Maria Kovacs

Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression: A Meta-analysis

CONTEXT Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. OBJECTIVE To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. DATA SOURCES Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. STUDY SELECTION Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. DATA EXTRACTION Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression. RESULTS In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. CONCLUSION This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.

Comparative Efficacy of Cognitive Therapy and Pharmacotherapy in the Treatment of Depressed Outpatients

Forty-one unipolar depressed outpatients were randomly assigned to individual treatment with either cognitive therapy (N =19)or imipramine (N =22).As a group, the patients had been intermittently or chronically depressed with a mean period of 8.8 years since the onset of their first episode of depression, and 75%were suicidal. For the cognitive therapy patients, the treatment protocol specified a maximum of 20 interviews over a period of 12 weeks. The pharmacotherapy patients received up to 250 mg/day of imipramine for a maximum of 12 weeks. Patients who completed cognitive therapy averaged 10.90 weeks in treatment; those in pharmacotherapy averaged 10.86 weeks. Both treatment groups showed statistically significant decreases in depressive symptomatology. Cognitive therapy resulted in significantly greater improvement than did pharmacotherapy on both a self-administered measure of depression (Beck Depression Inventory)and clinical ratings (Hamilton Rating Scale for Depression and Raskin Scale).Moreover, 78.9%of the patients in cognitive therapy showed marked improvement or complete remission of symptoms as compared to 22.7%of the pharmacotherapy patients. In addition, both treatment groups showed substantial decrease in anxiety ratings. The dropout rate was significantly higher with pharmacotherapy (8 Ss)than with cognitive therapy (1 S).Even when these dropouts were excluded from data analysis, the cognitive therapy patients showed a significantly greater improvement than the pharmacotherapy patients. Follow-up contacts at three and six months indicate that treatment gains evident at termination were maintained over time. Moreover, while 68%of the pharmacotherapy group re-entered treatment for depression, only 16%of the psychotherapy patients did so.

Internalizing disorders in childhood

In this selective review of recent research on internalizing disorders in childhood, we focus on four areas: the predictive validity of the diagnoses of depressive and anxiety disorders, rates of comorbidity, the chronology of onsets of the disorders of interest, and transmission of depressive and anxiety disorders in the pedigrees of affected individuals. To synthesize and reconcile findings in these four areas, we approach the information from a developmental perspective and assume that genetically driven biologic processes play a salient role in the expression of depressive and anxiety disorders in childhood. We also comment on the relevance of findings on children and adolescents to the field of depressive and anxiety disorders in adults and make recommendations for further research.

Presentation and Course of Major Depressive Disorder during Childhood and Later Years of the Life Span

OBJECTIVE To examine whether major depressive disorder (MDD) in childhood, adolescence, and adulthood represents essentially the same diagnostic entity. METHOD Recent publications on clinically referred patients with MDD that met certain selection criteria were examined to abstract information on six phenomenological features of the disorder: episode number, symptom presentation, psychiatric comorbidity, recovery from the index episode, recurrence of MDD, and switch to bipolar illness. The studies included both inpatients and outpatients with an age range of 6 to 80+ years. RESULTS Synthesizing the information across broad age groups revealed that clinically referred depressed youths, compared with adults and the elderly, are almost exclusively first-episode probands, evidence comparable symptom pictures, have similar rates of psychiatric comorbidity, recover somewhat faster from their index episode of MDD, have a similar recurrence rate, and are at greater risk for bipolar switch. CONCLUSIONS MDD in clinically referred youths is similar in many regards to MDD in adults and the elderly. However, the findings that the risk of recurrent MDD among children approximates the rate among adults but, on average, about 20 years earlier in their lives, and that youths with unipolar depression convert to bipolar illness more frequently than do adults, suggest that very early onset MDD is a particularly serious form of affective illness.

Psychiatric Disorders in Youths With IDDM: Rates and Risk Factors

OBJECTIVE To determine prevalence rates, associated features and risk factors for psychiatric disorders subsequent to the diagnosis of IDDM in youths. RESEARCH DESIGN AND METHODS Using a longitudinal, naturalistic design, 92 youths from 8 to 13 years old at onset of IDDM were followed from their initial diagnosis. They were repeatedly assessed by semistructured interview and diagnosed by operational criteria. RESULTS By the 10th year of IDDM and the mean age of 20 years, an estimated 47.6% of the sample developed psychiatric disorder. Major depressive, conduct, and generalized anxiety disorders were the most prevalent, and major depression had a significantly higher estimated rate (27.5%) than each other disorder. The highest incidence rates were during the 1st year of the medical condition. Initial maternal psychopathology increased the risk of psychiatric disorder in the subjects, and maternal depression was a specific risk factor for depression in the subjects. Earlier psychiatric disorder in the subjects also increased the risk of later disorder. CONCLUSIONS The results converge with findings from other studies, suggesting elevated psychiatric morbidity in contemporary samples of young people with IDDM. The morbidity partly reflects the high incidence of major depression in adolescence and generalized anxiety disorder in young adulthood. Monitoring the psychological status of young patients and their mothers may help to identify diabetic children at risk for psychiatric disorder and facilitate prevention or treatment efforts. Monitoring may be particularly beneficial during the 1st year of the IDDM.

