Jess G. Fiedorowicz

Subthreshold Hypomanic Symptoms in Progression From Unipolar Major Depression to Bipolar Disorder

OBJECTIVE The authors assessed whether subthreshold hypomanic symptoms in patients with major depression predicted new-onset mania or hypomania. METHOD The authors identified 550 individuals followed for at least 1 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 five manic symptoms: elevated mood, decreased need for sleep, unusually high energy, increased goal-directed activity, and grandiosity. Participants were followed prospectively for a mean of 17.5 years and up to 31 years. The Longitudinal Interval Follow-up Examination was used to monitor course of illness and to identify any hypomania or mania. The association of subthreshold hypomanic symptoms at baseline with subsequent hypomania or mania was determined in survival analyses using Cox proportional hazards regression. RESULTS With a cumulative probability of one in four on survival analysis, 19.6% (N=108) of the sample experienced hypomania or mania, resulting in revision of diagnoses for 12.2% to bipolar II disorder and 7.5% to bipolar I disorder. Number of subthreshold hypomanic symptoms, presence of psychosis, and age at illness onset predicted progression to bipolar disorder. Decreased need for sleep, unusually high energy, and increased goal-directed activity were specifically implicated. CONCLUSIONS Symptoms of hypomania, even when of low intensity, were frequently associated with subsequent progression to bipolar disorder, although the majority of patients who converted did not have any symptoms of hypomania at baseline. These results suggest that continued monitoring for the possibility of progression to bipolar disorder is necessary over the long-term course of major depressive disorder.

Elevated prevalence of obesity, metabolic syndrome, and cardiovascular risk factors in bipolar disorder:

BACKGROUND Bipolar disorder is associated with excess cardiovascular mortality. We hypothesized outpatients with bipolar disorder would exhibit excess cardiovascular risk factors, particularly among prevalent users of the second-generation antipsychotics associated with weight gain and valproic acid derivatives. METHODS This chart review of 217 patients with bipolar disorder examined cardiovascular risk factors of the metabolic syndrome. We also evaluated if certain medications were cross-sectionally associated with metabolic syndrome. RESULTS Fifty-six patients were not weighed and many did not have available lipid profiles. Over three-quarters of those with available data (n = 161) were overweight or obese (body mass index >or= 25) and nearly half were obese (body mass index >or= 30). A prevalence exceeding general population estimates was also observed for hypertriglyceridemia, elevated blood pressure/hypertension, and elevated fasting glucose/diabetes. Among those with all requisite data (n = 60), over 50% met criteria for National Cholesterol Education Program-defined metabolic syndrome, nearly double the expected prevalence. A trend toward greater prevalence of metabolic syndrome among prevalent users of the second-generation antipsychotics associated with weight gain was observed. CONCLUSIONS Obesity and the metabolic syndrome were common in patients with bipolar disorder. These patients may be under-evaluated for cardiovascular risk and warrant screening and early intervention.

Overt Irritability/Anger in Unipolar Major Depressive Episodes Past and Current Characteristics and Implications for Long-term Course

IMPORTANCE Although symptoms of irritability or anger are not central to the diagnosis of unipolar major depressive episodes (MDEs), these symptoms have been found, in cross-sectional studies, to be highly prevalent and associated with increased comorbidity and depressive illness burden. OBJECTIVE To determine the prevalence of overtly expressed irritability/anger and its effect on intake presentation and the long-term course of illness. DESIGN A prospective, naturalistic investigation of patients with unipolar MDEs, studied systematically at intake and during up to 31 years of follow-up. SETTING Five US academic medical centers. PARTICIPANTS Patients entered the National Institute of Mental Health Collaborative Depression Study during an MDE in 1978, 1979, 1980, or 1981. Patients with unipolar MDE at intake (n = 536) were divided into those with and those without current comorbid overtly expressed irritability/anger. EXPOSURE In this observational, longitudinal study, patients received treatment that was recorded but not controlled. MAIN OUTCOMES AND MEASURES Groups were compared on illness severity and chronicity, psychosocial impairment, quality of life, suicidal behavior, lifetime comorbid diagnoses, impulse control, and measures associated with bipolarity. RESULTS Overt irritability/anger was present in 292 of 536 participants with a unipolar MDE at study intake (54.5%). It was associated with significantly increased depressive severity, longer duration of the index MDE, poorer impulse control, a more chronic and severe long-term course of illness, higher rates of lifetime comorbid substance abuse and anxiety disorder, more antisocial personality disorders, greater psychosocial impairment before intake and during follow-up, reduced life satisfaction, and a higher rate of bipolar II disorder in relatives. No association was found with increased suicidal ideation or behavior. Results were not explained by comorbidity or other manic spectrum symptoms. CONCLUSIONS AND RELEVANCE This study extends results of cross-sectional investigations and indicates that irritability/anger during MDEs is a highly prevalent clinical marker of a more severe, chronic, and complex depressive illness. Findings have important implications for assessment and treatment.

Longitudinal Course of Bipolar I Disorder: Duration of Mood Episodes

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.

