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OBJECTIVE To provide the first head-to-head test of the predictive validity of 2 resolution levels included in the current consensus definition of major depressive episode (MDE) recovery and provide an empirically based, clinically useful definition of the end of an MDE. METHOD 322 participants entering the National Institute of Mental Health Collaborative Depression Study with MDE (diagnosed by Research Diagnostic Criteria) in 1978-1981, and followed thereafter for up to 31 years, were divided into those with 8 consecutive weeks of asymptomatic MDE recovery or residual subsyndromal depressive symptom (SSD) resolution of their index MDE. These 2 levels of recovery were defined based on weekly symptom status on all depressive conditions, assessed by Longitudinal Interval Follow-Up Evaluation (LIFE) interviews conducted every 6 months. Primary measures of validity of these 2 alternative definitions were first well interval duration and long-term depressive illness burden. Groups were also compared on clinical variables, antidepressant treatment, and psychosocial function. RESULTS 61.2% of subjects recovered asymptomatically from their index MDE. By survival analysis, they remained free of a depressive episode relapse or recurrence 4.2 times longer than those with SSD resolution (median = 135 vs 32 weeks; χ² = 70.65; P < .0001). This was not attributable to a difference in intensity of antidepressant medication. Compared to asymptomatic recovery, SSD resolution was associated with significantly longer and more severe index MDEs, with more miscellaneous psychopathology as well as increased long-term psychosocial dysfunction and a greater depressive illness burden during the ensuing 10 or 20 years. Asymptomatic MDE resolution was a stronger predictor of time well than any of 18 other predictors, singly or combined. Eight consecutive weeks of asymptomatic recovery had 93% overlap with a 4-week definition and conferred little benefit over 4 weeks. CONCLUSIONS Four consecutive weeks of asymptomatic recovery defines the end of an MDE and the beginning of a stable well state with improved psychosocial function. Residual symptom resolution is a continuation of an active state of the episode, not the end of an MDE.

OBJECTIVE Substantial evidence exists to indicate bidirectional relationships between obesity and depressive disorders and the importance of fat distribution to this relationship. This analysis used a well-characterized sample of individuals in late adolescence to determine the association between depressive illness and fat distribution. METHOD Medically healthy 15- to 20-year-olds, one-half of whom had recently begun treatment with a selective serotonin reuptake inhibitor, underwent a comprehensive psychiatric evaluation that resulted in diagnostic classification and weekly psychiatric disorder ratings over the prior 4 months using the Longitudinal Interval Follow-Up Evaluation. A whole-body scan, using dual-energy x-ray absorptiometry, allowed estimations of total body less head (TBLH), total mass, fat mass, and visceral adipose tissue (VAT) mass. Assessments occurred between September 2010 and April 2014. Multivariable linear regression analyses, adjusted for relevant covariates, examined the association between DSM-IV-TR-diagnosed major depressive disorder (MDD) and VAT, the primary outcome of interest. These procedures also determined whether significant associations were confined to overweight/obese participants. RESULTS The analysis included data from 200 participants (71% female; mean age = 19.0 ± 1.6 years), of whom 128 had current MDD. The presence of MDD was associated with increased fat mass among overweight/obese participants (Cohen d = 0.79, P < .02), but not normal weight participants. This was true of both visceral and nonvisceral fat mass measures. Accounting for the presence of generalized anxiety disorder (GAD) did not alter the findings. CONCLUSION In adolescents, relationships between central adiposity and MDD may be confined to those who are overweight/obese. Despite the high comorbidity of GAD and depressive disorders, only the latter appeared to be significantly associated with central adiposity.

To examine the risk of suicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar II, and unipolar major depressive disorders.A 27-year longitudinal (1981-2008) observational study of mood disorders (Research Diagnostic Criteria diagnoses based on Schedule for Affective Disorders and Schizophrenia and review of medical records) was used to evaluate antidepressants and risk for suicidal behavior. Mixed-effects logistic regression models examined propensity for antidepressant exposure. Mixed-effects survival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior.Five US academic medical centers.Analyses of 206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2,745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confirmed that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-effects survival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P.001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = -2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder.Based on observational data adjusted for propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.

From the Department of Psychiatry, University of New Mexico School of Medicine, Albuquerque (Dr. Fawcett); the Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts (Dr. Baldessarini); the Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Dr. Coryell); the Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois (Dr. Silverman); and the Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa, and the Mount Sinai School of Medicine, New York, New York (Dr. Stein).

