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Objective: To compare time to relapse in patients with major depressive disorder (MDD) stabilised on antidepressant treatment (ADT) + brexpiprazole who were randomised to continued adjunctive brexpiprazole or brexpiprazole withdrawal (switch to placebo)., Methods: This Phase 3, multicentre, double-blind, placebo-controlled, parallel-arm, randomised withdrawal study enrolled adults with MDD and inadequate response to 2–3 ADTs. All patients started on adjunctive brexpiprazole 2–3 mg/day (Phase A, 6–8 weeks). Patients whose symptoms stabilised (Phase B, 12 weeks) were randomised 1:1 to adjunctive brexpiprazole or adjunctive placebo (Phase C, 26 weeks). The primary endpoint was time to relapse in Phase C. Depression rating scale score changes were secondary endpoints., Results: 1149 patients were enrolled and 489 patients were randomised (ADT + brexpiprazole n = 240; ADT + placebo n = 249). Median time to relapse was 63 days from randomisation in both treatment groups for patients who received ≥1 dose. Relapse criteria were met by 22.5% of patients (54/240) on ADT + brexpiprazole and 20.6% (51/248) on ADT + placebo (hazard ratio, 1.14; 95% confidence interval, 0.78–1.67; p = 0.51, log-rank test). Depression scale scores improved during Phases A–B and were maintained in Phase C. Mean weight increased by 2.2 kg in Phases A–B and stabilised in Phase C., Conclusion: Time to relapse was similar between continued adjunctive brexpiprazole and brexpiprazole withdrawal; in both groups, ∼80% of stabilised patients remained relapse free at their last visit. Adjunctive brexpiprazole therapy was generally well tolerated over up to 46 weeks, with minimal adverse effects following brexpiprazole withdrawal.ClinicalTrials.gov identifier: NCT03538691. Funding: Otsuka, Lundbeck.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Background: Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear., Methods: Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response., Results: Compared to participants with WBC counts of 4.5-10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses., Conclusions: An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.

There is a great unmet need for new medications with novel mechanisms of action that can effectively treat patients who do not benefit from standard antidepressant therapies. After a period in which it seemed as if the pharmaceutical pipeline for new antidepressants was going dry, the past decade has witnessed renewed interest, beginning with discovery of the antidepressant effects of ketamine. This article briefly highlights more recent research on ketamine and other investigational antidepressants.

