Composite International Diagnostic Interview screening scales for DSM-IV anxiety and mood disorders.

BACKGROUND: Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem. METHOD: Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives. RESULTS: Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9-38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0-2.9, p = 0.09-0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81-0.86, sensitivity 68.0-80.2%, specificity 90.1-98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR- is 0.1 or less at informative thresholds for all diagnoses. CONCLUSIONS: CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD).

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.

Whole-genome association study of bipolar disorder.

We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Effects of bupropion SR on anterior paralimbic function during waking and REM sleep in depression: preliminary findings using.

This study sought to clarify the effects of bupropion SR on anterior paralimbic function in depressed patients by studying changes in the activation of these structures from waking to REM sleep both before and after treatment. Twelve depressed patients underwent concurrent EEG sleep studies and [18F]fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) scans during waking and during their second REM period of sleep before and after treatment with bupropion SR. Nine subjects completed pre- and post-treatment waking PET studies. Five subjects completed pre- and post-treatment waking and REM sleep PET studies. Bupropion SR treatment did not suppress electrophysiologic measures of REM sleep, nor did it alter an indirect measure of global metabolism during either waking or REM sleep. Bupropion SR treatment reversed the previously observed deficit in anterior cingulate, medial prefrontal cortex and right anterior insula activation from waking to REM sleep. In secondary analyses, this effect was related to a reduction in waking relative metabolism in these structures following treatment in the absence of a significant effect on REM sleep relative metabolism. The implications of these findings for the relative importance of anterior paralimbic function in REM sleep in depression and for the differential effects of anti-depressant treatment on brain function during waking vs. REM sleep are discussed.

Bupropion SR reduces periodic limb movements associated with arousals from sleep in depressed patients with periodic limb movement disorder.

BACKGROUND: Antidepressant-induced periodic limb movement disorder (PLMD) may limit the tolerability of some antidepressant medications and interfere with treatment response. Given the role of dopamine in PLMD and the effects of bupropion sustained-release (SR) on central dopaminergic function, we hypothesized that bupropion SR would not be associated with antidepressant-induced PLMD. METHOD: In an expanded case-series design, we compared the effects of bupropion SR, after about 10 weeks of treatment, on measures of PLMD, depression, and sleep in 5 depressed (Research Diagnostic Criteria) patients who also met criteria for having pretreatment PLMD. Depression was measured using the Beck Depression Inventory and the Hamilton Rating Scale for Depression. Patients were considered to have PLMD if polysomnographic recordings showed > 5 periodic limb movements/hour of sleep that were associated with arousals from sleep. RESULTS: Bupropion SR treatment was associated with a reduction in measures of PLMD and an improvement in depression. CONCLUSION: These results show that bupropion SR is not associated with antidepressant-induced PLMD. Rather, bupropion SR treatment reduces objective measures of PLMD in depressed patients with the disorder.

Treatment of men with major depression: a comparison of sequential cohorts treated with either cognitive-behavioral therapy or newer generation antidepressants.

OBJECTIVE: This report compares response to cognitive-behavioral therapy (CBT) and pharmacotherapy in sequential cohorts of men with DSM-III-R major depression. METHOD: Patients were enrolled in consecutive standardized 16-week treatment protocols conducted in the same research clinic. The first group (N = 52) was treated with Beck's model of CBT, whereas the second group (N = 23) received randomized but open-label treatment with either fluoxetine (N = 10) or bupropion (N = 13). Crossover to the alternate medication was permitted after 8 weeks of treatment for antidepressant nonresponders. The patient groups were well matched prior to treatment. Outcomes included remission and nonresponse rates, as well as both independent clinical evaluations and self-reported measures of depressive symptoms. RESULTS: Despite limited statistical power to detect differences between treatments, depressed men treated with pharmacotherapy had significantly greater improvements on 4 of 6 continuous dependent measures and a significantly lower rate of nonresponse (i.e., 13% vs. 46%). The difference favoring pharmacotherapy was late-emerging and partially explained by crossing over nonresponders to the alternate medication. The advantage of pharmacotherapy over CBT also tended to be larger among the subgroup of patients with chronic depression. CONCLUSION: Results of prior research comparing pharmacotherapy and CBT may have been influenced by the composition of study groups, particularly the gender composition, the choice of antidepressant comparators, or an interaction of these factors. Prospective studies utilizing flexible dosing of modern antidepressants and, if necessary, sequential trials of dissimilar medications are needed to confirm these findings.