Objective: Follow-up studies of patients with depressive disorders have identified only a few replicable predictors of suicide and have not explored possible interactions between them. The following analysis takes advantage of a large cohort of depressed patients given detailed, structured interviews 2 decades ago. Method: The data set on which this analysis is based was collected between 1976 and 1990. Research personnel administered the Schedule for Affective Disorders and Schizophrenia to 785 adults who had major depressive disorder (Research Diagnostic Criteria) but who lacked other Axis I disorders. The current analysis used the National Death Index to determine mortality status as of 2003. Results: One in 4 of the 134 deaths were by suicide for an overall suicide rate of 4.2%. In comparison to the remaining 752 patients, the 33 who died by suicide were more likely to have been inpatients and to have had a history of suicide attempts at the time of baseline assessment. They had also expressed more hopelessness and had higher ratings of suicidal tendency. The last of these variables was the most robust by far and, when tested with other predictors in regression analyses, was the only one to retain significance (p

OBJECTIVE The aim of this study was to characterize the relationship between serum low-density lipoprotein cholesterol (LDL-c) and subsequent depressive symptoms onset in postmenopausal women. We secondarily assessed serum high-density lipoprotein (HDL-c), total cholesterol, and triglycerides. METHOD This population-based prospective cohort study utilizes data from 24,216 women between 50 and 79 years of age who were participants of the Women's Health Initiative, which originally ran from 1993 to 2005 and has since incorporated 2 extension studies, with the most recent culminating in 2015. Fasting lipids were measured for all participants at baseline and for a subset through 6 years of follow-up. Depressive symptoms were characterized using the Burnam 8-item scale for depressive disorders (Center for Epidemiologic Studies-Depression/Diagnostic Interview Schedule short form) at baseline and during follow-up, using a cut point of 0.06 to indicate presence of depressive symptoms. RESULTS The lowest quintile of LDL-c was associated with an increased risk of subsequent depressive symptoms (hazard ratio [HR] = 1.25, 95% CI = 1.05-1.49, P = .01), and follow-up analyses demonstrated that the elevated risk appeared to be confined to the lowest decile (LDL-c < 100 mg/dL). Further, this elevated risk was moderated by lipid-lowering drug treatment. Elevated risk was demonstrated among those who reported no lipid-lowering medication use (HR = 1.23, 95% CI = 1.03-1.47, P = .02), but not among those reporting use (HR = 0.65, 95% CI = 0.18-2.29, P = .50). CONCLUSIONS Among postmenopausal women, untreated serum LDL-c below 100 mg/dL was associated with an increased risk of developing depressive symptoms. No excess risk was observed in those attaining LDL-c < 100 mg/dL with lipid-lowering therapy. These findings have important implications for risk assessment, treatment considerations, and mechanistic insight.