Objective: To evaluate the effects of levomilnacipran extended-release (ER) on suicidal ideation and behavior in adults with major depressive disorder (MDD)., Methods: Post hoc analyses were conducted in patients from 4 randomized, double-blind, placebo-controlled trials and a long-term, open-label extension study of levomilnacipran ER (40-120 mg/d) in adults with MDD. Analyses included incidence of suicide-related treatment-emergent adverse events (TEAEs); incidence of Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation (score=1-5) and behavior (score=6-10); percent of patients who shifted from no C-SSRS suicidal ideation/behavior at baseline to suicidal ideation during treatment (worsened from score=0 to score=1-5), or vice-versa (improved from score=1-5 to score=0)., Results: Suicide-related TEAEs occurred in<1% of patients in the levomilnacipran ER studies. The incidence of C-SSRS suicidal ideation was 22.2%, 23.9%, and 21.7% for placebo, short-term levomilnacipran ER, and long-term levomilnacipran ER, respectively; C-SSRS suicidal behavior was<1% in all of these groups. In the short-term studies, the percentage of patients with C-SSRS shifts were as follows: worsening from score=0 to score=1-5 (placebo, 8.6%; levomilnacipran ER, 11.0%); improvement from score=1-5 to score=0 (placebo, 24.0%; levomilnacipran ER, 27.7%)., Conclusion: In adult MDD patients, the incidence of suicidal ideation and behavior was similar between placebo and short-term levomilnacipran ER as indicated by TEAE reports and C-SSRS scores. Worsening in C-SSRS scores was also similar between placebo and levomilnacipran ER. There was no indication of increased suicidality during longer courses of continued therapy. Together, these findings suggest that this medication is not associated with increased risks of suicidal ideation or behavior.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Objective: The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating patients with major depressive disorder (MDD) with mixed features who present with mild and moderate-to-severe levels of anxiety., Methods: The data in this analysis were derived from a study of patients meeting the DSM-IV-TR criteria for unipolar MDD, with a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, who were randomized to 6 weeks of double-blind treatment with either lurasidone 20-60 mg/day (n=109) or placebo (n=100). Anxiety severity was evaluated using the Hamilton Anxiety Rating Scale (HAM-A). To evaluate the effect of baseline anxiety on response to lurasidone, the following two anxiety groups were defined: mild anxiety (HAM-A≤14) and moderate-to-severe anxiety (HAM-A≥15). Change from baseline in MADRS total score was analyzed for each group using a mixed model for repeated measures., Results: Treatment with lurasidone was associated with a significant week 6 change versus placebo in MADRS total score for patients with both mild anxiety (-18.4 vs. -12.8, p<0.01, effect size [ES]=0.59) and moderate-to-severe anxiety (-22.0 vs. -13.0, p<0.001, ES=0.95). Treatment with lurasidone was associated with a significant week 6 change versus placebo in HAM-A total score for patients with both mild anxiety (-7.6 vs. -4.0, p<0.01, ES=0.62), and moderate-to-severe anxiety (-11.4 vs. -6.1, p<0.0001, ES=0.91)., Conclusions: In this post-hoc analysis of an MDD with mixed features and anxiety population, treatment with lurasidone was associated with significant improvement in both depressive and anxiety symptoms in subgroups with mild and moderate-to-severe levels of anxiety at baseline.

The number needed to treat (NNT) statistic was developed to facilitate the practice of evidence-based medicine. Placebo was assumed to be therapeutically inert when the NNT was originally conceived, but more recent data for conditions such as major depressive disorder (MDD) suggest that the placebo control condition can have considerable therapeutic effects. Complications arise because the NNT calculated from randomised controlled trials (RCTs) reflects a comparison between medication plus clinical management and placebo plus clinical management, whereas, in the clinical setting, physicians choose between prescribing open medication, observing a patient over time with a supportive approach, and doing nothing. Thus, NNTs derived from clinical trials are not directly relevant to clinical decision-making, because they are based on control conditions that do not exist in standard practice. Additional difficulties may arise when using NNTs to compare alternative treatments for MDD, such as medication and psychotherapy, since these comparisons require the control conditions upon which the respective NNTs are based to be similar.Whereas pill placebo conditions include intensive clinical management and elicit expectations of improvement, attention control conditions for psychotherapy research are less well developed. Often the effects of psychotherapy are gauged against a wait-list control condition, which has substantially fewer therapeutic components than a pill placebo control condition. To improve the clinical utility of NNTs for the treatment of MDD, we advocate effectiveness studies that include treatment conditions resembling actual clinical practice, rather than using placebo-controlled RCTs for this purpose. Until such studies are performed, the effect of bias in comparing NNTs across treatments can be controlled by ensuring that the RCT control conditions upon which the NNTs are based are comparable., (© The Royal College of Psychiatrists 2016.)

