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1.  Finger volume pulse waveforms facilitate reliable assessment of heart rate variability, but not blood pressure variability or baroreflex function 
Background
We sought to determine whether heart rate variability (HRV), blood pressure (BP) variability, and baroreceptor-heart rate reflex sensitivity can be reliably assessed using finger volume pulse waveforms obtained from the commercially available EndoPAT device.
Methods
Non-invasive BP (Finometer Pro as a non-invasive standard) and finger volume (EndoPAT) waveforms were recorded in 65 adults (37 ± 14 years; 60% female) and systolic BP and heart rate (HR) time series were derived after calibrating the EndoPAT signal based on systolic and diastolic BP values obtained by a sphygomomanometer. Transfer function analyses were performed to test for coherence between systolic BP and HR time series derived from the Finometer and EndoPAT devices. Time-domain HRV parameters, frequency domain HR and systolic BP variability parameters, and baroreflex sensitivity (sequence technique) were computed from Finometer- and EndoPAT-derived time series and intraclass correlation coefficients (ICC) were calculated.
Results
Squared coherence between systolic BP time series derived from the Finometer and EndoPAT devices was low, suggesting poor correlation. In contrast, squared coherence between HR time series derived from the two devices was excellent [High Frequency (HF) = 0.80, Low Frequency (LF) = 0.81], with gain values close to 1.0. ICC values for time- and frequency-domain HRV parameters were excellent (>0.9 except for relative HF HRV, which was 0.77), while ICC values for frequency-domain BP variability parameters and baroreceptor-HR reflex sensitivity were low.
Conclusions
Finger volume pulse waveforms can be used to reliably assess both time-domain and frequency-domain HR variability. However, frequency domain BP variability parameters cannot be reliably assessed from finger volume pulse waveforms using the simple calibration technique used in this study.
doi:10.1186/1471-2261-14-180
PMCID: PMC4269858  PMID: 25487432
EndoPAT; Finometer Pro; Cardiovascular function; Device validation
3.  White matter fractional anisotropy is inversely related to anxious symptoms in older adults with atherosclerosis 
Objective
Clinical anxiety disorders are associated with white matter hyperintensities and diffusion abnormalities measured using diffusion tensor imaging (DTI). However, it is not known if this association extends into individuals with mild anxious symptoms without formal diagnosis, in those who are older, or in those who have atherosclerosis. The current study explored whether white matter integrity and/or organization significantly associates with anxious symptoms in older adults with and without atherosclerosis.
Methods
We recruited older adults (ages 55–90); 35 with clinically diagnosed atherosclerotic vascular disease (AVD) and 22 without AVD. Anxious symptoms were measured using the validated Symptom Checklist-90-Revised. Fractional anisotropy (FA), a proxy for white matter organization and health, was measured in the white matter globally, by lobe, and in several smaller regions of interest suggested by the literature. Partial correlations between anxious symptoms and FA were calculated, controlling for significant covariates.
Results
Participants with and without AVD did not differ in severity of anxious symptom endorsement. There was a unique inverse relationship between white matter health and anxious symptoms in the AVD participants, but not in healthy comparisons. Significant relationships were observed in the superior longitudinal fasciculus (r=−.476, df=32, p=.004), as well as the cingulum bundle, the frontal lobes, and the parietal lobes.
Conclusions
Anxiety symptoms uniquely correlated with low fractional anisotropy in older adults with atherosclerosis. These findings may have implications for future research on the topic of anxiety in aging and vascular disease and warrant replication.
doi:10.1002/gps.3930
PMCID: PMC3690172  PMID: 23348834
diffusion tensor imaging; anxiety; uncinate; cingulum; longitudinal fasciculus
4.  Characterization of Depression in Prodromal Huntington Disease in the Neurobiological Predictors of HD (PREDICT-HD) Study 
Journal of psychiatric research  2013;47(10):10.1016/j.jpsychires.2013.05.026.
Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.
doi:10.1016/j.jpsychires.2013.05.026
PMCID: PMC3808084  PMID: 23790259
Huntington Disease; Depression; Suicide; Genetic testing
5.  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
6.  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
7.  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
8.  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
9.  Rate of Weight Gain and Cardiometabolic Abnormalities in Children and Adolescents 
The Journal of pediatrics  2012;161(6):1010-1015.e1.
Objective
To investigate whether the rate of weight gain is associated with cardiometabolic risk, independent of weight measured concurrently.
Study design
Healthy 7–17 year-old risperidone-treated patients (n=105, 88% male) had blood pressure, anthropometry, and laboratory tests performed. Growth history was extracted from medical records. The rate of change in age-sex-adjusted weight and body mass index (BMI) z-score after the initiation of risperidone was individually modeled. Multivariable linear regression analyses explored the association of the rate of weight (BMI) z score change with cardiometabolic outcomes, independent of last measured weight (BMI) z score.
Results
Following a mean of 1.9 years (sd=1.0) of risperidone treatment, the absolute increase in weight and BMI z-scores was 0.61 (sd=0.61) and 0.62 (sd=0.73), respectively. After controlling for the final weight z-score, the rate of change in weight z-score was significantly associated with final glucose (p<0.04), C-peptide (p<0.004), HOMA-IR (p<0.02), HDL cholesterol (p<0.0001), a metabolic syndrome score (p<0.005), adiponectin (p<0.04), and hsCRP (p<0.04). After controlling for the final BMI z-score, the rate of change in BMI z-score was associated with final HDL cholesterol (p<0.04), leptin (p<0.03), and adiponectin (p<0.04), with a suggestion of an association with final HOMA-IR (p<0.08).
Conclusions
The rate of weight gain in risperidone-treated children explains equally or more of the variance in certain cardiometabolic outcomes (e.g., HDL cholesterol: ΔR2= 11% vs. ΔR2= 8% and hsCRP: ΔR2= 9% vs. ΔR2= 5%) than the weight measured concurrently, and may serve as a treatment target.
doi:10.1016/j.jpeds.2012.05.051
PMCID: PMC3461238  PMID: 22738944
Antipsychotics; Risperidone; Weight Gain; Cardiometabolic Abnormalities; Children; Adolescents
10.  Chryptochrome 2 Variants, Chronicity, and Seasonality of Mood Disorders 
Psychiatric genetics  2012;22(6):305-306.
doi:10.1097/YPG.0b013e3283539594
PMCID: PMC3485578  PMID: 23111457
11.  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
12.  Randomized Controlled Trial of Atomoxetine for Cognitive Dysfunction in Early Huntington Disease 
Background
Cognitive symptoms are associated with functional disability in Huntington disease; yet, few controlled trials have examined cognitive treatments that could improve patient independence and quality of life. Atomoxetine is a norepinephrine reuptake inhibitor approved for treatment of attention-deficit/hyperactivity disorder.
Methods
Twenty participants with mild Huntington disease who complained of inattention were randomized to receive atomoxetine (80 mg/d) or placebo in a 10-week double-blind crossover study. Primary outcome measures were self-reported attention and attention and executive neuropsychological composite scores. Secondary outcomes were psychiatric and motor symptom scores.
Results
The rate of reported adverse effects while on atomoxetine was 56% (vs 35% on placebo), which most commonly included dry mouth (39%), loss of appetite (22%), insomnia (22%), and dizziness (17%). There were no serious adverse events related to atomoxetine. There were statistically significant, although mild, increases in heart rate and diastolic blood pressure on atomoxetine, consistent with other studies and not requiring medical referral. There were no significant improvements while on atomoxetine compared with placebo on primary outcomes. However, there was evidence of significant placebo effects on self-reported attention and psychiatric functions. There were no group differences on the Unified Huntington's Disease Rating total motor score.
