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1.  Suicide Ideations, Suicide Attempts, and Completed Suicide in Persons with Pathological Gambling and their First-Degree Relatives 
We examined the relationship between suicidal ideations and attempts in 95 probands with pathological gambling (PG), 91 controls, and 1075 first-degree relatives. The results were analyzed using logistic regression with GEE. Thirty-four PG probands (35.8%) and 4 controls (4.4%) had attempted suicide (OR = 12.12, P < .001); in 13 the attempt occurred before PG onset. Lifetime suicidal ideations occurred in 60 PG probands (63.2%) and 12 controls (13.2%) (OR = 11.29, P < .001). Suicidality in PG probands is a marker of PG severity and is associated with greater psychiatric comorbidity. Offspring of PG probands had significantly higher rates of suicide attempts than control offspring.
PMCID: PMC4595153  PMID: 25845522
Family study; pathological gambling; suicidal ideations; suicide attempts
2.  Age at Onset of DSM-IV Pathological Gambling in a Non-Treatment Sample: Early- versus Later-Onset 
Comprehensive psychiatry  2015;60:40-46.
Pathological gambling (PG) is a prevalent and impairing public health problem. In this study we assessed age at onset in men and women with PG and compared the demographic and clinical picture of early- vs. later-onset individuals. We also compared age at onset in PG subjects and their first-degree relatives with PG.
Subjects with DSM-IV PG were recruited during the conduct of two non-treatment clinical studies. Subjects were evaluated with structured interviews and validated questionnaires. Early-onset was defined as PG starting prior to age 33 years.
Age at onset of PG in the 255 subjects ranged from 8 to 80 years with a mean (SD) of 34.0 (15.3) years. Men had an earlier onset than women. 84% of all subjects with PG had developed the disorder by age 50 years. Early-onset subjects were more likely to be male, to prefer action games, and to have substance use disorders, antisocial personality disorder, attention deficit/hyperactivity disorder, trait impulsiveness, and social anxiety disorder. Later-onset was more common in women and was associated with a preference for slots and a history of sexual abuse.
Age at onset of PG is bimodal and differs for men and women. Early- and later-onset PG have important demographic and clinical differences. The implications of the findings are discussed.
PMCID: PMC4459896  PMID: 25956751
pathological gambling; gambling disorder; family studies; longitudinal studies; age at onset
3.  The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample 
BMC Psychiatry  2016;16:129.
Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response.
This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response.
Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30–40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.
Trial registration
Identifier: NCT01272531
Registered: January 6, 2011
PMCID: PMC4857276  PMID: 27150464
Bipolar disorder; Lithium; Mood stabilizer; Pharmacogenetics; GWAS; Prospective trial; Personalized medicine; Precision medicine
4.  The Relationship of DSM-IV Pathological Gambling to Compulsive Buying and other Possible Spectrum Disorders: Results from the Iowa PG Family Study 
Psychiatry research  2015;226(1):273-276.
This study investigates the possible relationship between pathological gambling (PG) and potential spectrum disorders including the DSM-IV impulse control disorders (intermittent explosive disorder, kleptomania, pyromania, trichotillomania) and several non-DSM disorders (compulsive buying disorder, compulsive sexual behavior, Internet addiction). PG probands, controls, and their first-degree relatives were assessed with instruments of known reliability. Detailed family history information was collected on relatives who were deceased or unavailable. Best estimate diagnoses were assigned blind to family status. The results were analyzed using logistic regression by the method of generalized estimating equations. The sample included 95 probands with PG, 91 controls, and 1075 first-degree relatives (537 PG, 538 control). Compulsive buying disorder, having 1–2 spectrum disorder(s), and having “any spectrum disorder” were more frequent in the PG probands and their first-degree relatives vs. controls and their relatives. Spectrum disorders were significantly more prevalent among PG relatives compared to control relatives (adjusted OR = 8.37), though much of this difference was attributable to the contribution from compulsive buying disorder. We conclude that compulsive buying disorder is likely part of familial PG spectrum.
PMCID: PMC4361289  PMID: 25660732
family study; genetics; pathological gambling; gambling spectrum; impulse control disorders; compulsive buying disorder; compulsive sexual behavior
5.  Seasonal Variation of Depressive Symptoms in Unipolar Major Depressive Disorder 
Comprehensive psychiatry  2014;55(8):1891-1899.
Retrospective and cross-sectional studies of seasonal variation of depressive symptoms in unipolar major depression have yielded conflicting results. We examined seasonal variation of mood symptoms in a long-term prospective cohort – the Collaborative Depression Study (CDS).
The sample included 298 CDS participants from five academic centers with a prospectively derived diagnosis of unipolar major depression who were followed for at least ten years of annual or semi-annual assessments. Generalized linear mixed models were utilized to investigate the presence of seasonal patterns. In a subset of 271 participants followed for at least 20 years, the stability of a winter depressive pattern was assessed across the first two decades of follow-up.