Gender differences in treatment response to sertraline versus imipramine in chronic depression.

OBJECTIVE: The authors examined gender differences in treatment response to sertraline, a selective serotonin reuptake inhibitor (SSRI), and to imipramine, a tricyclic antidepressant, in chronic depression. METHOD: A total of 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were randomly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout. RESULTS: Women were significantly more likely to show a favorable response to sertraline than to imipramine, and men were significantly more likely to show a favorable response to imipramine than to sertraline. Gender and type of medication were also significantly related to dropout rates; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study. Gender differences in time to response were seen with imipramine, with women responding significantly more slowly than men. Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications. CONCLUSIONS: Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants. The differing response rates between the drug classes in women was observed primarily in premenopausal women. Thus, female sex hormones may enhance response to SSRIs or inhibit response to tricyclics. Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient.

Fluoxetine versus placebo for the marijuana use of depressed alcoholics.

The aim of this analysis was to evaluate the efficacy of the SSRI antidepressant fluoxetine versus placebo for the marijuana use of depressed alcoholics. There are no previous reports involving and SSRI antidepressant for marijuana abuse. This analysis involved a subsample of 22 depressed alcoholic marijuana users out of a total of 51 depressed alcoholics. The entire sample was involved in a 12-week double-blind, placebo-controlled study evaluating the efficacy of fluoxetine versus placebo in depressed alcoholics. During the course of the trial, the cumulative number of marijuana cigarettes used was almost 20 times as high in the placebo group as in the fluoxetine group. Also, the number of days of marijuana use during the study was five times higher in the placebo group than in the fluoxetine group. These data suggest efficacy for fluoxetine in decreasing marijuana use of depressed alcoholics.

Age of onset in chronic major depression: relation to demographic and clinical variables, family history, and treatment response.

BACKGROUND: The clinical and etiological significance of the early-late onset distinction in chronic major depressive disorder was explored. METHOD: Subjects were 289 outpatients with DSM-III-R chronic major depression drawn from a multi-site study comparing the efficacy of sertraline and imipramine in the acute and long-term treatment of chronic depression. Patients received comprehensive evaluations using semi-structured interviews and rating scales. RESULTS: Early-onset chronic major depression was associated with a longer index major depressive episode and higher rates of recurrent major depressive episodes, comorbid personality disorders, lifetime substance use disorders, depressive personality traits, and a history of psychiatric hospitalization. In addition, more early-onset patients tended to have a family history of mood disorders. The early-late onset distinction was not associated with differences in symptom severity, functional impairment, or treatment response. LIMITATIONS: Family members were not interviewed directly; there were a large number of statistical comparisons; and interrater reliability of the assessments was not evaluated. CONCLUSIONS: Early-onset chronic major depression has a more malignant course and is associated with greater comorbidity than late-onset chronic major depression.

Depression, sleep, and antidepressants.

Sleep disturbances are an integral feature of depressive disorders. Like the disorders themselves, the sleep disturbances associated with depression are heterogeneous, ranging from hypersomnia to marked difficulties maintaining sleep. These difficulties are to some extent age dependent and reflect abnormalities of central nervous system arousal. Moreover, the sleep disturbances associated with depression have both reversible, or state-dependent, and more persistent trait-like characteristics. Polysomnographic recordings can be used to document sleep maintenance difficulties, and they often also reveal reduced slow wave sleep, an early onset of the first episode of rapid eye movement (REM) sleep, and increased phasic REM sleep. A deficit of serotonergic neurotransmission, a relative increase in pontine cholinergic activity, and, perhaps, an excess of noradrenergic and corticotropin-releasing hormone activity have been implicated in the pathogenesis of the sleep disturbances of more severe depressive disorders. Antidepressant medications have class- and compound-specific effects on polysomnographic profiles. Unlike other antidepressants, bupropion may increase or intensify REM sleep. While no single effect of antidepressants on sleep neurophysiology is necessary or sufficient for treatment efficacy, differences in drug effects may provide important clues to selection of specific medications for particular patients.

