In a well-defined sample, we sought to determine what clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M).
We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder.
Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n = 21) was strongly associated with repeat episodes of H/M [hazard ratio (HR) = 2.01, 95% confidence interval (CI): 1.06–3.83, p = 0.03]. Those with treatment-associated episodes (n = 12) were less likely to experience subsequent episodes of H/M, though this was not significant in the multivariate model (HR = 0.25, 95% CI: 0.06–1.05, p = 0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode.
Family history of bipolar disorder influences course of illness even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes.
bipolar disorder; depressive disorder; antidepressants; prospective studies
Decades of research have highlighted the amygdala’s influential role in fear. Surprisingly, we found that inhalation of 35% CO2 evoked not only fear, but also panic attacks, in three rare patients with bilateral amygdala damage. These results indicate that the amygdala is not required for fear and panic, and make an important distinction between fear triggered by external threats from the environment versus fear triggered internally by CO2.
CO2; interoception; emotion; feeling; lesion
The phenomenology of bipolar I disorder affects treatment and prognosis.
To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.
Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model.
Five US academic medical centers.
Two hundred nineteen subjects with bipolar I disorder.
Main Outcome Measures
Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter.
The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR]=0.746; 95% confidence interval [CI], 0.578–0.963; P=.02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR=0.917; 95% CI, 0.886–0.948; P<.001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR=1.713; 95% CI, 1.373–2.137; P<.001), hypomania (HR=4.502; 95% CI, 3.466–5.849; P<.001), or minor depression (HR = 2.027; 95% CI, 1.622–2.534; P<.001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR=0.438; 95% CI, 0.351–0.548; P<.001).
The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.
There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.
Bipolar (type I or II) patients with an MDE at intake (N=142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.
Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.
The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.
The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
Mood disorders substantially increase risk of cardiovascular disease, though the mechanisms are unclear. We assessed for a dose-dependent relationship between course of illness or treatment with vasculopathy in a well-characterized cohort.
Participants with mood disorders were recruited for the National Institute of Mental Health Collaborative Depression Study (CDS) and followed prospectively. A cross-sectional metabolic and vascular function evaluation was performed on a sub-sample near completion after a mean follow-up of 27 years.
A total of 35 participants from the University of Iowa (33) and Washington University (2) sites of the CDS consented to a metabolic and vascular function assessment at the Iowa site. In multivariate linear regression, controlling for age, gender, and smoking, manic/hypomanic, but not depressive, symptom burden was associated with lower flow-mediated dilation (FMD). Cumulative exposure to antipsychotics and mood stabilizers was associated with elevated augmentation pressure and mean aortic systolic blood pressure. This appeared specifically related to first generation antipsychotic exposure and mediated by increases in brachial systolic pressure. Although second generation antipsychotics were associated with dyslipidemia and insulin resistance, they were not associated with vasculopathy.
These results provide evidence that chronicity of mood symptoms contribute to vasculopathy in a dose-dependent fashion. Patients with more manic/hypomanic symptoms had poorer endothelial function. First generation antipsychotic exposure was associated with arterial stiffness, evidenced by higher augmentation pressure, perhaps secondary to elevated blood pressure. Vascular phenotyping methods may provide a promising means of elucidating the mechanisms linking mood disorders to vascular disease.
adult; antipsychotics; major depression; bipolar disorder; cardiovascular mortality; mania
It is well established that the presence of prominent anxiety within depressive episodes portends poorer outcomes. Important questions remain as to which anxiety features are important to outcome and how sustained their prognostic effects are over time.
To examine the relative prognostic importance of specific anxiety features and to determine whether their effects persist over decades and apply to both unipolar and bipolar conditions.
Participants with unipolar (n = 476) or bipolar (n = 335) depressive disorders were intensively followed for a mean of 16.7 years (s.d. = 8.5).
The number and severity of anxiety symptoms, but not the presence of pre-existing anxiety disorders, showed a robust and continuous relationship to the subsequent time spent in depressive episodes in both unipolar and bipolar depressive disorder. The strength of this relationship changed little over five successive 5-year periods.
The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.
anxiety; bipolar disorder; symptom persistence
This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age-grouping, and whether age of onset plays an independent role in symptom persistence.
Participants in the NIMH Collaborative Depression Study who completed at least twenty years of follow-up and who met study criteria for bipolar I or schizoaffective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18–29 years, n = 56), middle (30–44 years, n = 68) and oldest (greater than 44 years, n = 24) groups.
