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1.  A Direct, Controlled, Blind Family Study of DSM-IV Pathological Gambling 
Objective
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.
Method
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.
Results
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).
Conclusions
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.
doi:10.4088/JCP.13m08566
PMCID: PMC4221079  PMID: 24500179
2.  POSTTRAUMATIC STRESS DISORDER INCREASES RISK FOR SUICIDE ATTEMPT IN ADULTS WITH RECURRENT MAJOR DEPRESSION 
Depression and anxiety  2013;30(10):940-946.
Background
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.
Methods
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.
Results
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).
Conclusions
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
doi:10.1002/da.22160
PMCID: PMC4026925  PMID: 23893768
3.  Risk of Suicidal Behavior With Antidepressants in Bipolar and Unipolar Disorders 
Objective
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.
Design
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.
Setting
Five US academic medical centers.
Results
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.
Condusions
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.
doi:10.4088/JCP.13m08744
PMCID: PMC4142755  PMID: 25093469
4.  Seasonal variation of manic and depressive symptoms in bipolar disorder 
Bipolar disorders  2013;15(4):377-384.
Objectives
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/bdi.12072
PMCID: PMC3731411  PMID: 23621686
bipolar I disorder; bipolar II disorder; depression; hypomania; mania; seasonal variation
5.  Age of Onset and the Prospectively Observed Course of Illness in Bipolar Disorder 
Journal of affective disorders  2012;146(1):34-38.
Background
To test the validity of age-of-onset grouping in bipolar disorder through the use of prospectively observed time in mood episodes.
Methods
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.
Results
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.
Limitations
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.
Conclusions
An early age of onset conveys, to a modest degree, a poorer prognosis as expressed in more depressive morbidity.
doi:10.1016/j.jad.2012.08.031
PMCID: PMC3605729  PMID: 23062746
bipolar disorder; age-of-onset; follow-up; prognosis
6.  Cholesterol fractions, symptom burden, and suicide attempts in mood disorders 
Psychiatry research  2012;200(0):10.1016/j.psychres.2012.06.039.
doi:10.1016/j.psychres.2012.06.039
PMCID: PMC3871860  PMID: 22789841
8.  Recovery from Multiple Episodes of Bipolar I Depression 
The Journal of clinical psychiatry  2013;74(3):10.4088/JCP.12m08049.
Objectives
To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery.
Method
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.
Results
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).
Conclusions
Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.
doi:10.4088/JCP.12m08049
PMCID: PMC3837577  PMID: 23561241
9.  Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression 
Bipolar disorders  2012;14(6):664-671.
Objectives
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1399-5618.2012.01041.x
PMCID: PMC3432672  PMID: 22816725
bipolar disorder; depressive disorder; antidepressants; prospective studies
10.  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.
doi:10.1038/nn.3323
PMCID: PMC3739474  PMID: 23377128
CO2; interoception; emotion; feeling; lesion
11.  Longitudinal Course of Bipolar I Disorder 
Archives of general psychiatry  2010;67(4):339-347.
Context
The phenomenology of bipolar I disorder affects treatment and prognosis.
Objective
To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.
Design
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.
Setting
Five US academic medical centers.
Participants
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.
Results
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).
Conclusions
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.
doi:10.1001/archgenpsychiatry.2010.15
PMCID: PMC3677763  PMID: 20368510
12.  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.
Background
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.
Methods
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.
Results
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.
Limitations
The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.
Conclusions
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.
doi:10.1016/j.jad.2011.12.046
PMCID: PMC3677770  PMID: 22314261
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
13.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1159/000334779
PMCID: PMC3567920  PMID: 22584147
adult; antipsychotics; major depression; bipolar disorder; cardiovascular mortality; mania
14.  Effects of anxiety on the long-term course of depressive disorders† 
The British Journal of Psychiatry  2012;200(3):210-215.
Background
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.
Aims
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.
Method
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).
Results
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.