Double-blind fluoxetine in depressed alcoholic smokers.

Treatment trials involving smoking in alcoholics with major depression are scarce, despite the common co-occurrence of these disorders. In this study, 25 smokers with DSM-III-R diagnoses of both major depressive disorder and alcohol dependence were randomized to fluoxetine or placebo in a 12-week, double-blind, parallel group trial. Almost half (48%) of the patients had made a suicide attempt in the week before hospitalization (where recruitment was performed), and 84 percent reported suicidal ideations during that week. Those in the fluoxetine group demonstrated a significant within-group decrease in smoking during the course of the study, whereas those in the placebo group did not. Those in the fluoxetine group smoked 27 percent fewer cigarettes than those in the placebo group, although this difference was not statistically significant. Cumulative alcohol consumption during the 12 weeks of the pharmacotherapy trial was four times as high in the placebo group as in the fluoxetine group, though this difference was not statistically significant in this limited-sized sample. The change in smoking was significantly associated with a change in drinking. These preliminary findings suggest that fluoxetine has the potential for treating the smoking and drinking behaviors of depressed alcoholic smokers.

REM sleep enhancement by bupropion in depressed men.

OBJECTIVE: The authors compared the effects of bupropion, fluoxetine, and cognitive behavior therapy on EEG sleep in depressed subjects. METHOD: All-night sleep EEG studies were performed before treatment and after partial or full remission on 18 men with depression diagnosed according to Research Diagnostic Criteria and randomly assigned to treatment with either bupropion (N = 7) or fluoxetine (N = 11). Response to these drugs was measured by changes in Hamilton Depression Rating Scale scores. Pre- and posttreatment EEG sleep study results before and after treatment with cognitive behavior therapy were also available for 18 men matched in age and severity of Hamilton depression scale score, and one-time EEG sleep measures were available for 36 men who were not depressed. RESULTS: REM latency was reduced and REM sleep percent and REM time increased after treatment in the depressed men given bupropion. These effects contrasted with the effects of fluoxetine and cognitive behavior therapy. CONCLUSIONS: This study represents the first report of an antidepressant medication that shortens REM latency and increases REM sleep. If confirmed, this finding may require a revision of our current understanding of the relation among depression, REM sleep, and anti-depressant mechanisms.

Assessment of depression in patients with chronic fatigue syndrome.

Assessment of the relationship of depression to chronic fatigue syndrome (CFS) is a complicated but important topic. This relationship may range from the misdiagnostic (i.e., depression misidentified as CFS) to the etiologic (i.e., CFS causes an organic affective syndrome). Assessment should focus on the symptoms and syndromes of depressive disorder, utilization of a single rating scale to assess presumed depression is discouraged, and alternate approaches to classification that allow for symptomatic overlap of a major depressive disorder and CFS are suggested. Careful attention needs to be given to the use of external validating criteria in empiric studies, such as natural history, clinical course (including treatment response), and family history.

Basal ganglia calcification and psychosis in Down's syndrome.

A case of basal ganglia calcification (diagnosed in vivo) and schizophreniform psychosis occurring in a young adult with Down's syndrome is reported. A stress-vulnerability model is suggested. Because of the relatively high prevalence of basal ganglia calcification to Down's syndrome, this population appears well suited for systematic study of the neuropsychiatric aspects associated with this neurological condition.

Longevity and mortality in Down's syndrome.

The life span of individuals with DS has gradually increased since the 1920s. The DS individual now has an average life expectancy of 35 years. Despite advances in the health care of the retarded and improvements in the quality of institutional care, the overall mortality rate remains elevated by five-fold. Specific mortality rates from respiratory diseases (particularly pneumonia), infectious diseases, congenital heart disease, leukaemia and neurological disorders are still substantially increased. Disorders of immunological functioning, particularly T-cell mediated, appear related to this increased vulnerability, although further research is necessary. The periods of highest risk are during infancy, when congenital heart disease, leukaemia and respiratory diseases are most lethal, and late adulthood, when Alzheimer-type dementia and declining immunological function appear to be significant factors.