Suicidal Behaviors and Childhood-Onset Depressive Disorders: A Longitudinal Investigation

In this longitudinal study, the rates and correlates of suicidal ideation and suicide attempts were determined among outpatient youths with depressive disorders and youths with other psychiatric disorders. At study entry, about 66% of the subjects evidenced suicidal ideation and 9% already attempted suicide. The rate of ideation remained fairly stable over time, whereas the rate of attempts reached 24% by the average age of 17 years. Major depressive and dysthymic disorders were associated with significantly higher rates of suicidal behaviors than were adjustment disorder with depressed mood and nondepressive disorders. In the presence of affective disorders, comorbid conduct and/or substance use disorders further increased the risk of suicide attempts.

Depressive disorders in childhood III. A longitudinal study of comorbidity with and risk for conduct disorders

As part of a longitudinal nosologic study of major depressive disorder (MDD), dysthymic disorder, and adjustment disorder with depressed mood in 104 school-aged probands, the prevalence and consequences of comorbid conduct disorders (CD) were examined. During the index depressive episodes, 16% of the patients had comorbid CD; during the full study observation 23% had CD; and the estimated time-dependent risk of conduct disorder developing was 36% by age 19. For most cases, comorbid CD developed as a complication of the depression and persisted after the depression remitted. Comorbid CD was not differentially associated with the type of depression at study entry, did not affect depressive symptom presentation, was similarly distributed among boys and girls, and was unrelated to demographic factors. Additionally, comorbid CD did not affect recovery from the index depressive episodes and did not influence the symptom-free interval before a recurrent depression among cases with MDD. The risk of CD developing was not altered by chronologically earlier family variables or demographic factors. But girls who had attention deficit disorder, compared to those who did not, seemed to be at higher risk for CD during study observation. Finally, in this depressed cohort, having CD any time was associated with an increased rate of long-term functional problems.

Hypothalamic-pituitary-adrenal axis dysregulation in depressed children and adolescents: a meta-analysis.

Research findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: (a) 17 published studies of HPA-axis response to the dexamethasone suppression test (DST) in depressed youth (DST; N=926) and (b) 17 studies of basal HPA-axis functioning (N=1332). We also examined descriptively studies that used corticotropin-releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was 0.57, z=4.18, p<0.01. The global standardized mean difference effect size in basal HPA-axis functioning was 0.20, z=4.53, p<0.01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axiss negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.

Bipolar Disorder and Comorbid Conduct Disorder in Childhood and Adolescence

OBJECTIVE To report on the rate and associated features of comorbid conduct disorder (CD) in 26 bipolar (BP) youths and examine whether comorbidity affects clinical course. METHOD The clinically referred subjects, 8 to 13 years old at study entry, were participating in a longitudinal investigation of childhood-onset psychiatric disorders. They were repeatedly examined during an interval of up to 12 years, and diagnosed by DSM-III criteria. RESULTS There was a 69% rate of lifetime comorbidity and 54% rate of episode comorbidity with CD. CD predated the first BP episode for 11 youths and postdated it for 7. Only 12% of the 26 children had primary uncomplicated affective illness. Youngsters without CD comorbidity had a higher rate of primary affective illness, a somewhat greater number of BP episodes, but slightly better overall clinical course. They also had a greatly elevated rate of maternal mania, whereas BP youths with CD were notable for the rate of paternal substance abuse. CONCLUSIONS Comorbid CD may exist in a large portion of young patients with BP disorder, confusing its clinical presentation and possibly accounting for some of the documented failure to detect BP disorder. Comorbid CD in bipolar youths appears to be associated with a somewhat worse clinical course. The overall indications are that comorbid CD may identify a subtype of very early onset BP disorder.

Prevalence and predictors of pervasive noncompliance with medical treatment among youths with insulin-dependent diabetes mellitus.

School-age children were assessed longitudinally for up to 9 years, after the onset of their insulin-dependent diabetes mellitus (IDDM), to determine the time-dependent risk of the psychiatric diagnosis of noncompliance with medical treatment and to examine protective and risk factors. The cumulative risk for this diagnosis over the 9 years was .45. Noncompliance tended to emerge in middle adolescence and was found to be protracted. Social competence, self-esteem, and aspects of family functioning at IDDM onset and initial psychiatric status did not predict noncompliance. However, noncompliance was associated with having major psychiatric disorder later in the course of IDDM.