J Clin Psychiatry 2015;76(2):e222–e223 (doi:10.4088/JCP.14com09639). © Copyright 2015 Physicians Postgraduate Press, Inc. O 40 years ago, clinical observations generated proposals for a distinction among mood-disordered patients between those who experience mania in the course of their illness and those who experience only hypomania.1 Concerns that this distinction could not be made reliably delayed its inclusion in official nomenclature until DSM-IV appeared 25 years later. The availability of other operational definitions and, in particular, the Research Diagnostic Criteria,2 nevertheless fostered an accumulation of findings in support of bipolar II disorder as a valid category. The JCP article by Frankland et al3 is among the most recent of these and is one of the few that have compared symptom profiles of major depressive disorder (MDD) to those of bipolar I depression and bipolar II depression separately. Both of the bipolar depression groups differed from the MDD group in nonoverlapping ways. Thus, contrasts in depressive symptom composition can be added to the other lines of evidence that bipolar I and bipolar II disorders differ. The strongest support for the separation lies in family studies. At least 7 show that bipolar II disorder is more prevalent among the relatives of bipolar II probands than among those of bipolar I probands and, conversely, that bipolar I disorder is more prevalent among the relatives of bipolar I probands.4–10 A prospective component of that study also showed that patients who switch from MDD to bipolar II disorder are more likely to have bipolar II relatives, while those who switch to bipolar I disorder instead have a preponderance of bipolar I relatives.11 Although measures of diagnostic stability are rare, their results can provide robust evidence for validity. Only a few reports have described the likelihood of shifts from bipolar II to bipolar I disorder, but those that have found that this happens in only 5%10 and 7.5%12 of adult samples. A higher rate of 25% reported by the Course and Outcome of Bipolar Youth study13 suggests that diagnostic stability may be lower in child and adolescent populations. Follow-up studies have also revealed differences between the courses of bipolar I and bipolar II disorder, though with less consistency. Some have found that patients with bipolar II disorder experience more depressive morbidity, less time in elevated mood states, more comorbidity, a greater likelihood of suicide attempts, and more psychological impairment.14 A particularly interesting difference between groups is in the likelihood of seasonal patterns. Seasonality among bipolar patients appears to be either confined to,15 or much more prevalent in,16,17 bipolar II groups. Individuals with bipolar II disorder thus may be more photosensitive, and those with bipolar II depression might therefore derive more benefit from light therapy than those with bipolar I depression. Although bipolar depression, with or without seasonal patterns, is often more responsive to phototherapy than is MDD,18 there seems to be no equivalent comparison between bipolar I and bipolar II depression in responsiveness to light therapy. Only a few genomic studies have separated bipolar I disorder from bipolar II disorder, but there are indications that doing so may be very worthwhile. In one, sibling pairs concordant for bipolar II disorder characterized families with evidence of linkage to 18q but not families that did not show linkage.19 More recently, a genomewide association study analysis of a combined cohort revealed that genomewide significance for an association with the adrenomedullary gene on 11p was specific to bipolar II disorder.20 Support for the validity of bipolar II disorder has emerged despite the obvious difficulty of accurately diagnosing hypomania, a syndrome that is rarely current at the time of the diagnostic assessment and that shades into normal periods of excitement or elation. In addition, the boundary between mania and hypomania is largely based on duration, on the need for hospitalization, or on the degree of resulting impairment rather than on symptom number and type. The evidence stands, though, and clearly argues for efforts to characterize how the bipolar I/bipolar II dichotomy might bear usefully on treatment selection. Unfortunately, most large-scale treatment studies are industry sponsored and are designed to achieve an indication for a particular disorder, very rarely for its subtypes. So far, psychiatric drug effects more often generalize across disorders than show specificity to a subtype. Support for the bipolar I/bipolar II distinction seems stronger than that for most other subtypes in psychiatric nosology, though, and therefore may prove a more useful tool for tailoring treatment.

Pathological gambling is a major public health problem characterized by poorly controlled and maladaptive gambling behavior. The disorder has a lifetime prevalence of 0.5%–1.5% in the general adult population and is costly to society in direct and indirect terms.1–6 First included in the psychiatric nomenclature in DSM-III,7 pathological gambling has been renamed “gambling disorder” in DSM-58 and classified as a non–substance-related disorder. Pathological gambling has long been thought to have a hereditary basis. Several family studies, including our own, have reported elevated rates of disordered gambling in first-degree relatives of probands with pathological gambling, along with elevated rates of mood and anxiety disorders, substance use disorders, and antisocial personality disorder.9–14 Twin data are congruent with family studies in suggesting that pathological gambling is not only familial but heritable.15–19 Eisen et al15 calculated that heredity explained 35%–54% of the liability for the 5 symptoms of pathological gambling in a study of 3,359 male twin pairs. Using the same data, Slutske et al16,17 concluded that pathological gambling, substance use disorders, and antisocial personality disorder were genetically-linked, while Potenza et al18 drew similar conclusions with regard to pathological gambling and major depression. In summary, converging data suggest that pathological gambling is familial, coaggregates with several psychiatric disorders, and is probably genetically transmitted to some extent. We now report the results of the world’s largest family study of pathological gambling. The study was developed to replicate and extend our pilot studies12,13 and improve upon earlier family studies. Pathological gambling probands were recruited from the community, and controls were recruited through random digit dialing procedures. Comprehensive evaluations of probands and first-degree relatives were conducted by trained raters. Detailed family history information was collected on relatives who were deceased or were unavailable, usually from multiple sources. The best estimate method was used to assign psychiatric diagnoses to all subjects. The primary goals of the study were to definitively determine whether pathological gambling is familial, examine patterns of familial aggregation of disorders, and investigate demographic and clinical characteristics that might contribute to the familial aggregation of pathological gambling. On the basis of earlier studies, we hypothesized that pathological gambling would occur significantly more often among the first-degree relatives of pathological gambling probands than among comparison relatives and that certain patterns of coaggregation of disorders would occur among pathological gambling first-degree relatives, including higher rates of mood and anxiety disorders, antisocial personality disorder, and substance use disorders. We believe the results will lead to a better understanding of the etiology and pathophysiology of pathological gambling, its classification, and both treatment and preventive strategies.