Manic/hypomanic Symptom Burden and Cardiovascular Mortality in Bipolar Disorder

Objectives: To compare the risk for cardiovascular mortality between bipolar I and bipolar II subtypes and determine correlates of cardiovascular mortality. Bipolar disorder conveys an increased risk of cardiovascular mortality. Methods: Participants with major affective disorders were recruited for the National Institute of Mental Health Collaborative Depression Study and followed prospectively for up to 25 years. A total of 435 participants met the diagnostic criteria for bipolar I (n = 288) or bipolar II (n = 147) disorder based on Research Diagnostic Criteria at intake and measures of psychiatric symptoms during follow-up. Diagnostic subtypes were contrasted by cardiovascular mortality risk using Cox proportional hazards regression. Affective symptom burden (the proportion of time with clinically significant manic/hypomanic or depressive symptoms) and treatment exposure were additionally included in the models. Results: Thirty-three participants died from cardiovascular causes. Participants with bipolar I disorder had more than double the cardiovascular mortality risk of those with bipolar II disorder, after controlling for age and gender (hazard ratio = 2.35, 95% Confidence Interval = 1.04-5.33; p = .04). The observed difference in cardiovascular mortality between these subtypes was at least partially confounded by the burden of clinically significant manic/hypomanic symptoms which predicted cardiovascular mortality independent of diagnosis, treatment exposure, age, gender, and cardiovascular risk factors at intake. Selective serotonin uptake inhibitors seemed protective although they were introduced late in follow-up. Depressive symptom burden was not related to cardiovascular mortality. Conclusions: Participants with bipolar I disorder may face a greater risk of cardiovascular mortality than those with bipolar II disorder. This difference in cardiovascular mortality risk may reflect manic/hypomanic symptom burden. CDS = collaborative depression study; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; RDC = Research Diagnostic Criteria; PSR = Psychiatric Status Rating.

The association between mood and anxiety disorders with vascular diseases and risk factors in a nationally representative sample

OBJECTIVE To investigate the association between mood and anxiety disorders and vascular diseases after controlling for vascular disease risk factors. METHODS Using a nationally representative sample of adults (N=5692) 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. RESULTS In multivariate logistic regression models that controlled for obesity, high blood pressure, smoking and diabetes, vascular disease was associated with bipolar disorder in women [odds ratio (OR) 2.80, 95% confidence interval (CI) 1.63-4.80], and major depressive disorder in men (OR 1.85, 95% CI 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. CONCLUSION These findings demonstrate the importance of evaluation of sex differences, mood disorder subtype and co-occurring 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.

A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease

We examined the effects of 3 dosages of pridopidine, a dopamine‐stabilizing compound, on motor function and other features of Huntingtons disease, with additional evaluation of its safety and tolerability. This was a randomized, double‐blind, placebo‐controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty‐seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntingtons Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was −1.2 points (95% confidence interval [CI], −2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was −2.8 points (95% CI, −5.4 to −0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntingtons disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated.

Anxiety and Outcome in Bipolar Disorder

OBJECTIVE Important differences exist between bipolar disorder with and without comorbid anxiety, but little is known about the long-term prognostic significance of coexisting anxiety in bipolar disorder. The authors sought to identify the anxiety features most predictive of subsequent affective morbidity and to evaluate the persistence of the prognostic relationship. METHOD Probands with bipolar I or II disorder from the National Institute of Mental Health Collaborative Depression Study were followed prospectively for a mean of 17.4 years (SD=8.4) and were characterized according to various manifestations of anxiety present at baseline. A series of general linear model analyses examined the relationship between these measures and the proportion of follow-up weeks in episodes of major depression and in episodes of mania or hypomania. RESULTS Patients whose episode at intake included a depressive phase spent nearly three times as many weeks in depressive episodes than did those whose intake episode was purely manic. Psychic and somatic anxiety ratings, but not the presence of panic attacks or of any lifetime anxiety disorder, added to the predictive model. Combined ratings of psychic and somatic anxiety were associated in a stepwise fashion with a greater proportion of weeks in depressive episodes, and this relationship persisted over the follow-up period. CONCLUSIONS The presence of higher levels of anxiety during bipolar mood episodes appears to mark an illness of substantially greater long-term depressive morbidity.

Cholesterol and suicide attempts: A prospective study of depressed inpatients

Low cholesterol levels have commonly been associated with various suicide measures. We sought to examine suicide attempts in a prospective sample of depressed patients that on prior analysis demonstrated an association between low cholesterol and subsequent suicide completions. Seventy-four inpatients with Research Diagnostic Criteria unipolar major depression, bipolar depression or schizoaffective depression entered a prospective follow-up study from 1978 to 1981. Kaplan-Meier survival analysis and Cox regression were utilized to elucidate the relationship between cholesterol levels and subsequent severe suicide attempts as well as all suicide attempts regardless of severity. Attempts preceding index hospitalization and other lifetime attempts were evaluated cross-sectionally. Low serum cholesterol levels did not predict subsequent suicide attempts. Contrary to our hypothesis, the high cholesterol group was associated with increased risk of suicide attempts on survival analysis in those less than median age. Nonetheless, in cross-sectional analysis, the low cholesterol group had more suicide attempts preceding index hospitalization and more remote lifetime attempts. The results from this prospective dataset do not support an association between low cholesterol and subsequent suicide attempts despite replicating the retrospective findings of previous case-control and cross-sectional studies.

The role of monoamine oxidase inhibitors in current psychiatric practice.

The use of monoamine oxidase inhibitors (MAOIs) by psychiatrists has declined over the past several decades with the expansion of psychiatrists’ pharmacologic armamentarium. This trend has also been driven by concern about food and drug interactions and side effects, as well as waning physician experience with these medications. Many psychiatrists, in fact, never prescribe MAOIs. Recent research has liberalized the MAOI diet and identified symptom presentations more likely to respond to these medications. Thus, clinicians must continue to familiarize themselves with the properties of and indications for prescribing MAOIs. (Journal of Psychiatric Practice 2004;10:239–248)