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1.  Seasonal variation of manic and depressive symptoms in bipolar disorder 
Bipolar disorders  2013;15(4):377-384.
Analyses of seasonal variation of manic and depressive symptoms in bipolar disorder in retrospective studies examining admission data have yielded conflicting results. We examined seasonal variation of mood symptoms in a prospective cohort with long-term follow-up: The Collaborative Depression Study (CDS).
The CDS included participants from five academic centers with a prospective diagnosis of bipolar I or II disorder. The sample was limited to those who were followed for at least 10 years of annual or semi-annual assessments. Time series analyses and autoregressive integrated moving average (ARIMA) models were used assess seasonal patterns of manic and depressive symptoms.
A total of 314 individuals were analyzed [bipolar I disorder: (n = 202) and bipolar II disorder: (n = 112)] with both disorders exhibiting the lowest depressive symptoms in summer and highest around the winter solstice, though the winter peak in symptoms was statistically significant only with bipolar I disorder. Variation of manic symptoms was more pronounced in bipolar II disorder, with a significant peak in hypomanic symptomatology in the months surrounding the fall equinox.
Significant seasonal variation exists in bipolar disorder with manic/hypomanic symptoms peaking around the fall equinox and depressive symptoms peaking in months surrounding the winter solstice in bipolar I disorder.
PMCID: PMC3731411  PMID: 23621686
bipolar I disorder; bipolar II disorder; depression; hypomania; mania; seasonal variation
2.  Age of Onset and the Prospectively Observed Course of Illness in Bipolar Disorder 
Journal of affective disorders  2012;146(1):34-38.
To test the validity of age-of-onset grouping in bipolar disorder through the use of prospectively observed time in mood episodes.
Age-of-onset ranges from prior admixture analyses were used to divide 427 individuals with bipolar I or bipolar II disorder into early-, middle- and late- onset groups. These were compared by the proportions of weeks depressed and manic or hypomanic during a mean (SD) prospective follow-up of 17.4 (8.4) years.
As predicted, the group with the earliest onsets reported at intake more previous episodes, more suicide attempts and panic attacks. An early age of onset, but not current age, was predictive of significantly more time in depressive episodes during follow-up but was not predictive of time in manic or hypomanic episodes.
This was a naturalistic study with no control of treatment so variability in treatment may have obscured relationships between predictors and outcomes. Age of onset was retrospectively determined and subject to inaccuracies in recall.
An early age of onset conveys, to a modest degree, a poorer prognosis as expressed in more depressive morbidity.
PMCID: PMC3605729  PMID: 23062746
bipolar disorder; age-of-onset; follow-up; prognosis
3.  Cholesterol fractions, symptom burden, and suicide attempts in mood disorders 
Psychiatry research  2012;200(0):10.1016/j.psychres.2012.06.039.
PMCID: PMC3871860  PMID: 22789841
4.  Rate of Weight Gain and Cardiometabolic Abnormalities in Children and Adolescents 
The Journal of pediatrics  2012;161(6):1010-1015.e1.
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.
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).
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.
PMCID: PMC3461238  PMID: 22738944
Antipsychotics; Risperidone; Weight Gain; Cardiometabolic Abnormalities; Children; Adolescents
6.  Recovery from Multiple Episodes of Bipolar I Depression 
The Journal of clinical psychiatry  2013;74(3):10.4088/JCP.12m08049.
To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery.
219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited from 1978–1981 and followed for up to 25 years. Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. The probability of recovery over time from multiple successive depressive episodes was examined with survival analytic techniques, including mixed-effects grouped-time survival models.
The median duration of major depressive episodes was 14 weeks, and over 70% recovered within 12 months of onset of the episode. The median duration of minor depressive episodes was 8 weeks, and approximately 90% recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first three major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient=0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio: 0.93, 95% CI: 0.89–0.98, p=0.002).
Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.