Conclusions
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.
doi:10.1192/bjp.bp.110.081992
PMCID: PMC3290796  PMID: 21984801
15.  Anxiety and Outcome in Bipolar Disorder 
The American journal of psychiatry  2009;166(11):1238-1243.
doi:10.1176/appi.ajp.2009.09020218
PMCID: PMC3551283  PMID: 19797434
anxiety; bipolar disorder; symptom persistence
16.  Age Transitions in the Course of Bipolar I Disorder 
Psychological medicine  2009;39(8):1247-1252.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1017/S0033291709005534
PMCID: PMC3551474  PMID: 19335937
major depression; age periods; age of onset; symptom persistence
17.  Does Major Depressive Disorder Change with Age? 
Psychological medicine  2009;39(10):1689-1695.
Objective
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).
Method
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.
Results
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.
Conclusion
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.
doi:10.1017/S0033291709005364
PMCID: PMC3533492  PMID: 19296865
major depression; age periods; age of onset; symptom persistence
18.  Cognition and nondysphoric depression among adoptees at high risk for psychopathology 
Comprehensive Psychiatry  2010;52(5):498-506.
Background
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.
Method
Subjects were adoptees enrolled in the Iowa Adoption Study [1]. 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).
Results
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.
Conclusions
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.
doi:10.1016/j.comppsych.2010.10.007
PMCID: PMC3348660  PMID: 21195396
19.  Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans 
Biological psychiatry  2010;68(9):801-810.
Background
Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2010.06.019
PMCID: PMC2955812  PMID: 20723887
CACNA1C; bipolar disorder; major depression; Cav1.2; animal model; gender; sex differences
20.  Clinical Variables Impacting Prescribing of Olanzapine, Quetiapine, and Risperidone 
Pharmacotherapy  2011;31(8):806-812.
Objective
To identify determinants of new use of the first-line SGAs associated with weight gain.
Design
Retrospective chart review.
Setting
Outpatient and inpatient psychiatry services at a tertiary, academic medical center.
Patients
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.
Interventions
None.
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.
Conclusions
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.
doi:10.1592/phco.31.8.806
PMCID: PMC3192400  PMID: 21923607
Antipsychotic agents; Bipolar disorder; Inpatients; Logistic models; Major Depressive Disorder; Outpatients; Propensity Score; Psychotic Disorders
21.  Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes 
PLoS Genetics  2011;7(6):e1002134.
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.
Author Summary
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.
doi:10.1371/journal.pgen.1002134
PMCID: PMC3128104  PMID: 21738484
22.  Subthreshold Hypomanic Symptoms in Progression From Unipolar Major Depression to Bipolar Disorder 
Objective
We determined if subthreshold hypomanic symptoms predicted new onset mania or hypomania.
Method
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.
Results
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.
Conclusions
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.
doi:10.1176/appi.ajp.2010.10030328
PMCID: PMC3042431  PMID: 21078709
Age of Onset; Bipolar disorder; Depressive disorder; Delusions; Prospective studies
23.  GENOME-WIDE ASSOCIATION STUDY OF BIPOLAR DISORDER IN EUROPEAN AMERICAN AND AFRICAN AMERICAN INDIVIDUALS 
Molecular psychiatry  2009;14(8):755-763.
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.
doi:10.1038/mp.2009.43
PMCID: PMC3035981  PMID: 19488044
ANK3; C15Orf53; NAP5; DPY19L3; NTRK2; SLITRK2; ROR1; Bipolar Genome Study; Genetic Information Association Network (GAIN); genetic background; allelic heterogeneity
24.  Neuroticism but not omega-3 fatty acid levels correlate with early responsiveness to escitalopram 
Background
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.
Methods
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.
Results
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).
Conclusions
Anxiety may have important prognostic implications on subsequent response to selective serotonin reuptake inhibitors, such as escitalopram.
PMCID: PMC3035677  PMID: 20680188
omega-3 fatty acids; anxiety; major depression; neuroticism; antidepressant
25.  Cholesterol and Affective Morbidity 
Psychiatry research  2009;175(1-2):78.
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.
doi:10.1016/j.psychres.2009.01.001
PMCID: PMC2814906  PMID: 19969372
Cholesterol; Major depression; Bipolar disorder; Mania; Depression

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