Individuals with bipolar disorder face a nearly two-fold increased risk of cardiovascular mortality relative to the general population. Endothelial dysfunction precedes cardiovascular disease and serves as a quantifiable phenotype for vasculopathy. We investigated whether individuals with bipolar disorder had poorer vascular function than controls using a case-control design.
The sample of 54 participants included 27 individuals with bipolar disorder and 27 age- and gender-matched controls. Participants underwent an assessment of metabolic (weight, lipids, and insulin resistance) and vascular parameters (endothelial function using flow-mediated dilation; arterial stiffness using pulse wave velocity and estimated aortic pressure).
Participants had a mean age of 32 years and 41% were female. No significant differences were found between groups in endothelial function or arterial stiffness. Individuals with bipolar disorder demonstrated 100% greater insulin resistance.
The lack of clinically significant differences in vascular function in this young sample suggests any increased risk either occurs later in the course of illness or is largely due to behavioral risk factors, such as smoking, which was balanced between groups. Substantial insulin resistance is identifiable early in course of illness, perhaps secondary to treatment.
Bipolar disorder; cardiovascular disease; cardiovascular mortality; endothelial dysfunction; insulin resistance; pulse wave analysis
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
Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established.
We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD.
From the prospective PREDICT-HD cohort, we identified 735 cases with HD gene expansion but no manifest symptoms of HD and 194 non-gene-expanded controls. In survival analysis, a number of potential risk factors for suicidal behavior were assessed, including symptoms of depression, hopelessness, substance abuse, marital status, gender, and psychiatric history.
During a mean of 3.7 years of prospective follow-up, 12 cases (1.6%) attempted suicide and 1 completed suicide (0.1%). No suicides were observed among controls. In univariate Cox proportional hazards regression models, a history of suicide attempts (HR 8.5, 95% CI 2.8–26.1, p < 0.0002) and a Beck Depression Inventory II score >13 (HR 7.2, 95% CI 2.3–22.0, p < 0.0006) were associated with suicidal behavior. These risk factors had independent effects in multivariate models. A history of incarceration in the past 2 years was also associated (HR 12.5, 95% CI 2.7–56.6, p < 0.002), though uncommon. No further risk factors were identified.
A history of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in prodromal HD. As these risk factors are among the most robust risk factors for suicide, established suicide risk factors appear applicable to those with prodromal HD.
Copyright © 2011 S. Karger AG, Basel
Attempted suicide; Cohort study; Huntington disease; Major depressive disorder; Risk factors; Suicide
Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer –induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97–4.89, p=0.003), H2 antagonists (1.78 kg (95% C.I. −0.50–4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77–6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. −0.06–2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.
Antipsychotic agents; Schizophrenia; Bipolar Disorder; Dyslipidemias; Major Depression; Meta-analysis; Obesity; Psychotic Disorders; Vascular Diseases; Weight Loss
To investigate the association between mood and anxiety disorders and vascular diseases after controlling for vascular disease risk factors.
Using a nationally representative sample of adults (N=5,692) from the National Comorbidity Survey Replication (NCS-R), participants with mood disorders were hierarchically classified as having any lifetime history of mania, hypomania, or major depression. Anxiety disorders were also assessed. The reference group consisted of those without mental disorders. Vascular disease was determined by self-reported history of heart disease, heart attack, or stroke on the NCS-R survey. Vascular risk factors included diabetes, high blood pressure, and obesity.
In multivariate logistic regression models that controlled for obesity, high blood pressure, smoking and diabetes, vascular disease was associated with bipolar disorder in women (OR 2.80, 95% C.I. 1.63–4.80), and major depressive disorder in men (OR 1.85, 95% C.I. 1.17–2.92). Controlling for anxiety disorders reduced the associations in both men and women, and in fact, anxiety disorders were more strongly associated with vascular diseases in men, whereas bipolar disorder continued to be an important correlate of vascular disease in women.
These findings demonstrate the importance of evaluation of sex differences, mood disorder subtype and co-occuring anxiety disorders in assessing the association between mood disorders and vascular diseases. Future research should investigate potential biologic mechanisms for these associations in order to define potential targets for intervention.
anxiety disorders; diabetes mellitus; hypertension; obesity; mood disorders; vascular diseases
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
There has been considerable interest in the elevated risk of cardiovascular disease associated with serious mental illness. While the contemporary literature has paid much attention to major depression and schizophrenia, there has been more limited focus on the risk of cardiovascular mortality for those suffering from bipolar disorder, despite some interest in the historical literature.
We reviewed the historical and contemporary literature related to cardiovascular morbidity and mortality in bipolar disorder.
In studies that specifically assess cardiovascular mortality, bipolar disorder has been associated with a near doubling of risk when compared to general population estimates. This may be explained by the elevated burden of cardiovascular risk factors found in this population. These findings pre-date modern treatments, which may further influence cardiovascular risk.
Given the substantial risk of cardiovascular disease, rigorous assessment of cardiovascular risk is warranted for patients with bipolar disorder. Modifiable risk factors should be treated when identified. Further work is warranted to study mechanisms by which this elevated risk for cardiovascular disease are mediated and to identify systems for effective delivery of integrated medical and psychiatric care for individuals with bipolar disorder.
