Steven P. Roose

Mood Disorders in the Medically Ill: Scientific Review and Recommendations

OBJECTIVE The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

bulimia and Depression

&NA; In recent years several lines of evidence have emerged suggesting that eating disorders in general, and bulimia in particular, are in some way linked to affective illness. However, there are few data on the frequency of affective syndromes among patients who have anorexia nervosa or bulimia. This report describes the results of semistructured interviews using the Schedule for Affective Disorders and Schizophrenia (SADS) to evaluate the frequency of the current and lifetime diagnoses of affective illness among 50 female patients meeting DSM‐III criteria for bulimia. Seventy percent of the patients had, at some time during their lives, met Research Diagnostic Criteria (RDC) for an episode of major depression and 88% had met RDC at some time during their lives for some affective disturbance. The implications of this high frequency of affective disturbance among patients with bulimia are discussed.

A Model of Placebo Response in Antidepressant Clinical Trials

Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for major depressive disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. In this review, the authors examine contributors to placebo response in antidepressant clinical trials and propose an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact designed to enhance treatment response.

Does study design influence outcome?. The effects of placebo control and treatment duration in antidepressant trials.

Background: Clinicians and researchers synthesize data from randomized controlled trials (RCTs) of antidepressants to make conclusions about the efficacy of medications for depression. All treatments include nonspecific factors in addition to the specific effects of drugs, and study design may influence patient outcomes via nonspecific factors. This study investigated whether placebo control and treatment duration affect the outcome in antidepressant RCTs. Methods: Medline and the Cochrane Database were searched to identify RCTs of antidepressants for major depression approved by the Food and Drug Administration. Included studies enrolled outpatient participants aged 18–65, lasted 6–12 weeks, compared an antidepressant to placebo or another antidepressant and were published in English after 1985. Excluded trials enrolled inpatients, pregnant women and subjects with psychosis or mania. Mixed-effects logistic regression models including study type (placebo-controlled or comparator) and study duration (6, 8 or 12 weeks) as fixed effects determined whether these factors affected response and remission rates. Results: In the 90 trials analyzed, the odds of depression response (OR = 1.79, 95% CI = 1.45–2.17, p < 0.001) and remission (OR 1.53, 95% CI = 1.11–2.11, p < 0.001) were significantly higher in comparator relative to placebo-controlled trials. Trials lasting 8 (OR = 1.37, CI = 1.14–1.64, p = 0.001) and 12 (OR = 1.52, CI = 1.12–2.07, p = 0.008) weeks had significantly greater response rates than 6-week trials without differing themselves. Conclusions: Response and remission rates to antidepressants are significantly affected by study type and duration. Clinicians and researchers must consider the study design when interpreting and designing RCTs of antidepressant medications.

The Vascular Depression Subtype: Evidence of Internal Validity

BACKGROUND Vascular depression has been proposed as a unique diagnostic subtype in late life, yet no study has evaluated whether the specified clinical features associated with the illness are jointly indicative of an underlying diagnostic class. METHODS We applied latent class analysis to two independent clinical samples: the prospective, cohort design, Neurocognitive Outcomes of Depression in the Elderly (NCODE) study and the 8-week, multicenter, double blind, placebo-controlled Old-Old study. RESULTS A two-class model consisting of vascular and nonvascular depressed patients provided an excellent fit to the data in both studies, chi(2)(6) = 2.02, p = .90 in the NCODE study and chi(2)(6) = 7.024, p = .32 in the Old-Old study. Although all of the proposed features of vascular depression were useful in identifying the illness, deep white matter lesion burden emerged with perfect sensitivity (1.00) and near-perfect specificity (.95), making it the only indicator necessary to determine class membership. CONCLUSIONS These findings, replicated across two independent clinical samples, provide the first support for the internal validity of vascular depression as a subtype of late-life depression.

Treatment of depression in patients with heart disease

Patients with depression are more likely than patients without depression to develop ischemic heart disease and suffer cardiac-related death. Recent evidence suggests that the association between depression and increased cardiac mortality may in part be due to an increase in platelet activity and an imbalance in sympathetic and parasympathetic activity that makes the patient more susceptible to ventricular fibrillation. Available data suggest that the tricyclic antidepressants (TCAs) may increase the risk of mortality in patients with ischemic heart disease. Three studies with the selective serotonin reuptake inhibitors (SSRIs), including a double-blind, randomized comparison of paroxetine with nortriptyline, support the conclusion that the SSRIs have a relatively benign cardiovascular profile. Therefore, they are preferable to the TCAs for treatment of depression in patients at risk for cardiac events. Additional studies are needed to definitively establish the cardiovascular safety of the SSRIs.

Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on long-term heart rate variability measures

BACKGROUND Studies have linked depression to sudden death and serious cardiovascular events in patients with preexisting cardiac illness. Recent studies have shown decreased vagal function in cardiac patients with depression and depressed patients without cardiac illness. METHODS We compared 20-hour, sleeping, and awake heart period variability measures using spectral analysis, fractal dimension, and symbolic dynamics in two patient groups with major depression and ischemic heart disease (mean age 59-60 years) before and after 6 weeks of paroxetine or nortriptyline treatment. RESULTS Spectral measures showed decreases in awake and sleeping total power (TP: 0.0-0.5 Hz), ultra low frequency power (ULF: 0-0.0033 Hz), very low frequency power (VLF: 0.0033-0.04 Hz), and low-frequency power (LF: 0.04-0.15 Hz) for nortriptyline condition and a decrease in high-frequency power (HF: 0.15-0.5 Hz) for the awake condition in patients who received nortriptyline. A measure of nonlinear complexity, WC-100, significantly increased after paroxetine during the awake condition. CONCLUSIONS These findings suggest that nortriptyline has stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Paroxetine may have some cardio-protective effects, especially in cardiac patients.

Cardiovascular effects of imipramine and bupropion in depressed patients with congestive heart failure.

There has been a long-standing concern over the cardiovascular effects of tricyclic antidepressants, particularly in patients with preexisiting cardiac disease. Recent studies have demonstrated that imipramine causes no deleterious effect on ejection fraction as determined by radionuclide angiography in patients with impaired left ventricular function (LVF). However, the high rate of severe orthostatic hypotension induced by imipramine makes use of the drug problematic in these patients. Bupropion is a new antidepressant of the aminoketone class which is structurally unrelated to the tricyclics and which is relatively free of cardiac side effects in healthy depressed patients. We compared imipramine and bupropion in 10 depressed patients with impaired LVF in a random, double-blind crossover study. Neither imipramine nor bupropion adversely affected ejection fraction or other indices of LVF. However, as previously reported, severe orthostatic hypotension requiring discontinuation of drug developed in 50% of patients on imipramine. This difficulty did not occur with bupropion. From a cardiac perspective, bupropion may offer a safe alternative to imipramine in depressed patients with congestive heart failure.

Placebo Response in Antipsychotic Clinical Trials A Meta-analysis

IMPORTANCE Because increasing placebo response rates decrease drug-placebo differences and increase the number of failed trials, it is imperative to determine what is causing this trend. OBJECTIVES To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables. DATA SOURCES MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013. STUDY SELECTION Included were randomized clinical trials lasting 4 to 24 weeks, contrasting antipsychotic medication with placebo or an active comparator, and enrolling patients 18 years of age or older with schizophrenia or schizoaffective disorder. DATA EXTRACTION AND SYNTHESIS Standardized mean change scores were calculated for each treatment arm, plotted against publication year, and tested with Spearman rank correlation coefficients. Hierarchical linear modeling identified factors associated with the standardized mean change across medication and placebo treatment arms. MAIN OUTCOMES AND MEASURES We hypothesized that the mean change in placebo-treated patients would significantly increase from 1960 to the present, that a greater change would be observed in active comparator vs placebo-controlled trials, and that more protocol visits would increase the symptom change observed. RESULTS In the 105 trials examined, the mean change observed in placebo arms increased significantly with year of publication (n=39, r=0.52, P=.001), while the mean change in effective dose medication arms decreased significantly (n=208, r=-0.26, P<.001). Significant interactions were found between assignment to effective dose medication and publication year (t260=-5.55, P<.001), baseline severity (t260=5.08, P<.001), and study duration (t260=-3.76, P<.001), indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity and with increasing study duration. Medication treatment in comparator studies was associated with significantly more improvement than medication treatment in placebo-controlled trials (t93=2.73, P=.008). CONCLUSIONS AND RELEVANCE The average treatment change associated with placebo treatment in antipsychotic trials increased since 1960, while the change associated with medication treatment decreased. Changes in randomized clinical trials leading to inflation of baseline scores, enrollment of less severely ill participants, and higher expectations of patients may all be responsible.

Reversible Loss of Nocturnal Penile Tumescence during Depression: A Preliminary Report

Depressed patients regularly report a loss of interest in sex, but whether this represents only a lack of psychological motivation or is a reflection of an underlying physiological abnormality is unknown. We have studied 2 men suffering from severe depression and have observed that nocturnal penile tumescence was virtually absent while the men were depressed but returned to normal on recovery.