Background: The cognitive model of depression suggests that cognitive therapy (CT) improves major depressive disorder (MDD) in part by changing depressive cognitive content (e.g. dysfunctional attitudes, hopelessness). The current analyses clarified: (1) the durability of improvements in cognitive content made by acute-phase CT responders; (2) whether continuation-phase CT (C-CT) or fluoxetine (FLX) further improves cognitive content; and (3) the extent to which cognitive content mediates continuation treatments' effects on depressive symptoms and major depressive relapse/recurrence., Method: Out-patients with recurrent MDD who responded to acute-phase CT (n = 241) were randomized to 8 months of C-CT, FLX or pill placebo (PBO) and followed for an 24 additional months. Cognitive content was assessed approximately every 4 months using five standard patient-report measures., Results: Large improvements in cognitive content made during acute-phase CT were maintained for 32 months, with 78-90% of patients scoring in normal ranges, on average. Cognitive content varied little between C-CT, FLX and PBO arms, overall. Small, transient improvements in cognitive content in C-CT or FLX compared with PBO patients did not clearly mediate the treatments' effects on depressive symptoms or on major depressive relapse/recurrence., Conclusions: Outpatients with recurrent MDD who respond to acute-phase CT show durable improvements in cognitive content. C-CT or FLX may not continue to improve patient-reported cognitive content substantively, and thus may treat recurrent MDD by other paths.

Background: Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem., Method: Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives., Results: Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9-38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0-2.9, p = 0.09-0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81-0.86, sensitivity 68.0-80.2%, specificity 90.1-98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR- is 0.1 or less at informative thresholds for all diagnoses., Conclusions: CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Background: Major depressive disorder (MDD) is highly prevalent, is recurrent, and impairs people's work, relationships and leisure. Acute-phase treatments improve psychosocial impairment associated with MDD, but how these improvements occur is unclear. In this study, we tested the hypotheses that reductions in depressive symptoms exceed, precede and predict improvements in psychosocial functioning., Method: Patients with recurrent MDD (n=523; 68% women, 81% Caucasian, mean age 42 years) received acute-phase cognitive therapy (CT). We measured functioning and symptom severity with the Social Adjustment Scale - Self-Report (SAS-SR), Range of Impaired Functioning Tool (RIFT), Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAMD) and Inventory for Depressive Symptomatology - Self-Report (IDS-SR). We tested cross-lagged correlations between functioning and symptoms measured at baseline and the beginning, middle and end of acute-phase CT., Results: Pre- to post-treatment improvement in psychosocial functioning and depressive symptoms was large and intercorrelated. Depressive symptoms improved more and sooner than did psychosocial functioning. However, among four assessments across the course of treatment, improvements in functioning more strongly predicted later improvement in symptoms than vice versa., Conclusions: Improvements in psychosocial functioning and depressive symptoms correlate substantially during acute-phase CT, and improvements in functioning may play a role in subsequent symptom reduction during acute-phase CT.

Background: There is controversy about the implications of relatively small average drug-placebo differences observed in randomised controlled trials of antidepressant medications., Aims: To investigate whether efficacy is better understood as a large effect in a subgroup of patients., Method: The mixture model was used to identify patient subgroups (patients benefiting or not benefiting from treatment) to directly model the skewness of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8., Results: The MADRS scores improved by 15.9 points (95% CI 15.2-16.6) among patients who benefited from treatment. The proportion of patients who benefited from escitalopram and not from placebo treatment was 19.5%, corresponding to a number needed to treat of 5., Conclusions: This model gave a considerably better fit to the data than the analysis of covariance model in which all patients were assumed to benefit from treatment. The small average antidepressant-placebo difference obscures a much larger effect in a clinically meaningful subgroup of patients.

Background: Dyadic discord, while common in depression, has not been specifically evaluated as an outcome predictor in chronic major depressive disorder. This study investigated pretreatment dyadic discord as a predictor of non-remission and its relationship to depressive symptom change during acute treatment for chronic depression., Method: Out-patients with chronic depression were randomized to 12 weeks of treatment with nefazodone, the Cognitive Behavioral Analysis System of Psychotherapy or their combination. Measures included the Marital Adjustment Scale (MAS) and the Inventory of Depressive Symptomatology - Self Report (IDS-SR30). Of 681 original patients, 316 were partnered and 171 of these completed a baseline and exit MAS, and at least one post-baseline IDS-SR30. MAS scores were analysed as continuous and categorical variables ('dyadic discord' v. 'no dyadic discord' defined as an MAS score >2.36. Remission was defined as an IDS-SR30 of 14 at exit (equivalent to a 17-item Hamilton Rating Scale for Depression of 7)., Results: Patients with dyadic discord at baseline had lower remission rates (34.1%) than those without dyadic discord (61.2%) (all three treatment groups) (chi2=12.6, df=1, p=0.0004). MAS scores improved significantly with each of the treatments, although the change was reduced by controlling for improvement in depression. Depression remission at exit was associated with less dyadic discord at exit than non-remission for all three groups [for total sample, 1.8 v. 2.4, t(169)=7.3, p<0.0001]., Conclusions: Dyadic discord in chronically depressed patients is predictive of a lower likelihood of remission of depression. Couple therapy for those with dyadic discord may increase remission rates.