PMCID: PMC3837577  PMID: 23561241
7.  Randomized Controlled Trial of Atomoxetine for Cognitive Dysfunction in Early Huntington Disease 
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.
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.
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.
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.
PMCID: PMC3806326  PMID: 19745649
Huntington disease; randomized controlled trial; neuropsychological assessment; clinical trials
8.  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.
PMCID: PMC3763706  PMID: 22397915
Psychiatric; Antidepressant; Neuroprotection; Clinical trials; SSRI
9.  Evidence for accelerated vascular aging in bipolar disorder 
Journal of psychosomatic research  2012;73(3):175-179.
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.
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.
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.
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.
PMCID: PMC3410319  PMID: 22850256
Bipolar disorder; cardiovascular disease; physical activity; diet; arterial stiffness; pulse wave analysis
10.  Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression 
Bipolar disorders  2012;14(6):664-671.
In a well-defined sample, we sought to determine what clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M).
We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder.
Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n = 21) was strongly associated with repeat episodes of H/M [hazard ratio (HR) = 2.01, 95% confidence interval (CI): 1.06–3.83, p = 0.03]. Those with treatment-associated episodes (n = 12) were less likely to experience subsequent episodes of H/M, though this was not significant in the multivariate model (HR = 0.25, 95% CI: 0.06–1.05, p = 0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode.
Family history of bipolar disorder influences course of illness even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes.
PMCID: PMC3432672  PMID: 22816725
bipolar disorder; depressive disorder; antidepressants; prospective studies
11.  Longitudinal Course of Bipolar I Disorder 
Archives of general psychiatry  2010;67(4):339-347.
The phenomenology of bipolar I disorder affects treatment and prognosis.
To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes.
Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model.
Five US academic medical centers.
Two hundred nineteen subjects with bipolar I disorder.
Main Outcome Measures
Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter.
The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR]=0.746; 95% confidence interval [CI], 0.578–0.963; P=.02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR=0.917; 95% CI, 0.886–0.948; P<.001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR=1.713; 95% CI, 1.373–2.137; P<.001), hypomania (HR=4.502; 95% CI, 3.466–5.849; P<.001), or minor depression (HR = 2.027; 95% CI, 1.622–2.534; P<.001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR=0.438; 95% CI, 0.351–0.548; P<.001).
The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.
PMCID: PMC3677763  PMID: 20368510
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.
There is increasing evidence that subsyndromal manic symptoms occur frequently during bipolar major depressive episodes (MDEs) and may be a subtle form of ‘depressive mixed state.’ This paper examines the prevalence and clinical characteristics of MDEs with subsyndromal manic symptoms. The specific effects of overt irritability and psychomotor agitation are examined.
Bipolar (type I or II) patients with an MDE at intake (N=142) were compared based on the presence or absence of concurrent subsyndromal manic symptoms. The groups were further subdivided by the presence of symptoms of overt irritability and/or psychomotor agitation.
Subsyndromal manic symptoms during bipolar MDEs were highly prevalent (76.1%), and were associated with significantly increased severity of depression/dysphoria in the intake episode, longer episode duration, and more suicidal ideation and behavior (past, current, and during long-term follow-up). Overt irritability and psychomotor agitation were the most prevalent subsyndromal manic symptoms (co-occurring in 57% and 39% of MDEs, respectively), and accounted for most of the negative effects associated with subsyndromal manic symptoms.
The findings need to be confirmed in larger samples, which also examine the relationship to adequate antidepressant and/or mood stabilizing treatment.
The presence of one or more subsyndromal manic symptoms appears to be the modal presentation of bipolar MDEs and a marker for a subtle form of bipolar mixed depressive state. In particular, patients with symptoms of overt irritability and/or psychomotor agitation should be monitored closely to avoid serious clinical outcomes such as longer affective episodes, exacerbation of manic symptoms syndromal mania, and heightened suicidality.
PMCID: PMC3677770  PMID: 22314261
Bipolar; Major depressive episodes; Subsyndromal manic symptoms; Irritability; Psychomotor agitation
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.