Objective To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery. Method As part of the National Institute of Mental Health Collaborative Depression Study, 219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited at 5 academic medical centers from 1978 to 1981 and followed for up to 25 years with the Longitudinal Interval Follow-Up Evaluation. The probability of recovery over time from depressive episodes, the primary outcome measure, was examined with mixed-effects grouped-time survival models. Results The median duration of major depressive episodes was 14 weeks, and over 70% of participants recovered within 12 months of episode onset. The median duration of minor depressive episodes was 8 weeks, and approximately 90% of participants recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first 3 major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient = 0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio = 0.93; 95% CI, 0.89-0.98; P = .002). Conclusions Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.

On December 13, 2006, the Psychopharmacologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) considered the risk of suicidality among adults who took antidepressants by reviewing results of 372 industry-sponsored randomized controlled clinical trials with 99,839 participants for a range of indications.1 The FDA conducted its own meta-analyses that focused on the 77,382 adults from 295 randomized controlled clinical trials that evaluated treatments for major depressive disorder (MDD) and other psychiatric disorders.1 The primary outcome in the meta-analyses was suicidality, defined as suicidal ideation, preparatory acts, attempts, or completions, and the trials evaluated the 11 antidepressants approved by the FDA since 1985. About 70% of the suicidality was suicidal thoughts, but there were 8 suicide deaths in the adult trials (5 in participants randomized to the investigational agent, 1to an active comparator, and 2 to placebo). The meta-analyses showed a significant protective effect of antidepressants for ages ≥65 years and a marginal, yet nonsignificant, elevation in risk of suicidality for ages 18–25 years. The FDA briefing document1 displayed these results superimposed on their earlier meta-analyses, which showed a significantly elevated risk of suicidality for children and adolescents randomized to antidepressants. Overall, the document portrayed decreasing antidepressant protection against and increasing risk of suicidality for younger patients. On the basis of these analyses, the FDA issued a revised black box warning for all antidepressants on May 2, 2007, extending the coverage of the 2004 warning that applied to children and adolescents to include patients under 25 years of age.2 The warning label3 currently reads, "(A]ntidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders:' It further warns that "[d]epression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide': Moreover, the warning is not entirely age-specific in that it says, "[P]atients of all ages who are started on anti-depressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.' One limitation of the data that the FDA analyzed is that those results do not generalize to most patients treated with antidepressants. The data primarily came from clinical trials lasting 4 to 8 weeks involving participants in episodes of major depression and other psychiatric disorders. However, a vast majority of patients with major depression, for example, are excluded from clinical trials.4, 5 This occurs because the inclusion criteria of those trials had thresholds for illness severity and exclusion criteria that usually excluded patients who were recently or currently suicidal or psychotic. In addition, the trials usually excluded patients with medical or psychiatric comorbidity or those taking concomitant medications. Therefore, the results of the FDA meta-analyses do not necessarily apply to patients with suicidality, psychosis, comorbid illnesses, or those receiving maintenance therapy or polypharmacy. The objective of this article is to examine the risk of suicide attempts or suicide deaths associated with antidepressants in a broader range of participants that are more representative of the population of patients treated with antidepressants. Our goal was to focus exclusively on the FDA warning about antidepressant risk, not to examine the wide range of variables with hypothesized relationships to suicidality. The data come from the NIMH Collaborative Program on the Psychobiology of Depression-Clinical Studies (Collaborative Depression Study [CDS]), which began collecting prospective follow-up data in 1978.6 The study provides a unique opportunity to examine risk of suicidality with antidepressants due to the combination of methodological strengths of the study, including direct participant interviews, standardized diagnostic and follow-up instruments, frequent follow-up assessments, and up to 27 years of prospective follow-up. We include all study participants whether in a mood disorder episode or in recovery. We hypothesized that, on the basis of the FDA findings, there would be an elevation in suicide attempts and suicide deaths among participants who received an antidepressant compared with those who did not.