Introduction: Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials., Methods: Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14)., Results: Clinically significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%)., Conclusion: For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy (ClinicalTrials.gov study NCT00105196).

Introduction: To assess the efficacy of desvenlafaxine (administered as desvenlafaxine succinate) in outpatients with major depressive disorder., Methods: A meta-analysis of individual patient data was performed on the complete set of registration trials (nine randomized, double-blind, placebo-controlled 8-week studies) of desvenlafaxine. Patients received fixed (50, 100, 200, or 400 mg/day; n=1,342) or flexible doses (100-400 mg/day; n=463) of desvenlafaxine or placebo (n=1,108). The primary efficacy variable was the 17-item Hamilton Rating Scale for Depression (HAM-D(17)); the primary intent to treat analyses used the last-observation-carried-forward method., Results: Significantly greater improvement with desvenlafaxine versus placebo on the HAM-D(17) total score was observed for the full data set (difference in adjusted means: -1.9; P<.001), each fixed-dose group (all P<.001), and the flexible-dose group (P=.024). Overall rates of HAM-D1(17) response (> or =150% decrease from baseline score: 53% vs 41%) and remission (HAM-D(17) < or =7: 32% vs 23%) were significantly greater for desvenlafaxine versus placebo (all P<.001). Discontinuation rates due to adverse events increased with dose (4% to 18%; placebo: 3%)., Conclusion: Desvenlafaxine demonstrated short-term efficacy for treating major depressive disorder across the range of doses studied. No evidence of greater efficacy was observed with doses >50 mg/day; a strong dose-response effect on tolerability was observed.

Bipolar depression remains one of the most challenging conditions for clinicians to accurately diagnose and effectively treat. For hospitalized patients with bipolar disorder, mood stabilizers--a term often used by clinicians to denote medications that treat acute manic, hypomanic, and depressive symptoms--are often used as first-line treatment. Despite the short- and long-term benefit of a mood stabilizer, comorbid factors, such as substance abuse, can affect patient treatment response. Thus, once the patient's mood is stable and diagnosis is confirmed, clinicians should work with patients on hospital discharge planning, including outpatient follow-up and psychosocial education. In addition to preventing bipolar depression relapse, outpatient initiatives may focus on substance abuse or other comorbid factors. In order to make an accurate diagnosis of bipolar depression, clinicians should perform a complete assessment of the patient and the patient's family at presentation as well as determine whether symptoms are due to bipolar type I disorder or bipolar type II disorder. Presence of substance abuse may complicate initial assessment as patients may be experiencing symptoms related to abuse, including withdrawal. Beyond mood stabilizers and atypical antipsychotics, which should be optimized and chosen based on the treatment history of the patient, antidepressants offer another treatment option for bipolar depression, although they should not be used first line or as monotherapy. As substance abuse often occurs comorbid with bipolar depression, both problems should be addressed with a treatment plan. This expert roundtable supplement addresses the course of diagnosis and treatment for hospitalized patients with bipolar depression and presents a case study to demonstrate clinical challenges related to bipolar patients. The onset and severity of bipolar depression, prevalence of substance abuse, psychosocial treatment options, and clinical issues for the long-term treatment of bipolar depression are also discussed.