The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the twenty years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, though correlations were stronger for depressive symptoms and for shorter intervals.
Regardless of age at onset, the passage of decades in bipolar illness appears to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and appears to reflect traits that manifest early an individual’s illness.
major depression; age periods; age of onset; symptom persistence
The authors used results from a twenty-year, high-intensity follow-up to measure the influence of aging, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD).
Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD, or schizoaffective disorder other than mainly schizophrenic, (n = 220), were divided according to their ages at intake into youngest (18–29 years), middle (30–44 years), and oldest (≥45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizoaffective episodes. General linear models (GLM) then tested for effects of time and time-by-group interactions on these measures. Regression analyses compared the influence of age of onset and of current age.
Analyses revealed no significant time or group-by-time effects on the proportions of weeks in major depressive episodes in any of three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group.
These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.
major depression; age periods; age of onset; symptom persistence
Association between poor cognition and symptom clusters including depressive ideation (e.g., guilt) and vegetative symptoms in the absence of dysphoria (nondysphoric depression - NDD) has been suggested in the elderly. The current study examined associations between NDD and pre-morbid and concurrent cognitive functioning in younger adults at high risk for psychopathology. NDD and depressed subjects were expected to show poorer pre-morbid and current cognition than non-depressed participants.
Subjects were adoptees enrolled in the Iowa Adoption Study . NDD subjects were compared with non-depressed comparison subjects and with subjects with dysphoric depression (DD) on measures of pre-morbid cognition (estimated by standardized school achievement test scores) and concurrent cognition (intelligence, attention, memory, executive abilities).
NDD and DD showed lower pre-morbid cognition and executive functioning, while DD showed lower verbal and performance IQ compared to non-depressed subjects. The size of the comparison between NDD and non-depressed subjects for pre-morbid cognition was double that between DD and non-depressed subjects. No significant differences in cognition were found between NDD and DD. These effects were no longer significant after controlling for pre-morbid cognition.
Poorer pre-morbid cognition and executive functions in NDD (and the absence of current cognitive differences compared with DD) suggest that NDD may be a condition of clinical interest. Because poor cognition is a known correlate of alexithymia, these results (including their magnitude) are consistent with the view that NDD may be a paradoxical presentation of depression in persons with limited ability to be aware and verbally report emotions.
Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis.
The behaviors of wild type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene x sex interaction for diagnosis of mood disorders in human subjects. Data from the NIMH-BP Consortium and the GenRED Consortium were examined utilizing a combined dataset that included 2,021 mood disorder cases (1,223 females) and 1,840 controls (837 females).
In both male and female mice, Cacna1c haploinsufficiency is associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms (SNPs), rs2370419 and rs2470411, in CACNA1C, with effects in females (OR=1.64, 1.32), but not in males (OR=0.82, 0.86). The interactions by sex were significant after correction for testing 190 SNPs (P=1.4 x 10−4, 2.1 x 10−4; Pcorrected=0.03, 0.04), and were consistent across two large data sets.
Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.
CACNA1C; bipolar disorder; major depression; Cav1.2; animal model; gender; sex differences
To identify determinants of new use of the first-line SGAs associated with weight gain.
Retrospective chart review.
Outpatient and inpatient psychiatry services at a tertiary, academic medical center.
Sample of 340 consecutive patients over two time periods with major depression with psychotic features, bipolar I, bipolar II, bipolar not otherwise specified, and schizoaffective disorder.
Measurements and Main Results
Clinical and sociodemographic variables associated with new use of olanzapine, risperidone, and quetiapine were identified using univariate and multivariate logistic regression. Several clinical factors were individually associated with initiation of these SGAs: mania (OR 3.6, 95% CI 1.2–10.8), psychosis (OR 3.3, 95% CI 1.5–6.9), and inpatient treatment (OR 3.8, 95% CI 1.8–7.9). Prevalent use of lithium (OR 0.3, 95% CI 0.1–0.9) and being married (OR 0.3, 95% CI 0.1–0.8) were inversely associated. Mania, psychosis, married status, and lithium use remained independently associated on multivariate analysis. Factors related to metabolic or vascular risk were not associated with SGA initiation.
Psychiatric clinicians weigh clinical features related to mental status and acuity heavily in determining whether to initiate SGAs. However, factors related to vascular risk were not associated. Future observational studies should consider current clinical status as an important factor in determining propensity to receive antipsychotics or other acute treatments for bipolar disorder.