Conclusions
Atomoxetine demonstrated no advantages over placebo for primary or secondary outcomes. Although atomoxetine was not effective at improving attention at this dose, its safety and tolerability were similar to other studies.
doi:10.1097/JCP.0b013e3181b2ac0a
PMCID: PMC3806326  PMID: 19745649
Huntington disease; randomized controlled trial; neuropsychological assessment; clinical trials
13.  Patterns of serotonergic antidepressant usage in prodromal Huntington disease☆ 
Psychiatry research  2012;196(0):309-314.
Antidepressant usage in prodromal Huntington Disease (HD) remains uncharacterized, despite its relevance in designing experiments, studying outcomes of HD, and evaluating the efficacy of therapeutic interventions. We searched baseline medication logs of 787 prodromal HD and 215 healthy comparison (HC) participants for antidepressant use. Descriptive and mixed-effects logistic regression modeling characterized usage across participants. At baseline, approximately one in five prodromal HD participants took antidepressants. Of those, the vast majority took serotonergic antidepressants (selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI)). Significantly more prodromal HD participants used serotonergic antidepressants than their HC counterparts. Because of the prevalence of these medications, further analyses focused on this group alone. Mixed-effects logistic regression modeling revealed significant relationships of both closer proximity to diagnosis and female sex with greater likelihood to be prescribed a serotonergic antidepressant. More prodromal HD participants took antidepressants in general and specifically the subclass of serotonergic antidepressants than their at-risk counterparts, particularly when they were closer to predicted time of conversion to manifest HD. These propensities must be considered in studies of prodromal HD participants.
doi:10.1016/j.psychres.2011.09.005
PMCID: PMC3763706  PMID: 22397915
Psychiatric; Antidepressant; Neuroprotection; Clinical trials; SSRI
14.  Evidence for accelerated vascular aging in bipolar disorder 
Journal of psychosomatic research  2012;73(3):175-179.
Objective
Persons with bipolar disorder face excess risk of cardiovascular disease, although the biobehavioral mechanisms and time course are unclear. We measured vascular stiffness in a cross-sectional sample of participants with bipolar disorder and compared results to published normative data to assess time-course and relationship to behavioral risk factors.
Methods
62 individuals with bipolar disorder (33±6.7 years; 64% female) underwent non-invasive assessment of arterial stiffness through arterial applanation tonometry. Lifetime tobacco exposure was estimated on clinical interview. Physical activity was assessed using the long-version of the International Physical Activity Questionnaire (IPAQ). A food frequency questionnaire was used to compute Alternate Healthy Eating Index (AHEI), a measure of overall dietary quality. Medication histories were systematically abstracted from pharmacy records.
Results
Participants over the age of 32 (median split) had greater arterial stiffness than expected from age-based population norms for pulse wave velocity (PWV) (7.6 vs. 7.0 m/s, p=0.02) and estimated aortic augmentation pressure (AIx) (14.2 vs. 8.2%, p=0.0002). The younger portion of the sample did not differ from population norms on these measures (PWV 6.3 vs. 6.4 m/s, p=0.45 and AIx 7.6 vs. 7.4%, p=0.60). In the older half of the sample, physical activity was inversely associated with AIx and poorer diet marginally associated with PWV. These findings were independent of body mass index (BMI), which was strongly related to arterial stiffness.
Conclusion
Risk for vascular disease may be acquired over the long-term course of affective illness. This risk appears to reflect maladaptive health behaviors, which may be amenable to intervention.