A small increase in proportion of time depressed was found in the months surrounding the winter solstice, although the greatest symptom burden was seen in December through April with a peak in March. The relative burden of winter depressive symptoms in the first decade demonstrated no relationship to that of the second decade. The onset of new episodes was highest October through January, peaking in January.
There exists a small but statistically significant peak in depressive symptoms from the month of the winter solstice to the month of the spring equinox. However, the predominance of winter depressive symptoms did not appear stable over the long-term course of illness.
PMCID: PMC4254297  PMID: 25176622
Seasonal Affective Disorder; Seasonal Mood Disorder; Major Depressive Disorder; Seasonal Pattern; Seasonality; Stability; Prospective Studies; Longitudinal Studies
6.  Vascular Mortality in Participants of the Bipolar Genomics Study 
Psychosomatics  2014;55(5):485-490.
In prior work, we have identified a relationship between symptom burden and vascular outcomes in bipolar disorder. We sought to replicate these findings using a readily accessible measure of mood disorder chronicity and vascular mortality.
We conducted a mortality assessment using the National Death Index for 1,716 participants with bipolar I disorder from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium. We assessed the relationship between the duration of the most severe depressive and manic episodes and time to vascular mortality (cardiovascular or cerebrovascular) using Cox Proportional Hazards Models, adjusting for potentially confounding variables.
Mortality was assessed a mean of 7 years following study intake at which time 58 participants died, 18 from vascular causes. These participants were depressed much longer than their counterparts (Wilcoxon Rank Sum Z=2.30, p=0.02) and the duration of the longest depressive episode in years was significantly associated with time to vascular mortality in models (HR=1.16, 95% C.I. 1.02–1.33, p=0.02), which controlled for age, gender, vascular disease equivalents, and vascular disease risk factors. The duration of longest mania was not related to vascular mortality.
The duration of the most severe depression is independently predictive of vascular mortality, lending further support to the idea that mood disorders hasten vascular mortality in a dose-dependent fashion. Further study of relevant mechanisms by which mood disorders may hasten vascular disease and of integrated treatments for mood and cardiovascular risk factors is warranted.
PMCID: PMC4125557  PMID: 24746452
bipolar disorder; cardiovascular disease; cerebrovascular disease; epidemiology mortality
7.  Omega-3 Fatty Acid Biomarkers and Subsequent Depressive Symptoms 
We sought to determine the relationship between the omega-3 fatty acid content of red blood cell membranes (RBC), in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and baseline and new-onset depressive symptoms in postmenopausal women. We secondarily sought to characterize the association between dietary omega-3 fatty acid intake and depressive symptomatology.
Study participants included 7,086 members of the Women's Health Initiative Memory Study (aged 63–81) who had an assessment of RBC omega-3 fatty acid concentrations at the baseline screening visit. Depressive symptoms at baseline and follow-up were characterized using the Burnam 8-item scale for depressive disorders (CES-D/DIS short form), and secondarily additionally inferred by antidepressant medication use.
In multivariable-adjusted models, our primary exposure, RBC DHA+EPA, was not related to depressive symptoms by any measure at baseline or follow-up, nor were RBC total omega-3, DHA, or EPA (all p>0.2). In contrast, dietary intake of omega-3 was positively associated with depressive symptoms at baseline (adjusted OR 1.082, 95% C.I. 1.004–1.166; p=0.04 for dietary DHA+EPA and Burnam Score ≥ 0.06), although this generally did not persist at follow-up.
No relationship between RBC omega-3 levels and subsequent depressive symptoms was evident, and associations between dietary omega-3 and depressive symptoms were variable. Biomarkers of omega-3 status do not appear to be related to risk of new depression in post-menopausal women.
PMCID: PMC4048630  PMID: 24338726
Omega-3 Fatty Acids; Biological Markers; Diet; Eicosapentaenoic Acid; Depression; Epidemiologic Studies
8.  Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20 
Psychiatric genetics  2008;18(4):191-198.
Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder.
We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons).
Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases.
The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions.
PMCID: PMC4418612  PMID: 18628681
bipolar disorder; chromosome 16; chromosome 20; complex disorder; genetics; gene mapping; linkage analysis; parametric analysis
9.  A Direct, Controlled, Blind Family Study of DSM-IV Pathological Gambling 
Pathological gambling is a major public health problem. We sought to examine the familiality of pathological gambling and determine patterns of familial aggregation of disorders.
We assessed probands with DSM-IV pathological gambling, controls, and their first-degree relatives. Detailed family history information was collected on relatives who were deceased or unavailable.