Antipsychotic agents; Bipolar disorder; Inpatients; Logistic models; Major Depressive Disorder; Outpatients; Propensity Score; Psychotic Disorders
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Bipolar disorder (BD) is a highly heritable disease that has been difficult to characterize genetically. We have genotyped 1,190 BD cases and 401 controls to find regions of the genome associated with BD. After combining these data with previously existing genotyped samples, we did not find any genome-wide significant associations. However, when we used an additional study to prioritize loci for replication and meta-analysis purposes, we found that we were more likely to see an association in our sample with variants for which we had the highest power. We quantified this effect using logistic regression and saw a strong association between power to detect an effect based on an initial study's results and replication P-value in a second study (P = 1.5×10−7), supporting the presence of shared genetic risk factors across the studies. Moreover, this association was stronger when we restricted analysis to SNPs near coding regions, and it was further enriched when SNPs had the same direction of effect in both studies. This result supports the presence of genetic factors underlying BD near exons whose collective effect results in a detectable signal and provides a framework for assessing the potential for replication when combining results from multiple studies.
We determined if subthreshold hypomanic symptoms predicted new onset mania or hypomania.
We identified 550 individuals followed for at least one year in the National Institute of Mental Health Collaborative Depression Study with a diagnosis of major depression at intake. All participants were screened at baseline for a total of five manic symptoms: elevated mood, decreased need for sleep, high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 and up to 31 years. Longitudinal Interval Follow-up Examinations monitored course of illness and identified any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox Proportional-Hazards Regression.
With a cumulative probability of one-in-four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II and 7.5% to bipolar I disorder. The number of subthreshold hypomanic symptoms, psychosis, and age of onset predicted progression to bipolar disorder. Less need for sleep, unusual energy, and increased goal-directed activities were specifically implicated.
Symptoms of hypomania, even when of low intensity, were very frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. Therefore, continued monitoring for the possibility of progression to bipolar disorder over the long-term course of major depressive disorder is necessary.
Age of Onset; Bipolar disorder; Depressive disorder; Delusions; Prospective studies
To identify Bipolar Disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n = 1,001 cases; n = 1,033 controls) and one involving a sample of individuals of African ancestry (AA; n = 345 cases; n = 670 controls). For the EA sample, SNPs with strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (p = 1.6 × 10-6) and rs10193871 in NAP5 at 2q21.2 (p = 9.8 × 10-6). For the AA sample, SNPs with strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (p = 1.5 × 10-6) and rs2769605 in NTRK2 at 9q21.33 (p = 4.5 × 10-5). We also investigated whether we could provide support for three regions previously associated with BD, and we show that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects; SNPs with the strongest statistical evidence for this included rs11208285 in ROR1 at 1p31.3 (p = 1.4 × 10-6), rs4657247 in RGS5 at 1q23.3 (p = 4.1 × 10-6), and rs7078071 in BTBD16 at 10q26.13 (p = 4.5 × 10-6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.
ANK3; C15Orf53; NAP5; DPY19L3; NTRK2; SLITRK2; ROR1; Bipolar Genome Study; Genetic Information Association Network (GAIN); genetic background; allelic heterogeneity
Omega-3 fatty acid (O3FA) levels and dimensional personality measures have been associated with major depression and the course of depressive illness. We sought to study the utility of O3FA levels and dimensional personality measures as predictors of early improvement with escitalopram.
Twenty-four participants were enrolled in an open-label trial of escitalopram 10 mg/d for 4 weeks. Baseline erythrocyte O3 levels and dimensional personal assessments were obtained.
Using a conservative, intention-to-treat analysis, baseline neuroticism (r = −0.57; P = .007), as measured by the Revised NEO Personality Inventory (NEO-PI-R) but not erythrocyte O3 levels, was correlated with improvements on escitalopram. A facet analysis of the neuroticism domain showed the relationship with antidepressant response to be focused on trait anxiety (r = −0.65; P = .002).