The US Food and Drug Administration warnings that psychotropic medications may increase the risk of suicidality have generated concern about prescribing these agents to patients with psychiatric disorders, many of whom are already at increased risk for suicide. To effectively prevent suicidal behaviors and suicide in clinical practice, clinicians must understand the dangers and benefits associated with psychotropic medications. In addition, they must learn how to identify and manage suicidal risk during treatment. Language: en

Background: Patients with bipolar I or II major depression are often misdiagnosed with unipolar major depression. The goal of this study was to develop and validate a brief instrument to screen for bipolar disorder in patients actively ill with major depression. Method: The sample consisted of subjects who enrolled in the National Institute of Mental Health-Collaborative Program on the Psychobiology of Depression-Clinical Studies from 1978 to 1981 during an episode of major depression and included 91 subjects with bipolar I major depression, 52 with bipolar II major depression, and 338 with unipolar major depression diagnosed according to Research Diagnostic Criteria. Most of the subjects were inpatients at the time of enrollment, and subjects were prospectively followed for up to 20 years. In order to create, test, and cross-validate the screening instrument, a split-sample data analytic procedure was performed. This procedure yielded 3 groups of subjects: the bipolar I index sample, the bipolar I cross-validation sample, and the bipolar II cross-validation sample. Each group included subjects with bipolar major depression and subjects with unipolar major depression. Within the bipolar I index sample, subjects with bipolar I major depression at study intake were compared with subjects with unipolar major depression at study intake on a pool of 59 sociodemographic and clinical candidate variables. The 3 variables showing the greatest disparity between bipolar I subjects and unipolar subjects were selected for the screen, the Screening Assessment of Depression-Polarity (SAD-P). The operating characteristics of the SAD-P were then examined within the bipolar I index sample, bipolar I cross-validation sample, and bipolar II cross-validation sample. Results: The items selected for the screening instrument were (1) presence of delusions during the current episode of major depression, (2) number of prior episodes of major depression, and (3) family history of major depression or mania. The screen identified bipolar major depression with a sensitivity of 0.82 in the bipolar I index sample, 0.72 in the bipolar I cross-validation sample, and 0.58 in the bipolar II cross-validation sample. With regard to misclassifying subjects with unipolar major depression, the screen provided a positive predictive value of 0.36 in the bipolar I index sample, 0.29 in the bipolar I cross-validation sample, and 0.27 in the bipolar II cross-validation sample. Conclusion: We suggest using the 3-item SAD-P as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression.

Background Major depressive disorder is usually a recurring illness, and maintenance treatment is used to forestall or prevent recurrent episodes of depression. This study describes recurrence of major depression despite maintenance pharmacotherapy, termed tachyphylaxis. Method The study sample consisted of 103 subjects who participated in the NIMH Collaborative Depression Study, a multicenter longitudinal observational study of the mood disorders. Subjects diagnosed with unipolar major depressive disorder according to Research Diagnostic Criteria were enrolled from 1978-1981 and prospectively followed for up to 20 years. As an observational study, treatment was recorded but not controlled by anyone connected with the study. Subjects were selected for the present study if at some point during follow-up they received antidepressant medication for treatment of an episode of major depressive disorder, recovered from this episode, and subsequently received maintenance pharmacotherapy. Some subjects were successfully treated for multiple episodes of major depressive disorder and then received maintenance medication after each of these episodes, resulting in multiple maintenance treatment intervals. Data were collected using the Longitudinal Interval Follow-Up Evaluation, and mixed-effects logistic regression was used to test the association of sociodemographic and clinical variables with tachyphylaxis. Results For the 103 subjects, there were 171 maintenance treatment intervals in which a subject received maintenance pharmacotherapy after having recovered from an episode of major depressive disorder. The median duration of maintenance treatment was 20 weeks. Tachyphylaxis occurred during 43 (25%) of these 171 maintenance treatment intervals. The subtype of melancholic (endogenous) major depressive disorder significantly elevated the risk of tachyphylaxis during the subsequent maintenance treatment interval. Conclusions Despite the use of maintenance pharmacotherapy, major depression recurs in a considerable number of patients. Improved prophylaxis for these patients requires other treatment strategies based upon a greater understanding of recurrence.

Psychotic depression is marked by increased severity, longer episodes, greater incapacity, and a lower likelihood of placebo response. Psychotic features often recur in subsequent episodes and interepisode intervals are shorter when psychotic features have been previously present. Among the treatment options for psychotic depression, electroconvulsive therapy is particularly effective. Conventional pharmacotherapy consists of tricyclic antidepressants combined with antipsychotics; recovery with tricyclic antidepressant monotherapy is less likely. Serotonin selective reuptake inhibitors may prove useful but the relevant literature is scant. Pharmacokinetic interactions are likely in combination treatment, as are side effects that may mimic the underlying condition. Little is known regarding the importance of antipsychotics to maintenance therapy.