Ninety-five pathological gambling probands, 91 controls, and their 1,075 first-degree relatives over age 18 (537 relatives of pathological gambling probands, 538 relatives of controls) were evaluated between February 2005 and June 2010. Relatives were assessed blind to proband status. Best estimate diagnoses were assigned. Rates of lifetime pathological gambling (definite/probable) was significantly greater among the first-degree relatives of probands with pathological gambling than among comparison relatives (11% vs 1%, OR = 8.19, P < .001). The prevalence of pathological gambling and subclinical pathological gambling combined was 16% and 3% in case and control relatives, respectively (OR = 6.57, P < .001). Pathological gambling relatives had higher rates of major depression (OR = 1.49, P < .05), bipolar disorder (OR = 3.82, P < .05), any mood disorder (OR = 1.59, P < .05), social anxiety disorder (OR = 4.76, P < .01), any substance use disorder (OR = 1.47, P < .05), posttraumatic stress disorder (OR = 2.59, P < .05), and antisocial personality disorder (OR = 3.72, P < .001). Antisocial personality disorder (OR = 3.12, P < .01), social anxiety disorder (OR = 4.15, P < .01), and posttraumatic stress disorder (OR = 2.85, P < .05) were more frequent in case relatives independent of the presence of pathological gambling. Age at onset of pathological gambling in case probands (< 40 years/≥ 40 years) was not related to familiality in their first-degree relatives (OR = 1.03, P = .927).
Pathological gambling is familial. Mood and substance use disorders may emerge as a consequence of the pathological gambling or as a more complex syndrome. In contrast, antisocial personality disorder, social anxiety disorder, and posttraumatic stress disorder may share a common familial etiology with pathological gambling. The phenotype may extend beyond pathological gambling to include subclinical forms of the disorder.
PMCID: PMC4221079  PMID: 24500179
Depression and anxiety  2013;30(10):940-946.
Genetics of Recurrent Early-Onset Depression study (GenRED II) data were used to examine the relationship between posttraumatic stress disorder (PTSD) and attempted suicide in a population of 1,433 individuals with recurrent early-onset major depressive disorder (MDD). We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD.
Data on lifetime trauma exposures and clinical symptoms were collected using the Diagnostic Interview for Genetic Studies version 3.0 and best estimate diagnoses of MDD, PTSD, and other DSM-IV Axis I disorders were reported with best estimated age of onset.
The lifetime prevalence of suicide attempt in this sample was 28%. Lifetime PTSD was diagnosed in 205 (14.3%) participants. We used discrete time-survival analyses to take into account timing in the PTSD-suicide attempt relationship while adjusting for demographic variables (gender, race, age, and education level) and comorbid diagnoses prior to trauma exposure. PTSD was an independent predictor of subsequent suicide attempt (HR = 2.5, 95% CI: 1.6, 3.8; P < .0001). Neither assaultive nor nonassaultive trauma without PTSD significantly predicted subsequent suicide attempt after Bonferroni correction. The association between PTSD and subsequent suicide attempt was driven by traumatic events involving assaultive violence (HR = 1.7, 95% CI: 1.3, 2.2; P < .0001).
Among those with recurrent MDD, PTSD appears to be a vulnerability marker of maladaptive responses to traumatic events and an independent risk factor for attempted suicide. Additional studies examining differences between those with and without PTSD on biological measures might shed light on this potential vulnerability
PMCID: PMC4026925  PMID: 23893768
11.  Risk of Suicidal Behavior With Antidepressants in Bipolar and Unipolar Disorders 
To examine the risk ofsuicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar n, and unipolar major depressive disorders.
A 27-year longitudinal (1981-2008) observational study ofmood disorders (Research Diagnostic Criteria diagnoses based on Schedule Dr Afi:ctive Disorders and Schizophrenia and review ofmedical records) was used to evaluate antidepressants and risk Dr suicidal behavior. Mixed-efi:cts logistic regression models examined propensity Dr antidepressant exposure. Mixed-efi:cts swvival 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 of206 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 confinned that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-elects swvival 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 obsetVational data adjusted Dr propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.
PMCID: PMC4142755  PMID: 25093469
12.  Seasonal variation of manic and depressive symptoms in bipolar disorder 
Bipolar disorders  2013;15(4):377-384.
Analyses of seasonal variation of manic and depressive symptoms in bipolar disorder in retrospective studies examining admission data have yielded conflicting results. We examined seasonal variation of mood symptoms in a prospective cohort with long-term follow-up: The Collaborative Depression Study (CDS).
The CDS included participants from five academic centers with a prospective diagnosis of bipolar I or II disorder. The sample was limited to those who were followed for at least 10 years of annual or semi-annual assessments. Time series analyses and autoregressive integrated moving average (ARIMA) models were used assess seasonal patterns of manic and depressive symptoms.