Anxiety may have important prognostic implications on subsequent response to selective serotonin reuptake inhibitors, such as escitalopram.
omega-3 fatty acids; anxiety; major depression; neuroticism; antidepressant
Depression and mania have been linked with low cholesterol though there has been limited prospective study of cholesterol and subsequent course of affective illness. We studied the relationship between fasting total cholesterol and subsequent depressive and manic symptoms. A total of 131 participants from a prospective cohort study were identified as having had a fasting total cholesterol evaluation at intake. Participants were predominantly inpatients at index visit and were followed for a median of 20 and up to 25 years. Cholesterol was modeled with age, gender, and index use of a mood stabilizer in linear regression to assess its influence on subsequent depressive symptom burden in participants with unipolar disorder as well as depressive and manic symptom burden in participants with bipolar disorder. Among bipolar participants (N=65), low cholesterol predicted a higher proportion of follow-up weeks with manic, but not depressive symptoms. Cholesterol did not appear to predict depressive symptom burden among participants with unipolar depression (N=66). Lower cholesterol levels may predispose individuals with bipolar disorder to a greater burden of manic symptomatology and may provide some insight into the underlying neurobiology.
Cholesterol; Major depression; Bipolar disorder; Mania; Depression
Much remains unknown about the phenomenology of bipolar I disorder.
To determine the type of bipolar I mood episodes that occur over time, and their relative frequency.
A total of 219 individuals with Research Diagnostic Criteria bipolar I disorder were prospectively followed for up to 25 years (median 20 years). Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation.
Overall, 1208 mood episodes were prospectively observed. The episodes were empirically classified as follows: major depression, 30.9% (n = 373); minor depression, 13.0% (n = 157); mania, 20.4% (n = 246); hypomania, 10.4% (n = 126); cycling, 17.3% (n = 210); cycling plus mixed state, 7.8% (n = 94); and mixed, 0.2% (n = 2).
Cycling episodes constituted 25% of all episodes. Work groups revising ICD–10 and DSM–IV should add a category for bipolar I cycling episode.
Brain-derived neurotrophic factor (BDNF) plays an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons throughout adulthood. There is growing evidence suggesting that BDNF is involved in the pathophysiology of mood disorders.
Ten SNPs across the BDNF gene were genotyped in a sample of 1,749 Caucasian Americans from 250 multiplex bipolar families. Family-based association analysis was employed with three hierarchical bipolar disorder models to test for association between SNPs in BDNF and the risk for bipolar disorder. In addition, an exploratory analysis was performed to test for an association of the SNPs in BDNF and the phenotypes of rapid cycling and episode frequency.
Evidence of association (p<0.05) was found with several of the SNPs using multiple models of bipolar disorder; one of these SNPs also showed evidence of association (p<0.05) with rapid cycling.
These results provide further evidence that variation in BDNF affects the risk for bipolar disorder.
brain-derived neurotrophic factor; bipolar disorder; association study; single nucleotide polymorphism
Bipolar disorder conveys an increased risk of cardiovascular mortality. We compared the risk for cardiovascular mortality between bipolar I and bipolar II subtypes and determined correlates of cardiovascular mortality.
Participants with major affective disorders were recruited for the National Institute of Mental Health Collaborative Depression Study and followed prospectively for up to twenty-five years. A total of 435 participants met diagnostic criteria for bipolar I (N=288) or bipolar II (N=147) disorder based on Research Diagnostic Criteria at intake and measures of psychiatric symptoms during follow-up. Diagnostic subtypes were contrasted by cardiovascular mortality risk using Cox proportional-hazards regression. Affective symptom burden (the proportion of time with clinically significant manic/hypomanic or depressive symptoms) and treatment exposure were additionally included in the models.
Thirty-three participants died from cardiovascular causes. Participants with bipolar I disorder had more than double the cardiovascular mortality risk of those with bipolar II disorder, after controlling for age and gender (HR=2.35, 95% C.I. 1.04–5.33, p=0.04). The observed difference in cardiovascular mortality between these subtypes was at least partially confounded by the burden of clinically significant manic/hypomanic symptoms which predicted cardiovascular mortality independent of diagnosis, treatment exposure, age, gender, and cardiovascular risk factors at intake. Selective serotonin uptake inhibitors appeared protective though were introduced late in follow-up. Depressive symptom burden was not related to cardiovascular mortality.
Participants with bipolar I disorder may face greater risk of cardiovascular mortality than those with bipolar II disorder. This difference in cardiovascular mortality risk may reflect manic/hypomanic symptom burden.
adult; bipolar disorder; cardiovascular mortality; mania; prospective cohort study; risk factors
Suicide is a leading cause of death and has been strongly associated with affective disorders. The influence of affective disorder polarity on subsequent suicide attempts or completions and any differential effect of suicide risk factors by polarity were assessed in a prospective cohort.
