfactory therapeutic response during a subsequent 4-month continuation phase.Main Outcome Measure: Time to recurrence of major depression.Results: Sertraline afforded significantly greater prophylaxis against recurrence than did placebo (5 [6%] of 77 in the sertraline group vs 19 [23%] of 84 in the placebo group; P = .002 for the log-rank test of time-to-recurrence distributions). Clinically significant depressive symptoms reemerged in 20 (26%) of 77 patients treated with sertraline vs 42 (50%) of 84 patients who received placebo (P = .001). With use of a Cox proportional hazards model, patients receiving placebo were 4.07 times more likely (95% CI, 1.51-10.95; P = .005) to experience a depression recurrence, after adjustment for study site, type of depression, and randomization strata.Conclusions: Maintenance therapy with sertraline is well tolerated and has significant efficacy in preventing recurrence or reemergence of depression in chronically depressed patients. [ABSTRACT FROM AUTHOR]

Objective: A consensus conference on the reasons for the undertreatment of depression was organized by the National Depressive and Manic Depressive Association (NDMDA) on January 17-18, 1996. The target audience included health policymakers, clinicians, patients and their families, and the public at large. Six key questions were addressed: (1) Is depression undertreated in the community and in the clinic? (2) What is the economic cost to society of depression? (3) What have been the efforts in the past to redress undertreatment and how successful have they been? (4) What are the reasons for the gap between our knowledge of the diagnosis and treatment of depression and actual treatment received in this country? (5) What can we do to narrow this gap? (6) What can we do immediately to narrow this gap?Participants: Consensus panel members were drawn from psychiatry, psychology, family practice, internal medicine, managed care and public health, consumers, and the general public. The panelists listened to a set of presentations with background papers from experts on diagnosis, epidemiology, treatment, and cost of treatment.Evidence: Experts summarized relevant data from the world scientific literature on the 6 questions posed for the conference.Consensus Process: Panel members discussed openly all material presented to them in executive session. Selected panelists prepared first drafts of the consensus statements for each question. All of these drafts were read by all panelists and were edited and reedited until consensus was achieved.Conclusions: There is overwhelming evidence that individuals with depression are being seriously undertreated. Safe, effective, and economical treatments are available. The cost to individuals and society of this undertreatment is substantial. Long suffering, suicide, occupational impairment, and impairment in interpersonal and family relationships exist. Efforts to redress this gap have included provider educational programs and public educational programs. Reasons for the continuing gap include patient, provider, and health care system factors. Patient-based reasons include failure to recognize the symptoms, underestimating the severity, limited access, reluctance to see a mental health care specialist due to stigma, noncompliance with treatment, and lack of health insurance. Provider factors include poor professional school education about depression, limited training in interpersonal skills, stigma, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches, and prescription of inadequate doses of antidepressant medication for inadequate durations. Mental health care systems create barriers to receiving optimal treatment. Strategies to narrow the gap include enhancing the role of patients and families as participants in care and advocates; developing performance standards for behavioral health care systems, including incentives for positive identification, assessment, and treatment of depression; enhancing educational programs for providers and the public; enhancing collaboration among provider subtypes (eg, primary care providers and mental health professionals); and conducting research on development and testing of new treatments for depression. [ABSTRACT FROM AUTHOR]

For treatment to succeed, bipolar patients need mood-stabilization and a good long-term therapeutic relationship. First, though, you must decide if you have the time and expertise to provide appropriate care. [ABSTRACT FROM AUTHOR]

Do you ask about mania in patients with mood symptoms? Bioplar disorders are treatable, but you have to recognize them first. A missed diagnosis can have serious -- even deadly -- results. [ABSTRACT FROM AUTHOR]