Mood disorders substantially increase risk of cardiovascular disease, though the mechanisms are unclear. We assessed for a dose-dependent relationship between course of illness or treatment with vasculopathy in a well-characterized cohort.
Participants with mood disorders were recruited for the National Institute of Mental Health Collaborative Depression Study (CDS) and followed prospectively. A cross-sectional metabolic and vascular function evaluation was performed on a sub-sample near completion after a mean follow-up of 27 years.
A total of 35 participants from the University of Iowa (33) and Washington University (2) sites of the CDS consented to a metabolic and vascular function assessment at the Iowa site. In multivariate linear regression, controlling for age, gender, and smoking, manic/hypomanic, but not depressive, symptom burden was associated with lower flow-mediated dilation (FMD). Cumulative exposure to antipsychotics and mood stabilizers was associated with elevated augmentation pressure and mean aortic systolic blood pressure. This appeared specifically related to first generation antipsychotic exposure and mediated by increases in brachial systolic pressure. Although second generation antipsychotics were associated with dyslipidemia and insulin resistance, they were not associated with vasculopathy.
These results provide evidence that chronicity of mood symptoms contribute to vasculopathy in a dose-dependent fashion. Patients with more manic/hypomanic symptoms had poorer endothelial function. First generation antipsychotic exposure was associated with arterial stiffness, evidenced by higher augmentation pressure, perhaps secondary to elevated blood pressure. Vascular phenotyping methods may provide a promising means of elucidating the mechanisms linking mood disorders to vascular disease.
PMCID: PMC3567920  PMID: 22584147
adult; antipsychotics; major depression; bipolar disorder; cardiovascular mortality; mania
14.  Vascular function is not impaired early in the course of bipolar disorder 
Journal of Psychosomatic Research  2012;72(3):195-198.
Individuals with bipolar disorder face a nearly two-fold increased risk of cardiovascular mortality relative to the general population. Endothelial dysfunction precedes cardiovascular disease and serves as a quantifiable phenotype for vasculopathy. We investigated whether individuals with bipolar disorder had poorer vascular function than controls using a case-control design.
The sample of 54 participants included 27 individuals with bipolar disorder and 27 age- and gender-matched controls. Participants underwent an assessment of metabolic (weight, lipids, and insulin resistance) and vascular parameters (endothelial function using flow-mediated dilation; arterial stiffness using pulse wave velocity and estimated aortic pressure).
Participants had a mean age of 32 years and 41% were female. No significant differences were found between groups in endothelial function or arterial stiffness. Individuals with bipolar disorder demonstrated 100% greater insulin resistance.
The lack of clinically significant differences in vascular function in this young sample suggests any increased risk either occurs later in the course of illness or is largely due to behavioral risk factors, such as smoking, which was balanced between groups. Substantial insulin resistance is identifiable early in course of illness, perhaps secondary to treatment.
PMCID: PMC3278715  PMID: 22325698
Bipolar disorder; cardiovascular disease; cardiovascular mortality; endothelial dysfunction; insulin resistance; pulse wave analysis
15.  Effects of anxiety on the long-term course of depressive disorders† 
The British Journal of Psychiatry  2012;200(3):210-215.
It is well established that the presence of prominent anxiety within depressive episodes portends poorer outcomes. Important questions remain as to which anxiety features are important to outcome and how sustained their prognostic effects are over time.
To examine the relative prognostic importance of specific anxiety features and to determine whether their effects persist over decades and apply to both unipolar and bipolar conditions.
Participants with unipolar (n = 476) or bipolar (n = 335) depressive disorders were intensively followed for a mean of 16.7 years (s.d. = 8.5).
The number and severity of anxiety symptoms, but not the presence of pre-existing anxiety disorders, showed a robust and continuous relationship to the subsequent time spent in depressive episodes in both unipolar and bipolar depressive disorder. The strength of this relationship changed little over five successive 5-year periods.