doi:10.1016/j.jpsychores.2012.06.004
PMCID: PMC3410319  PMID: 22850256
Bipolar disorder; cardiovascular disease; physical activity; diet; arterial stiffness; pulse wave analysis
15.  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
16.  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
17.  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
18.  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
19.  CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion 
Lee, J.-M. | Ramos, E.M. | Lee, J.-H. | Gillis, T. | Mysore, J.S. | Hayden, M.R. | Warby, S.C. | Morrison, P. | Nance, M. | Ross, C.A. | Margolis, R.L. | Squitieri, F. | Orobello, S. | Di Donato, S. | Gomez-Tortosa, E. | Ayuso, C. | Suchowersky, O. | Trent, R.J.A. | McCusker, E. | Novelletto, A. | Frontali, M. | Jones, R. | Ashizawa, T. | Frank, S. | Saint-Hilaire, M.H. | Hersch, S.M. | Rosas, H.D. | Lucente, D. | Harrison, M.B. | Zanko, A. | Abramson, R.K. | Marder, K. | Sequeiros, J. | Paulsen, J.S. | Landwehrmeyer, G.B. | Myers, R.H. | MacDonald, M.E. | Gusella, J.F. | Durr, Alexandra | Rosenblatt, Adam | Frati, Luigi | Perlman, Susan | Conneally, Patrick M. | Klimek, Mary Lou | Diggin, Melissa | Hadzi, Tiffany | Duckett, Ayana | Ahmed, Anwar | Allen, Paul | Ames, David | Anderson, Christine | Anderson, Karla | Anderson, Karen | Andrews, Thomasin | Ashburner, John | Axelson, Eric | Aylward, Elizabeth | Barker, Roger A. | Barth, Katrin | Barton, Stacey | Baynes, Kathleen | Bea, Alexandra | Beall, Erik | Beg, Mirza Faisal | Beglinger, Leigh J. | Biglan, Kevin | Bjork, Kristine | Blanchard, Steve | Bockholt, Jeremy | Bommu, Sudharshan Reddy | Brossman, Bradley | Burrows, Maggie | Calhoun, Vince | Carlozzi, Noelle | Chesire, Amy | Chiu, Edmond | Chua, Phyllis | Connell, R.J. | Connor, Carmela | Corey-Bloom, Jody | Craufurd, David | Cross, Stephen | Cysique, Lucette | Santos, Rachelle Dar | Davis, Jennifer | Decolongon, Joji | DiPietro, Anna | Doucette, Nicholas | Downing, Nancy | Dudler, Ann | Dunn, Steve | Ecker, Daniel | Epping, Eric A. | Erickson, Diane | Erwin, Cheryl | Evans, Ken | Factor, Stewart A. | Farias, Sarah | Fatas, Marta | Fiedorowicz, Jess | Fullam, Ruth | Furtado, Sarah | Garde, Monica Bascunana | Gehl, Carissa | Geschwind, Michael D. | Goh, Anita | Gooblar, Jon | Goodman, Anna | Griffith, Jane | Groves, Mark | Guttman, Mark | Hamilton, Joanne | Harrington, Deborah | Harris, Greg | Heaton, Robert K. | Helmer, Karl | Henneberry, Machelle | Hershey, Tamara | Herwig, Kelly | Howard, Elizabeth | Hunter, Christine | Jankovic, Joseph | Johnson, Hans | Johnson, Arik | Jones, Kathy | Juhl, Andrew | Kim, Eun Young | Kimble, Mycah | King, Pamela | Klimek, Mary Lou | Klöppel, Stefan | Koenig, Katherine | Komiti, Angela | Kumar, Rajeev | Langbehn, Douglas | Leavitt, Blair | Leserman, Anne | Lim, Kelvin | Lipe, Hillary | Lowe, Mark | Magnotta, Vincent A. | Mallonee, William M. | Mans, Nicole | Marietta, Jacquie | Marshall, Frederick | Martin, Wayne | Mason, Sarah | Matheson, Kirsty | Matson, Wayne | Mazzoni, Pietro | McDowell, William | Miedzybrodzka, Zosia | Miller, Michael | Mills, James | Miracle, Dawn | Montross, Kelsey | Moore, David | Mori, Sasumu | Moser, David J. | Moskowitz, Carol | Newman, Emily | Nopoulos, Peg | Novak, Marianne | O'Rourke, Justin | Oakes, David | Ondo, William | Orth, Michael | Panegyres, Peter | Pease, Karen | Perlman, Susan | Perlmutter, Joel | Peterson, Asa | Phillips, Michael | Pierson, Ron | Potkin, Steve | Preston, Joy | Quaid, Kimberly | Radtke, Dawn | Rae, Daniela | Rao, Stephen | Raymond, Lynn | Reading, Sarah | Ready, Rebecca | Reece, Christine | Reilmann, Ralf | Reynolds, Norm | Richardson, Kylie | Rickards, Hugh | Ro, Eunyoe | Robinson, Robert | Rodnitzky, Robert | Rogers, Ben | Rosenblatt, Adam | Rosser, Elisabeth | Rosser, Anne | Price, Kathy | Price, Kathy | Ryan, Pat | Salmon, David | Samii, Ali | Schumacher, Jamy | Schumacher, Jessica | Sendon, Jose Luis Lópenz | Shear, Paula | Sheinberg, Alanna | Shpritz, Barnett | Siedlecki, Karen | Simpson, Sheila A. | Singer, Adam | Smith, Jim | Smith, Megan | Smith, Glenn | Snyder, Pete | Song, Allen | Sran, Satwinder | Stephan, Klaas | Stober, Janice | Sü?muth, Sigurd | Suter, Greg | Tabrizi, Sarah | Tempkin, Terry | Testa, Claudia | Thompson, Sean | Thomsen, Teri | Thumma, Kelli | Toga, Arthur | Trautmann, Sonja | Tremont, Geoff | Turner, Jessica | Uc, Ergun | Vaccarino, Anthony | van Duijn, Eric | Van Walsem, Marleen | Vik, Stacie | Vonsattel, Jean Paul | Vuletich, Elizabeth | Warner, Tom | Wasserman, Paula | Wassink, Thomas | Waterman, Elijah | Weaver, Kurt | Weir, David | Welsh, Claire | Werling-Witkoske, Chris | Wesson, Melissa | Westervelt, Holly | Weydt, Patrick | Wheelock, Vicki | Williams, Kent | Williams, Janet | Wodarski, Mary | Wojcieszek, Joanne | Wood, Jessica | Wood-Siverio, Cathy | Wu, Shuhua | Yastrubetskaya, Olga | de Yebenes, Justo Garcia | Zhao, Yong Qiang | Zimbelman, Janice | Zschiegner, Roland | Aaserud, Olaf | Abbruzzese, Giovanni | Andrews, Thomasin | Andrich, Jurgin | Antczak, Jakub | Arran, Natalie | Artiga, Maria J. Saiz | Bachoud-Lévi, Anne-Catherine | Banaszkiewicz, Krysztof | di Poggio, Monica Bandettini | Bandmann, Oliver | Barbera, Miguel A. | Barker, Roger A. | Barrero, Francisco | Barth, Katrin | Bas, Jordi | Beister, Antoine | Bentivoglio, Anna Rita | Bertini, Elisabetta | Biunno, Ida | Bjørgo, Kathrine | Bjørnevoll, Inga | Bohlen, Stefan | Bonelli, Raphael M. | Bos, Reineke | Bourne, Colin | Bradbury, Alyson | Brockie, Peter | Brown, Felicity | Bruno, Stefania | Bryl, Anna | Buck, Andrea | Burg, Sabrina | Burgunder, Jean-Marc | Burns, Peter | Burrows, Liz | Busquets, Nuria | Busse, Monica | Calopa, Matilde | Carruesco, Gemma T. | Casado, Ana Gonzalez | Catena, Judit López | Chu, Carol | Ciesielska, Anna | Clapton, Jackie | Clayton, Carole | Clenaghan, Catherine | Coelho, Miguel | Connemann, Julia | Craufurd, David | Crooks, Jenny | Cubillo, Patricia Trigo | Cubo, Esther | Curtis, Adrienne | De Michele, Giuseppe | De Nicola, A. | de Souza, Jenny | de Weert, A. Marit | de Yébenes, Justo Garcia | Dekker, M. | Descals, A. Martínez | Di Maio, Luigi | Di Pietro, Anna | Dipple, Heather | Dose, Matthias | Dumas, Eve M. | Dunnett, Stephen | Ecker, Daniel | Elifani, F. | Ellison-Rose, Lynda | Elorza, Marina D. | Eschenbach, Carolin | Evans, Carole | Fairtlough, Helen | Fannemel, Madelein | Fasano, Alfonso | Fenollar, Maria | Ferrandes, Giovanna | Ferreira, Jaoquim J. | Fillingham, Kay | Finisterra, Ana Maria | Fisher, K. | Fletcher, Amy | Foster, Jillian | Foustanos, Isabella | Frech, Fernando A. | Fullam, Robert | Fullham, Ruth | Gago, Miguel | García, RocioGarcía-Ramos | García, Socorro S. | Garrett, Carolina | Gellera, Cinzia | Gill, Paul | Ginestroni, Andrea | Golding, Charlotte | Goodman, Anna | Gørvell, Per | Grant, Janet | Griguoli, A. | Gross, Diana | Guedes, Leonor | BascuñanaGuerra, Monica | Guerra, Maria Rosalia | Guerrero, Rosa | Guia, Dolores B. | Guidubaldi, Arianna | Hallam, Caroline | Hamer, Stephanie | Hammer, Kathrin | Handley, Olivia J. | Harding, Alison | Hasholt, Lis | Hedge, Reikha | Heiberg, Arvid | Heinicke, Walburgis | Held, Christine | Hernanz, Laura Casas | Herranhof, Briggitte | Herrera, Carmen Durán | Hidding, Ute | Hiivola, Heli | Hill, Susan | Hjermind, Lena. E. | Hobson, Emma | Hoffmann, Rainer | Holl, Anna Hödl | Howard, Liz | Hunt, Sarah | Huson, Susan | Ialongo, Tamara | Idiago, Jesus Miguel R. | Illmann, Torsten | Jachinska, Katarzyna | Jacopini, Gioia | Jakobsen, Oda | Jamieson, Stuart | Jamrozik, Zygmunt | Janik, Piotr | Johns, Nicola | Jones, Lesley | Jones, Una | Jurgens, Caroline K. | Kaelin, Alain | Kalbarczyk, Anna | Kershaw, Ann | Khalil, Hanan | Kieni, Janina | Klimberg, Aneta | Koivisto, Susana P. | Koppers, Kerstin | Kosinski, Christoph Michael | Krawczyk, Malgorzata | Kremer, Berry | Krysa, Wioletta | Kwiecinski, Hubert | Lahiri, Nayana | Lambeck, Johann | Lange, Herwig | Laver, Fiona | Leenders, K.L. | Levey, Jamie | Leythaeuser, Gabriele | Lezius, Franziska | Llesoy, Joan Roig | Löhle, Matthias | López, Cristobal Diez-Aja | Lorenza, Fortuna | Loria, Giovanna | Magnet, Markus | Mandich, Paola | Marchese, Roberta | Marcinkowski, Jerzy | Mariotti, Caterina | Mariscal, Natividad | Markova, Ivana | Marquard, Ralf | Martikainen, Kirsti | Martínez, Isabel Haro | Martínez-Descals, Asuncion | Martino, T. | Mason, Sarah | McKenzie, Sue | Mechi, Claudia | Mendes, Tiago | Mestre, Tiago | Middleton, Julia | Milkereit, Eva | Miller, Joanne | Miller, Julie | Minster, Sara | Möller, Jens Carsten | Monza, Daniela | Morales, Blas | Moreau, Laura V. | Moreno, Jose L. López-Sendón | Münchau, Alexander | Murch, Ann | Nielsen, Jørgen E. | Niess, Anke | Nørremølle, Anne | Novak, Marianne | O'Donovan, Kristy | Orth, Michael | Otti, Daniela | Owen, Michael | Padieu, Helene | Paganini, Marco | Painold, Annamaria | Päivärinta, Markku | Partington-Jones, Lucy | Paterski, Laurent | Paterson, Nicole | Patino, Dawn | Patton, Michael | Peinemann, Alexander | Peppa, Nadia | Perea, Maria Fuensanta Noguera | Peterson, Maria | Piacentini, Silvia | Piano, Carla | Càrdenas, Regina Pons i | Prehn, Christian | Price, Kathleen | Probst, Daniela | Quarrell, Oliver | Quiroga, Purificacion Pin | Raab, Tina | Rakowicz, Maryla | Raman, Ashok | Raymond, Lucy | Reilmann, Ralf | Reinante, Gema | Reisinger, Karin | Retterstol, Lars | Ribaï, Pascale | Riballo, Antonio V. | Ribas, Guillermo G. | Richter, Sven | Rickards, Hugh | Rinaldi, Carlo | Rissling, Ida | Ritchie, Stuart | Rivera, Susana Vázquez | Robert, Misericordia Floriach | Roca, Elvira | Romano, Silvia | Romoli, Anna Maria | Roos, Raymond A.C. | Røren, Niini | Rose, Sarah | Rosser, Elisabeth | Rosser, Anne | Rossi, Fabiana | Rothery, Jean | Rudzinska, Monika | Ruíz, Pedro J. García | Ruíz, Belan Garzon | Russo, Cinzia Valeria | Ryglewicz, Danuta | Saft, Carston | Salvatore, Elena | Sánchez, Vicenta | Sando, Sigrid Botne | Šašinková, Pavla | Sass, Christian | Scheibl, Monika | Schiefer, Johannes | Schlangen, Christiane | Schmidt, Simone | Schöggl, Helmut | Schrenk, Caroline | Schüpbach, Michael | Schuierer, Michele | Sebastián, Ana Rojo | Selimbegovic-Turkovic, Amina | Sempolowicz, Justyna | Silva, Mark | Sitek, Emilia | Slawek, Jaroslaw | Snowden, Julie | Soleti, Francesco | Soliveri, Paola | Sollom, Andrea | Soltan, Witold | Sorbi, Sandro | Sorensen, Sven Asger | Spadaro, Maria | Städtler, Michael | Stamm, Christiane | Steiner, Tanja | Stokholm, Jette | Stokke, Bodil | Stopford, Cheryl | Storch, Alexander | Straßburger, Katrin | Stubbe, Lars | Sulek, Anna | Szczudlik, Andrzej | Tabrizi, Sarah | Taylor, Rachel | Terol, Santiago Duran-Sindreu | Thomas, Gareth | Thompson, Jennifer | Thomson, Aileen | Tidswell, Katherine | Torres, Maria M. Antequera | Toscano, Jean | Townhill, Jenny | Trautmann, Sonja | Tucci, Tecla | Tuuha, Katri | Uhrova, Tereza | Valadas, Anabela | van Hout, Monique S.E. | van Oostrom, J.C.H. | van Vugt, Jeroen P.P. | vanm, Walsem Marleen R. | Vandenberghe, Wim | Verellen-Dumoulin, Christine | Vergara, Mar Ruiz | Verstappen, C.C.P. | Verstraelen, Nichola | Viladrich, Celia Mareca | Villanueva, Clara | Wahlström, Jan | Warner, Thomas | Wehus, Raghild | Weindl, Adolf | Werner, Cornelius J. | Westmoreland, Leann | Weydt, Patrick | Wiedemann, Alexandra | Wild, Edward | Wild, Sue | Witjes-Ané, Marie-Noelle | Witkowski, Grzegorz | Wójcik, Magdalena | Wolz, Martin | Wolz, Annett | Wright, Jan | Yardumian, Pam | Yates, Shona | Yudina, Elizaveta | Zaremba, Jacek | Zaugg, Sabine W. | Zdzienicka, Elzbieta | Zielonka, Daniel | Zielonka, Euginiusz | Zinzi, Paola | Zittel, Simone | Zucker, Birgrit | Adams, John | Agarwal, Pinky | Antonijevic, Irina | Beck, Christopher | Chiu, Edmond | Churchyard, Andrew | Colcher, Amy | Corey-Bloom, Jody | Dorsey, Ray | Drazinic, Carolyn | Dubinsky, Richard | Duff, Kevin | Factor, Stewart | Foroud, Tatiana | Furtado, Sarah | Giuliano, Joe | Greenamyre, Timothy | Higgins, Don | Jankovic, Joseph | Jennings, Dana | Kang, Un Jung | Kostyk, Sandra | Kumar, Rajeev | Leavitt, Blair | LeDoux, Mark | Mallonee, William | Marshall, Frederick | Mohlo, Eric | Morgan, John | Oakes, David | Panegyres, Peter | Panisset, Michel | Perlman, Susan | Perlmutter, Joel | Quaid, Kimberly | Raymond, Lynn | Revilla, Fredy | Robertson, Suzanne | Robottom, Bradley | Sanchez-Ramos, Juan | Scott, Burton | Shannon, Kathleen | Shoulson, Ira | Singer, Carlos | Tabbal, Samer | Testa, Claudia | van, Kammen Dan | Vetter, Louise | Walker, Francis | Warner, John | Weiner, illiam | Wheelock, Vicki | Yastrubetskaya, Olga | Barton, Stacey | Broyles, Janice | Clouse, Ronda | Coleman, Allison | Davis, Robert | Decolongon, Joji | DeLaRosa, Jeanene | Deuel, Lisa | Dietrich, Susan | Dubinsky, Hilary | Eaton, Ken | Erickson, Diane | Fitzpatrick, Mary Jane | Frucht, Steven | Gartner, Maureen | Goldstein, Jody | Griffith, Jane | Hickey, Charlyne | Hunt, Victoria | Jaglin, Jeana | Klimek, Mary Lou | Lindsay, Pat | Louis, Elan | Loy, Clemet | Lucarelli, Nancy | Malarick, Keith | Martin, Amanda | McInnis, Robert | Moskowitz, Carol | Muratori, Lisa | Nucifora, Frederick | O'Neill, Christine | Palao, Alicia | Peavy, Guerry | Quesada, Monica | Schmidt, Amy | Segro, Vicki | Sperin, Elaine | Suter, Greg | Tanev, Kalo | Tempkin, Teresa | Thiede, Curtis | Wasserman, Paula | Welsh, Claire | Wesson, Melissa | Zauber, Elizabeth
Neurology  2012;78(10):690-695.
Objective:
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
Methods:
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
Results:
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Conclusions:
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
doi:10.1212/WNL.0b013e318249f683
PMCID: PMC3306163  PMID: 22323755
20.  Vascular function is not impaired early in the course of bipolar disorder 
Journal of Psychosomatic Research  2012;72(3):195-198.
Objective
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1016/j.jpsychores.2011.12.006
PMCID: PMC3278715  PMID: 22325698
Bipolar disorder; cardiovascular disease; cardiovascular mortality; endothelial dysfunction; insulin resistance; pulse wave analysis
21.  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
22.  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
23.  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
24.  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
25.  Suicidal Behavior in Prodromal Huntington Disease 
Neuro-Degenerative Diseases  2011;8(6):483-490.
Background
Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established.
Objective
We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD.
Methods
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.
Results
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.
Conclusion
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
doi:10.1159/000327754
PMCID: PMC3186721  PMID: 21659725
Attempted suicide; Cohort study; Huntington disease; Major depressive disorder; Risk factors; Suicide

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