Depression is increasingly recognized as a highly recurrent and potentially chronic illness that imposes a substantial burden on individuals, families, and society. Evidence indicates that the risks of depressive recurrence, treatment resistance, and chronicity increase as the illness becomes more highly recurrent. Up to 1 year of continuation phase therapy is now recommended for virtually all depressed patients who respond to antidepressants, with a longer course of maintenance phase pharmacotherapy recommended for those who have experienced multiple episodes. Antidepressants, when effective during the acute phase of therapy, reduce the risk of depressive relapse (continuation phase) and recurrence (maintenance phase) by at least 50%. Longer-term antidepressant pharmacotherapy is most effective when the full dose of medication effective during acute-phase treatment is continued. As combined treatment with antidepressants and psychotherapy may improve shorter-term outcomes for patients with more severe recurrent depression, ongoing combined therapy may be indicated, especially for patients at particularly high risk. Approximately 5% to 10% of patients maintained on antidepressants relapse yearly, leading some to implicate tachyphylaxis. However, before attributing relapse or recurrence to diminished responsiveness to antidepressant medication at the neurochemical level, clinicians should ensure that the patient has been adherent to therapy as prescribed and consider other explanations.

Bipolar affective disorder is a recurrent, disabling, and potentially lethal illness that typically begins early in life. Although the disorder is defined by the manic and hypomanic episodes, for most people the depression episodes are the more virulent aspect of the illness. Specifically, the depressive episodes are more numerous, last longer, and are more difficult to treat than the manias, and depression is the principal cause of the illness's increased mortality due to suicide. For people with early-onset depression, predictors of subsequent bipolarity include a family history, psychotic features, and reverse neurovegetative features. Initial episodes of depression are commonly misdiagnosed, which often delays initiation of appropriate therapy and increases the likelihood of treatment with antidepressants alone. Unfortunately, the correct diagnosis is often not made until there has been a treatment-emergent affective switch. There are no treatments specifically approved for bipolar disorder in youth and, among antidepressants, only fluoxetine has received approved. When bipolarity is suspected, treatment with mood stabilizers, both conventional (i.e., lithium, valproate, and carbamazapine) and more recently classified (lamotrigine) and atypical antipsychotics should be prioritized. When antidepressants are indicated in combination with mood stabilizers, first choice options include bupropion and the selective serotonin reuptake inhibitors. Studies of adults indicate that several forms of focused psychotherapy may improve longer term outcomes.

Introduction: Many patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitors have residual symptoms (eg, persistent fatigue, excessive sleepiness) despite an overall antidepressant response. Placebo-controlled studies indicate that modafinil, a wake-promoting agent, may relieve residual symptoms., Methods: This 12-week, open-label, dose titration, extension study followed an 8-week placebo-controlled study of modafinil augmentation in patients with MDD. The dose was 100-400 mg/day. The median stable dose was 300 mg/day. Assessments were the Epworth Sleepiness Scale, Brief Fatigue Inventory, Clinical Global Impression of Improvement scale, 17-item Hamilton Rating Scale for Depression, and Montgomery-Asberg Depression Rating Scale., Results: Of the 245 patients treated, 194 completed the study; 70% reported Clinical Global Impression of Improvement scale responses of "much improved" or "very much improved" between open-label baseline and final visit (previous randomized modafinil group: 74%; placebo group: 66%). When data were analyzed for four subsets of patients (former modafinil responders, placebo responders, modafinil nonresponders, and placebo nonresponders), improvements in scores on all outcome measures were at least twice as great among former modafinil and placebo nonresponders compared with responders. Most common adverse events were headache (18%), nausea (9%), and dizziness (7%); all were generally mild to moderate in severity., Conclusion: Twelve weeks of modafinil augmentation relieved excessive sleepiness, reduced fatigue, and improved patients' overall clinical condition, including mood.