The severity of current anxiety symptoms within depressive episodes correlates strongly with the persistence of subsequent depressive symptoms and this relationship is stable over decades.
PMCID: PMC3290796  PMID: 21984801
16.  Anxiety and Outcome in Bipolar Disorder 
The American journal of psychiatry  2009;166(11):1238-1243.
PMCID: PMC3551283  PMID: 19797434
anxiety; bipolar disorder; symptom persistence
17.  Age Transitions in the Course of Bipolar I Disorder 
Psychological medicine  2009;39(8):1247-1252.
This analysis aimed to show whether symptoms of either pole change in their persistence as individuals move through two decades, whether such changes differ by age-grouping, and whether age of onset plays an independent role in symptom persistence.
Participants in the NIMH Collaborative Depression Study who completed at least twenty years of follow-up and who met study criteria for bipolar I or schizoaffective manic disorder, before intake or during follow-up, were divided by age at intake into youngest (18–29 years, n = 56), middle (30–44 years, n = 68) and oldest (greater than 44 years, n = 24) groups.
The persistence of depressive symptoms increased significantly in the two younger groups. Earlier ages of onset were associated with higher depressive morbidity throughout the twenty years of follow-up but did not predict changes in symptom persistence. The proportions of weeks spent in episodes of either pole correlated across follow-up periods in all age groupings, though correlations were stronger for depressive symptoms and for shorter intervals.
Regardless of age at onset, the passage of decades in bipolar illness appears to bring an increase in the predominance of depressive symptoms in individuals in their third, fourth and fifth decades and an earlier age of onset portends a persistently greater depressive symptom burden. The degree to which either depression or manic/hypomanic symptoms persist has significant stability over lengthy periods and appears to reflect traits that manifest early an individual’s illness.
PMCID: PMC3551474  PMID: 19335937
major depression; age periods; age of onset; symptom persistence
18.  Does Major Depressive Disorder Change with Age? 
Psychological medicine  2009;39(10):1689-1695.
The authors used results from a twenty-year, high-intensity follow-up to measure the influence of aging, and of age at onset, on the long-term persistence of symptoms in major depressive disorder (MDD).
Subjects who completed a 20-year series of semi-annual and then annual assessments with a stable diagnosis of MDD, or schizoaffective disorder other than mainly schizophrenic, (n = 220), were divided according to their ages at intake into youngest (18–29 years), middle (30–44 years), and oldest (≥45 years) groups. Depressive morbidity was quantified as the proportion of weeks spent in major depressive or schizoaffective episodes. General linear models (GLM) then tested for effects of time and time-by-group interactions on these measures. Regression analyses compared the influence of age of onset and of current age.
Analyses revealed no significant time or group-by-time effects on the proportions of weeks in major depressive episodes in any of three age groups. Earlier ages of onset were associated with greater symptom persistence, particularly in the youngest group. The proportions of weeks ill showed intra-individual stability over time that was most evident in the oldest group.
These results indicate that the persistence of depressive symptoms in MDD does not change as individuals move from their third to their fifth decade, from their fourth to their sixth decade, or from their sixth to their eighth decade. An early age of onset, rather than youth per se, is associated with greater morbidity over two decades.
PMCID: PMC3533492  PMID: 19296865
major depression; age periods; age of onset; symptom persistence
19.  Suicidal Behavior in Prodromal Huntington Disease 
Neuro-Degenerative Diseases  2011;8(6):483-490.
Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established.
We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD.
From the prospective PREDICT-HD cohort, we identified 735 cases with HD gene expansion but no manifest symptoms of HD and 194 non-gene-expanded controls. In survival analysis, a number of potential risk factors for suicidal behavior were assessed, including symptoms of depression, hopelessness, substance abuse, marital status, gender, and psychiatric history.