A total of 314 individuals were analyzed [bipolar I disorder: (n = 202) and bipolar II disorder: (n = 112)] with both disorders exhibiting the lowest depressive symptoms in summer and highest around the winter solstice, though the winter peak in symptoms was statistically significant only with bipolar I disorder. Variation of manic symptoms was more pronounced in bipolar II disorder, with a significant peak in hypomanic symptomatology in the months surrounding the fall equinox.
Significant seasonal variation exists in bipolar disorder with manic/hypomanic symptoms peaking around the fall equinox and depressive symptoms peaking in months surrounding the winter solstice in bipolar I disorder.
PMCID: PMC3731411  PMID: 23621686
bipolar I disorder; bipolar II disorder; depression; hypomania; mania; seasonal variation
13.  Age of Onset and the Prospectively Observed Course of Illness in Bipolar Disorder 
Journal of affective disorders  2012;146(1):34-38.
To test the validity of age-of-onset grouping in bipolar disorder through the use of prospectively observed time in mood episodes.
Age-of-onset ranges from prior admixture analyses were used to divide 427 individuals with bipolar I or bipolar II disorder into early-, middle- and late- onset groups. These were compared by the proportions of weeks depressed and manic or hypomanic during a mean (SD) prospective follow-up of 17.4 (8.4) years.
As predicted, the group with the earliest onsets reported at intake more previous episodes, more suicide attempts and panic attacks. An early age of onset, but not current age, was predictive of significantly more time in depressive episodes during follow-up but was not predictive of time in manic or hypomanic episodes.
This was a naturalistic study with no control of treatment so variability in treatment may have obscured relationships between predictors and outcomes. Age of onset was retrospectively determined and subject to inaccuracies in recall.
An early age of onset conveys, to a modest degree, a poorer prognosis as expressed in more depressive morbidity.
PMCID: PMC3605729  PMID: 23062746
bipolar disorder; age-of-onset; follow-up; prognosis
14.  Cholesterol fractions, symptom burden, and suicide attempts in mood disorders 
Psychiatry research  2012;200(0):10.1016/j.psychres.2012.06.039.
PMCID: PMC3871860  PMID: 22789841
15.  Chryptochrome 2 Variants, Chronicity, and Seasonality of Mood Disorders 
Psychiatric genetics  2012;22(6):305-306.
PMCID: PMC3485578  PMID: 23111457
16.  Recovery from Multiple Episodes of Bipolar I Depression 
The Journal of clinical psychiatry  2013;74(3):10.4088/JCP.12m08049.
To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery.
219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited from 1978–1981 and followed for up to 25 years. Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. The probability of recovery over time from multiple successive depressive episodes was examined with survival analytic techniques, including mixed-effects grouped-time survival models.
The median duration of major depressive episodes was 14 weeks, and over 70% recovered within 12 months of onset of the episode. The median duration of minor depressive episodes was 8 weeks, and approximately 90% recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first three 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=0.002).
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.
PMCID: PMC3837577  PMID: 23561241
17.  Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression 
Bipolar disorders  2012;14(6):664-671.
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.
PMCID: PMC3432672  PMID: 22816725
bipolar disorder; depressive disorder; antidepressants; prospective studies
18.  Fear and panic in humans with bilateral amygdala damage 
Nature neuroscience  2013;16(3):270-272.
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.
PMCID: PMC3739474  PMID: 23377128
CO2; interoception; emotion; feeling; lesion
19.  Longitudinal Course of Bipolar I Disorder 
Archives of general psychiatry  2010;67(4):339-347.
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.
PMCID: PMC3677763  PMID: 20368510
20.  Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes 
Journal of affective disorders  2012;138(3):440-448.
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.
PMCID: PMC3677770  PMID: 22314261
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
21.  Vasculopathy related to manic/hypomanic symptom burden and first generation antipsychotics in a sub-sample from the Collaborative Depression Study (CDS) 
Psychotherapy and psychosomatics  2012;81(4):235-243.
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.
PMCID: PMC3567920  PMID: 22584147
adult; antipsychotics; major depression; bipolar disorder; cardiovascular mortality; mania
22.  Effects of anxiety on the long-term course of depressive disorders† 
The British Journal of Psychiatry  2012;200(3):210-215.
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.
PMCID: PMC3290796  PMID: 21984801
23.  Anxiety and Outcome in Bipolar Disorder 
The American journal of psychiatry  2009;166(11):1238-1243.
PMCID: PMC3551283  PMID: 19797434
anxiety; bipolar disorder; symptom persistence
24.  Age Transitions in the Course of Bipolar I Disorder 
Psychological medicine  2009;39(8):1247-1252.
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.
PMCID: PMC3551474  PMID: 19335937
major depression; age periods; age of onset; symptom persistence
25.  Does Major Depressive Disorder Change with Age? 
Psychological medicine  2009;39(10):1689-1695.
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.
PMCID: PMC3533492  PMID: 19296865
major depression; age periods; age of onset; symptom persistence

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