OBJECTIVE: The authors conducted a meta-analysis of relevant data from primary studies of the genetic epidemiology of major depression.METHOD: The authors searched MEDLINE and the reference lists of previous review articles to identify relevant primary studies. On the basis of a review of family, adoption, and twin studies that met specific inclusion criteria, the authors derived quantitative summary statistics. RESULTS: Five family studies met the inclusion criteria. The odds ratios for proband (subjects with major depression or comparison subjects) versus first-degree relative status (affected or unaffected with major depression) were homogeneous across the five studies (Mantel-Haenszel odds ratio=2.84, 95% CI=2.31–3.49). No adoption study met the inclusion criteria, but the results of two of the three reports were consistent with genetic influences on liability to major depression. Five twin studies met the inclusion criteria, and their statistical summation suggested that familial aggregation was due ...

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.157.10.1552

Genetic Epidemiology of Major Depression: Review and Meta-Analysis

• Four hundred thirty-eight subjects underwent an overnight dexamethasone suppression test (DST) to standardize the test for the diagnosis of melancholia (endogenous depression). Abnormal plasma cortisol concentrations within 24 hours after dexamethasone administration occurred almost exclusively in melancholic patients. The best plasma cortisol criterion concentration, above which a DST result may be considered abnormal, was 5 ug/dL. The optimal dose of dexamethasone was 1 rather than 2 mg. Two blood samples obtained at 4 and 11 PM after dexamethasone administration detected 98% of the abnormal test results. This version of the DST identified melancholic patients with a sensitivity of 67% and a specificity of 96%. Baseline nocturnal plasma cortisol concentrations were not useful. Abnormal DST results were found with similar frequency among outpatients and inpatients with melancholia; but they were not related to age, sex, recent use of psychotropic drugs, or severity of depressive symptoms. Extensive evidence validates this practical test for the diagnosis of melancholia.

A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility.

Data from rodent studies indicate that cumulative stress exposure may accelerate senescence and offer a theory to explain differences in the rate of aging. Cumulative exposure to glucocorticoids causes hippocampal defects, resulting in an impairment of the ability to terminate glucocorticoid secretion at the end of stress and, therefore, in increased exposure to glucocorticoids which, in turn, further decreases the ability of the hypothalamo-pituitary-adrenal axis to recover from a challenge. However, the consensus emerging from reviews of human studies is that basal corticotropic function is unaffected by aging, suggesting that the negative interaction of stress and aging does not occur in man. In the present study, a total of 177 temporal profiles of plasma cortisol from 90 normal men and 87 women, aged 18-83 yr, were collected from 7 laboratories and reanalyzed. Twelve parameters quantifying mean levels, value and timing of morning maximum and nocturnal nadir, circadian rhythm amplitude, and start and end of quiescent period were calculated for each individual profile. In both men and women, mean cortisol levels increased by 20-50% between 20-80 yr of age. Premenopausal women had slightly lower mean levels than men in the same age range, primarily because of lower morning maxima. The level of the nocturnal nadir increased progressively with aging in both sexes. An age-related elevation in the morning acrophase occurred in women, but not in men. The diurnal rhythmicity of cortisol secretion was preserved in old age, but the relative amplitude was dampened, and the timing of the circadian elevation was advanced. We conclude that there are marked gender-specific effects of aging on the levels and diurnal variation of human adrenocorticotropic activity, consistent with the hypothesis of the "wear and tear" of lifelong exposure to stress. The alterations in circadian amplitude and phase could be involved in the etiology of sleep disorders in the elderly.

Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol.

The Genetics of Depression: A Review

The significant role of emotions in evolution and adaptation suggests that there must be more than 1 mechanism for generating them. Nevertheless, much of current emotion theory focuses on cognitive processes (appraisal, attribution, and construal) as the sole, or primary, means of eliciting emotions. As an alternative to this position, the present model describes 4 types of emotion-activating systems, 3 of which involve noncognitive information processing. From an evolutionary-developmental perspective, the systems maybe viewed as a loosely organized hierarchical arrangement, with neural systems, the simplest and most rapid, at the base and cognitive systems, the most complex and versatile, at the top. The emotion-activating systems operate under a number of constraints, including genetically influenced individual differences. The hierarchical organization of the systems for generating emotions provides an adaptive advantage.

/pdf/four-systems-for-emotion-activation-cognitive-and-7krvuxrfnq.pdf

Four Systems for Emotion Activation: Cognitive and Noncognitive Processes

• Serum cortisol response to the 1-mg overnight dexamethasone suppression test was studied in 221 depressed patients and 109 nondepressed psychiatric controls. Nonsuppression distinguished patients with primary unipolar depression (65/ 146) from patients with secondary unipolar depression (0/42) and nondepressed controls (0/109). Furthermore, nonsuppression distinguished the three familial subtypes of primary unipolar depressive illness: familial pure depressive disease (FPDD; 38/50 patients), sporadic depressive disease (SDD; 24/55 patients), and depression spectrum disease (3/41 patients). Moderate elevations in baseline serum cortisol levels were found in FPDD, SDD, and bipolar depression. Medication did not affect the results. The data suggest that the depressive syndrome is composed of separate illnesses, each of which has a distinctive pattern of hypothalamic-pituitary-adrenal axis activity during the depressed state as well as a specific clinical and familial psychiatric history.

https://jamanetwork.com/journals/PSYCH/articlepdf/492349/archpsyc_37_7_001.pdf

Hypothalamic-pituitary-adrenal axis activity in depressive illness. Its relationship to classification.

The relationship of age of onset in unipolar affective disorder to risk of alcoholism and depression in parents.

Hypothalamic-Pituitary-Adrenal Axis Activity in Depressive Illness: Its Relationship to Classification

A major problem with studies in the field of quantitative genetics is that of phenotypical heterogeneity. In particular, such heterogeneities show up in psychiatric investigations: index cases often tend to display more severe forms of disorders than the respective affected relatives. The principal goal of the present investigation was to test the phenotypical equivalence of the two populations of index cases and their affected relatives. Our analyses were based on 269 hospitalized patients with functional psychoses and 350 affected first degree relatives. As opposed to the majority of earlier investigations in which phenotypes were uniquely defined by diagnoses, phenotypes were represented in this study by a list of 22 psychiatric syndromes. Accordingly, multivariate statistical procedures were applied to analyze the intrinsic properties of the empirical lists. The results showed that typical syndrome patterns clearly appeared in both populations and that the phenotypical equivalence of the corresponding population sample sets lay between satisfactory and good. Furthermore, it was possible to select phenotypically homogeneous and reproducible subsets on the basis of the 22 syndromes. These subgroups can be used as basic material to study the genetic modes via current models from quantitative genetics. Nevertheless, our analyses revealed no clear breeding true of either affective disorders or schizophrenia.

George Winokur

Papers

Hypothalamic-pituitary-adrenal axis activity in depressive illness. Its relationship to classification.

The relationship of age of onset in unipolar affective disorder to risk of alcoholism and depression in parents.

Hypothalamic-Pituitary-Adrenal Axis Activity in Depressive Illness: Its Relationship to Classification

Familial syndrome patterns in schizophrenia, schizoaffective disorder, mania, and depression.

Evidence for possible linkage between genetic markers and affective disorders