During a mean of 3.7 years of prospective follow-up, 12 cases (1.6%) attempted suicide and 1 completed suicide (0.1%). No suicides were observed among controls. In univariate Cox proportional hazards regression models, a history of suicide attempts (HR 8.5, 95% CI 2.8–26.1, p < 0.0002) and a Beck Depression Inventory II score >13 (HR 7.2, 95% CI 2.3–22.0, p < 0.0006) were associated with suicidal behavior. These risk factors had independent effects in multivariate models. A history of incarceration in the past 2 years was also associated (HR 12.5, 95% CI 2.7–56.6, p < 0.002), though uncommon. No further risk factors were identified.
A history of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in prodromal HD. As these risk factors are among the most robust risk factors for suicide, established suicide risk factors appear applicable to those with prodromal HD.
Copyright © 2011 S. Karger AG, Basel
PMCID: PMC3186721  PMID: 21659725
Attempted suicide; Cohort study; Huntington disease; Major depressive disorder; Risk factors; Suicide
20.  Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers 
Current psychiatry reviews  2012;8(1):25-36.
Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer –induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97–4.89, p=0.003), H2 antagonists (1.78 kg (95% C.I. −0.50–4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77–6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. −0.06–2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.
PMCID: PMC3375952  PMID: 22712004
Antipsychotic agents; Schizophrenia; Bipolar Disorder; Dyslipidemias; Major Depression; Meta-analysis; Obesity; Psychotic Disorders; Vascular Diseases; Weight Loss
21.  The association between mood and anxiety disorders with vascular diseases and risk factors in a nationally-representative sample 
Journal of psychosomatic research  2010;70(2):145-154.
To investigate the association between mood and anxiety disorders and vascular diseases after controlling for vascular disease risk factors.
Using a nationally representative sample of adults (N=5,692) from the National Comorbidity Survey Replication (NCS-R), participants with mood disorders were hierarchically classified as having any lifetime history of mania, hypomania, or major depression. Anxiety disorders were also assessed. The reference group consisted of those without mental disorders. Vascular disease was determined by self-reported history of heart disease, heart attack, or stroke on the NCS-R survey. Vascular risk factors included diabetes, high blood pressure, and obesity.
In multivariate logistic regression models that controlled for obesity, high blood pressure, smoking and diabetes, vascular disease was associated with bipolar disorder in women (OR 2.80, 95% C.I. 1.63–4.80), and major depressive disorder in men (OR 1.85, 95% C.I. 1.17–2.92). Controlling for anxiety disorders reduced the associations in both men and women, and in fact, anxiety disorders were more strongly associated with vascular diseases in men, whereas bipolar disorder continued to be an important correlate of vascular disease in women.
These findings demonstrate the importance of evaluation of sex differences, mood disorder subtype and co-occuring anxiety disorders in assessing the association between mood disorders and vascular diseases. Future research should investigate potential biologic mechanisms for these associations in order to define potential targets for intervention.
PMCID: PMC3052932  PMID: 21262417
anxiety disorders; diabetes mellitus; hypertension; obesity; mood disorders; vascular diseases
22.  Clinical Variables Impacting Prescribing of Olanzapine, Quetiapine, and Risperidone 
Pharmacotherapy  2011;31(8):806-812.
To identify determinants of new use of the first-line SGAs associated with weight gain.
Retrospective chart review.
Outpatient and inpatient psychiatry services at a tertiary, academic medical center.
Sample of 340 consecutive patients over two time periods with major depression with psychotic features, bipolar I, bipolar II, bipolar not otherwise specified, and schizoaffective disorder.
Measurements and Main Results
Clinical and sociodemographic variables associated with new use of olanzapine, risperidone, and quetiapine were identified using univariate and multivariate logistic regression. Several clinical factors were individually associated with initiation of these SGAs: mania (OR 3.6, 95% CI 1.2–10.8), psychosis (OR 3.3, 95% CI 1.5–6.9), and inpatient treatment (OR 3.8, 95% CI 1.8–7.9). Prevalent use of lithium (OR 0.3, 95% CI 0.1–0.9) and being married (OR 0.3, 95% CI 0.1–0.8) were inversely associated. Mania, psychosis, married status, and lithium use remained independently associated on multivariate analysis. Factors related to metabolic or vascular risk were not associated with SGA initiation.