Bipolar disorder; Cardiovascular disease; Mortality; Metabolic Syndrome; Obesity; Hypertension
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
Edema associated with quetiapine has been described in only one case report to date and represents a potentially serious adverse reaction.
We present a case series of three patients who developed bilateral leg edema following initiation of quetiapine.
One of these patients had a recurrence of edema with subsequent rechallenge. Another patient developed quetiapine-induced edema following a prior episode of olanzapine-induced edema. All the cases present a compelling temporal relationship between the drug challenge and the adverse event.
Prompt recognition and intervention with discontinuation of the offending agent is important for this potentially serious, seemingly idiosyncratic, vascular complication.
Antipsychotics; Cardiovascular; Edema; Quetiapine
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.
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
Bipolar disorder is associated with excess cardiovascular mortality. We hypothesized outpatients with bipolar disorder would exhibit excess cardiovascular risk factors, particularly among prevalent users of the second generation antipsychotics associated with weight gain and valproic acid derivatives.
This chart review of 217 patients with bipolar disorder examined cardiovascular risk factors of the metabolic syndrome. We also evaluated if certain medications were cross-sectionally associated with metabolic syndrome.
Fifty-six patients were not weighed and many did not have available lipid profiles. Over three-quarters of those with available data (N=161) were overweight or obese (body-mass index ≥ 25) and nearly half were obese (body-mass index ≥ 30). A prevalence exceeding general population estimates was also observed for hypertriglyceridemia, elevated blood pressure/hypertension, and elevated fasting glucose/diabetes. Among those with all requisite data (n = 60), over 50% met criteria for National Cholesterol Education Program defined metabolic syndrome, nearly double the expected prevalence. A trend toward greater prevalence of metabolic syndrome among prevalent users of the second generation antipsychotics associated with weight gain was observed.
Obesity and the metabolic syndrome were common in patients with bipolar disorder. These patients may be under-evaluated for cardiovascular risk and warrant screening and early intervention.
bipolar disorder; obesity; hyperlipidemia; hypertension; diabetes mellitus; metabolic syndrome
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
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.
Although the neural substrates of induced emotion have been the focus of numerous investigations, the factors related to individual variation in emotional experience have rarely been investigated in older adults. Twenty-six older normal subjects (mean age, 54) were shown color slides to elicit emotions of sadness, fear, or happiness and asked to rate the intensity of their emotional responses. Subjects who experienced negative emotion most intensely showed relative impairment on every aspect of the Wisconsin Card Sorting Test. Intense positive emotion was associated with relatively impaired performance on the Rey Complex Figure Test. The volume of frontal brain structures, however, was not associated with emotion responses. Hemisphere-specific executive dysfunction was associated with greater intensity of emotional experience in normal older subjects. The role of these differences in intensity of induced emotion and impairment in executive function in daily social and vocational activity should be investigated.
Emotion; induced mood; neuropsychological tests; Wisconsin Card Sorting test; Rey Complex Figure Test
The use of monoamine oxidase inhibitors (MAOIs) by psychiatrists has declined over the past several decades with the expansion of psychiatrists’ pharmacologic armamentarium. This trend has also been driven by concern about food and drug interactions and side effects, as well as waning physician experience with these medications. Many psychiatrists, in fact, never prescribe MAOIs. Recent research has liberalized the MAOI diet and identified symptom presentations more likely to respond to these medications. Thus, clinicians must continue to familiarize themselves with the properties of and indications for prescribing MAOIs.
psychopharmacology; drug response; monoamine oxidase inhibitors (MAOIs); phenelzine; isocarboxazid; tranylcypromine; moclobemide; selegiline; dosage; physician prescribing practices; major depression; bipolar depression; atypical depression; treatment-refractory depression
Low cholesterol levels have commonly been associated with various suicide measures. We sought to examine suicide attempts in a prospective sample of depressed patients that on prior analysis demonstrated an association between low cholesterol and subsequent suicide completions. Seventy-four inpatients with Research Diagnostic Criteria unipolar major depression, bipolar depression or schizoaffective depression entered a prospective follow-up study from 1978 - 1981. Kaplan-Meier survival analysis and Cox regression were utilized to elucidate the relationship between cholesterol levels and subsequent severe suicide attempts as well as all suicide attempts regardless of severity. Attempts preceding index hospitalization and other lifetime attempts were evaluated cross-sectionally. Low serum cholesterol levels did not predict subsequent suicide attempts. Contrary to our hypothesis, the high cholesterol group was associated with increased risk of suicide attempts on survival analysis in those less than median age. Nonetheless, in cross-sectional analysis, the low cholesterol group had more suicide attempts preceding index hospitalization and more remote lifetime attempts. The results from this prospective dataset do not support an association between low cholesterol and subsequent suicide attempts despite replicating the retrospective findings of previous case-control and cross-sectional studies.
adult; major depression; bipolar depression; suicide; prospective cohort study; risk factors