Participants with major affective disorders in the National Institute of Mental Health Collaborative Depression Study were followed prospectively for up to twenty-five years. A total of 909 participants meeting prospective diagnostic criteria for major depressive and bipolar disorders were followed through 4,204 mood cycles. Suicidal behavior was defined as suicide attempts or completions. Mixed-effects, grouped-time survival analysis assessed risk of suicidal behavior and differential effects of risk factors for suicidal behavior by polarity. In addition to polarity, the main effects of age, gender, hopelessness, married status, prior suicide attempts, and active substance abuse were modeled with mood cycle as the unit of analysis.
After controlling for age of onset, there were no differences in prior suicide attempts by polarity though bipolar participants had more prior severe attempts. During follow-up, forty cycles ended in suicide and 384 cycles contained at least one suicide attempt. Age, hopelessness, and active substance abuse but not polarity predicted suicidal behavior. The effects of risk factors did not differ by polarity.
Bipolarity does not independently influence risk of suicidal behavior or the influence of well-established suicide risk factors within affective disorders. Suicide risk assessment strategies may continue to appraise these common risk factors without regard to mood polarity.
Adult; major depression; bipolar disorder; completed suicide; prospective cohort study; risk factors
An overall burden of rare structural genomic variants has not been reported in Bipolar Disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix SNP 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kilobases in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation p = 0.007). This effect was more pronounced for age at onset of mania ≤ 18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.
The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the HPA-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder.
The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m.
Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to cardiovascular (CV) causes (t = 4.01, p < .001 and t = 3.03, p = .004, respectively); the 11 p.m. cortisol concentration predicted death due to suicide (t = 2.05, p = 0.048). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0) μg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6) μg/dl (t = 3.03, df = 53, p = 0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t = 2.05, p = 0.048).
Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.
This study examined psychosocial functioning as a predictor of recovery from episodes of unipolar major depression.
231 subjects diagnosed with major depressive disorder according to Research Diagnostic Criteria were prospectively followed for up to 20 years as part of the NIMH Collaborative Depression Study. The association between psychosocial functioning and recovery from episodes of unipolar major depression was analyzed with a mixed-effects logistic regression model which controlled for cumulative morbidity, defined as the amount of time ill with major depression during prospective follow-up. Recovery was defined as at least eight consecutive weeks with either no symptoms of major depression, or only one or two symptoms at a mild level of severity.
In the mixed-effects model, a one standard deviation increase in psychosocial impairment was significantly associated with a 22% decrease in the likelihood of subsequent recovery from an episode of major depression (OR = 0.78, 95% CI: 0.74–0.82, Z = −3.17, p < 0.002). Also, a one standard deviation increase in cumulative morbidity was significantly associated with a 61% decrease in the probability of recovery (OR = 0.3899, 95% CI: 0.3894–0.3903, Z = −7.21, p < 0.001).
The generalizability of the study is limited in so far as subjects were recruited as they sought treatment at academic medical centers. The analyses examined the relationship between psychosocial functioning and recovery from major depression, and did not include episodes of minor depression. Furthermore, this was an observational study and the investigators did not control treatment.
Assessment of psychosocial impairment may help identify patients less likely to recover from an episode of major depression.
major depression; recovery; psychosocial functioning; psychosocial impairment; risk factors; predictors
The rostral anterior cingulate cortex (rACC) has been implicated as a structural neural correlate of familial major depressive disorder, raising the possibility that the structure of this region may act as a biologic marker of depression vulnerability. The aim of the current study was to determine whether children and adolescents with depressive symptoms have lower rACC volume relative to those without symptoms and examine how a positive family history of depression affects this relationship.
112 normal healthy children (59 boys, 53 girls), age 7–17, without a current diagnosis or history of depression or other psychiatric illness, were recruited from the community. Mood symptoms were collected using the Pediatric Behavior Scale, a parent- and teacher-reported questionnaire. Volumetric measures of the rACC were generated using structural MRI. The relationship of depressive symptoms and rACC volume was examined.
1) The rACC volume was significantly lower in boys with subclinical depressive symptoms compared to boys with no depressive symptoms, particularly on the left side (14.6% reduction; F = 8.90, p = .005). 2) In comparing the correlation of depressive symptoms and rACC volume in boys with a positive family history of depression to those with no family history there was a more robust negative correlation in subjects with a positive family history. 3) In girls there was not a significant association of depressive symptoms and rACC volume.
These findings lend further support to the notion that rACC structure may act as a biologic marker of vulnerability or trait-marker of depression.
Depression; FreeSurfer; children; anterior cingulate; subgenual