Psychiatric clinicians weigh clinical features related to mental status and acuity heavily in determining whether to initiate SGAs. However, factors related to vascular risk were not associated. Future observational studies should consider current clinical status as an important factor in determining propensity to receive antipsychotics or other acute treatments for bipolar disorder.
PMCID: PMC3192400  PMID: 21923607
Antipsychotic agents; Bipolar disorder; Inpatients; Logistic models; Major Depressive Disorder; Outpatients; Propensity Score; Psychotic Disorders
23.  Cardiovascular Morbidity and Mortality in Bipolar Disorder 
There has been considerable interest in the elevated risk of cardiovascular disease associated with serious mental illness. While the contemporary literature has paid much attention to major depression and schizophrenia, there has been more limited focus on the risk of cardiovascular mortality for those suffering from bipolar disorder, despite some interest in the historical literature.
We reviewed the historical and contemporary literature related to cardiovascular morbidity and mortality in bipolar disorder.
In studies that specifically assess cardiovascular mortality, bipolar disorder has been associated with a near doubling of risk when compared to general population estimates. This may be explained by the elevated burden of cardiovascular risk factors found in this population. These findings pre-date modern treatments, which may further influence cardiovascular risk.
Given the substantial risk of cardiovascular disease, rigorous assessment of cardiovascular risk is warranted for patients with bipolar disorder. Modifiable risk factors should be treated when identified. Further work is warranted to study mechanisms by which this elevated risk for cardiovascular disease are mediated and to identify systems for effective delivery of integrated medical and psychiatric care for individuals with bipolar disorder.
PMCID: PMC3190964  PMID: 21318195
Bipolar disorder; Cardiovascular disease; Mortality; Metabolic Syndrome; Obesity; Hypertension
24.  Subthreshold Hypomanic Symptoms in Progression From Unipolar Major Depression to Bipolar Disorder 
We determined if subthreshold hypomanic symptoms predicted new onset mania or hypomania.
We identified 550 individuals followed for at least one year in the National Institute of Mental Health Collaborative Depression Study with a diagnosis of major depression at intake. All participants were screened at baseline for a total of five manic symptoms: elevated mood, decreased need for sleep, high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 and up to 31 years. Longitudinal Interval Follow-up Examinations monitored course of illness and identified any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox Proportional-Hazards Regression.
With a cumulative probability of one-in-four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II and 7.5% to bipolar I disorder. The number of subthreshold hypomanic symptoms, psychosis, and age of onset predicted progression to bipolar disorder. Less need for sleep, unusual energy, and increased goal-directed activities were specifically implicated.
Symptoms of hypomania, even when of low intensity, were very frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. Therefore, continued monitoring for the possibility of progression to bipolar disorder over the long-term course of major depressive disorder is necessary.
PMCID: PMC3042431  PMID: 21078709
Age of Onset; Bipolar disorder; Depressive disorder; Delusions; Prospective studies
25.  Edema associated with quetiapine 
Edema associated with quetiapine has been described in only one case report to date and represents a potentially serious adverse reaction.
We present a case series of three patients who developed bilateral leg edema following initiation of quetiapine.
One of these patients had a recurrence of edema with subsequent rechallenge. Another patient developed quetiapine-induced edema following a prior episode of olanzapine-induced edema. All the cases present a compelling temporal relationship between the drug challenge and the adverse event.
Prompt recognition and intervention with discontinuation of the offending agent is important for this potentially serious, seemingly idiosyncratic, vascular complication.
PMCID: PMC3043556  PMID: 19439156
Antipsychotics; Cardiovascular; Edema; Quetiapine

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