Despite the large number of depressed patients who do not respond to first-line antidepressants, the evidence base of alternate strategies is quite thin. In this article, a simple 5-stage system for categorizing treatment-resistant depression (TRD) is described and the evidence pertaining to the major strategies currently utilized is summarized using four grades, ranging from D (case reports only) to A (multiple positive placebo-controlled trials). It is concluded that the level of evidence supporting many of the contemporary strategies used for TRD (eg, combinations of antidepressants and augmentation with medications such as pindolol, buspirone, or modafinil) is scanty at best. Even the fundamental question concerning "to augment or to switch" is not answerable with available data. It is noted that the best-documented treatments (ie, lithium augmentation, switching to a monoamine oxidase inhibitor, and electroconvulsive therapy) are among the least utilized. This state of affairs will improve with completion of the studies of Systematic Treatment Alternatives to Relieve Depression, a large multicenter study of difficult-to-treat depression funded by the National Institute of Mental Health. There is a need for greater collaboration among academicians and organizations, such as the American Psychiatric Association, the National Institute of Mental Health, and the pharmaceutical industry, to ensure that sufficient research is conducted so that clinician's choices for patients with TRD can be guided by empirical evidence.

Background: We tested the hypotheses that the addition of medication to psychotherapy enhances participation in the latter by: (1) speeding the acquisition of the psychotherapy's targeted skill; and (2) facilitating higher skill level acquisition., Method: Participants were 431 chronically depressed patients who received Cognitive Behavioral Analysis System of Psychotherapy (CBASP), alone (N=214) or in combination with nefazodone (N=217), as part of a randomized chronic depression study (Keller et al. 2000). CBASP, developed specifically to treat chronic depression, uses a specific procedure, 'situational analysis' to help patients engage in more effective goal-oriented interpersonal behaviours. At the end of each session, therapists rated patients on their performance of situational analysis. Outcome on depressive symptoms was assessed with the 24-item Hamilton Rating Scale for Depression., Results: Although reductions in depression were significantly greater in combined treatment compared to CBASP alone, there were no between-group differences in either the rate of skill acquisition or overall skill level at the end of treatment. Proficiency in the use of the main skill taught in psychotherapy at treatment midpoint predicted outcome independently of medication status and of baseline depressive severity., Conclusions: Effective participation in CBASP, as reflected by proficiency in the compensatory skill taught in psychotherapy, is not enhanced by the addition of medication and does not mediate the between-group difference in depression outcome.

Background: It had been suggested that the antidepressant venlafaxine, which inhibits reuptake of both serotonin and (at higher doses) noradrenaline, may result in better outcomes than treatment with selective serotonin reuptake inhibitors (SSRIs)., Aims: To compare remission rates during treatment with SSRIs or venlafaxine., Method: Data from eight comparable randomised, double-blind studies of major depressive disorder were pooled to compare remission rates (Hamilton Rating Scale for Depression score < or = 7) during treatment with venlafaxine (n = 851), SSRIs (fluoxetine, paroxetine, fluvoxamine; n = 748) or placebo (four studies; n = 446)., Results: Remission rates were: venlafaxine, 45% (382/851); SSRIs, 35% (260/748); placebo, 25% (110/446) (P: < 0.001; odds ratio for remission is 1.50 (1.3-1.9), favouring venlafaxine v. SSRIs). The difference between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. Results were not dependent on any one study or the definition of remission., Conclusions: Remission rates were significantly higher with venlafaxine than with an SSRI.

This article reviews recent studies of psychotherapy for treatment of depression. There is evidence that cognitive behavioral and interpersonal therapies are useful treatments for depressed outpatients, roughly comparable to antidepressant pharmacotherapy. Pharmacotherapy and psychotherapy do not, however, necessarily treat the same patients and there is emerging evidence of a neurobiological "boundary" that may delimit therapy response. Psychotherapy plus pharmacotherapy combinations appear particularly useful for outpatients with more severe, recurrent depressions. Depression-focused psychotherapy may also provide an important alternative to an indefinite course of maintenance pharmacotherapy for patients at high risk for recurrence.