In a prospective-longitudinal study of a representative birth cohort, we tested why stressful experiences lead to depression in some people but not in others. A functional polymorphism in the promoter region of the serotonin transporter (5-HT T) gene was found to moderate the influence of stressful life events on depression. Individuals with one or two copies of the short allele of the 5-HT T promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events than individuals homozygous for the long allele. This epidemiological study thus provides evidence of a gene-by-environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup.

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Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

Background Current and comprehensive information on the epidemiology of DSM-IV 12-month and lifetime drug use disorders in the United States has not been available. Objectives To present detailed information on drug abuse and dependence prevalence, correlates, and comorbidity with other Axis I and II disorders. Design, Setting, and Participants Face-to-face interviews using the Alcohol Use Disorder and Associated Disabilities Interview Schedule of the National Institute on Alcohol Abuse and Alcoholism in a large representative sample of US adults (N = 43 093). Main Outcome Measures Twelve-month and lifetime prevalence of drug abuse and dependence and the associated correlates, treatment rates, disability, and comorbidity with other Axis I and II disorders. Results Prevalences of 12-month and lifetime drug abuse (1.4% and 7.7%, respectively) exceeded rates of drug dependence (0.6% and 2.6%, respectively). Rates of abuse and dependence were generally greater among men, Native Americans, respondents aged 18 to 44 years, those of lower socioeconomic status, those residing in the West, and those who were never married or widowed, separated, or divorced (all P Conclusions Most individuals with drug use disorders have never been treated, and treatment disparities exist among those at high risk, despite substantial disability and comorbidity. Comorbidity of drug use disorders with other substance use disorders and antisocial personality disorder, as well as dependence with mood disorders and generalized anxiety disorder, appears to be due in part to unique factors underlying each pair of these disorders studied. The persistence of low treatment rates despite the availability of effective treatments indicates the need for vigorous educational efforts for the public and professionals.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/482282/yoa60081_566_576.pdf

Prevalence, Correlates, Disability, and Comorbidity of DSM-IV Alcohol Abuse and Dependence in the United States: Results From the National Epidemiologic Survey on Alcohol and Related Conditions

Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

/pdf/the-molecular-neurobiology-of-depression-19u214boy3.pdf

The molecular neurobiology of depression

Improved methods of assessment and research design have established a robust and causal association between stressful life events and major depressive episodes. The chapter reviews these developments briefly and attempts to identify gaps in the field and new directions in recent research. There are notable shortcomings in several important topics: measurement and evaluation of chronic stress and depression; exploration of potentially different processes of stress and depression associated with first-onset versus recurrent episodes; possible gender differences in exposure and reactivity to stressors; testing kindling/sensitization processes; longitudinal tests of diathesis-stress models; and understanding biological stress processes associated with naturally occurring stress and depressive outcomes. There is growing interest in moving away from unidirectional models of the stress-depression association, toward recognition of the effects of contexts and personal characteristics on the occurrence of stressors, and on the likelihood of progressive and dynamic relationships between stress and depression over time-including effects of childhood and lifetime stress exposure on later reactivity to stress.

/pdf/stress-and-depression-2zp4i7xmjt.pdf

Stress and Depression

Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction.

https://www.ausl.fe.it/azienda/dipartimenti/daismdp/staff/osservatorio-epidemiologico/documenti-scaricabili/convegni/corso-di-formazione-aggiornamento-di-farmacoterapia-in-uso-al-sert/3-himan-mecc-dipendenza/at_download/file

NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and Memory

OBJECTIVE: Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression. METHOD: The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent’s behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressog...

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.6.837

Causal Relationship Between Stressful Life Events and the Onset of Major Depression

Background In order to develop informed approaches to prevention and treatment of illicit psychoactive substance use, abuse, and dependence, we need to understand the sources of individual differences in risk. Methods In personal interviews with 1198 male-male twin pairs (708 monozygotic and 490 dizygotic) ascertained from a population-based registry, we assessed lifetime use, heavy use, and abuse of and dependence on cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Twin resemblance was assessed by probandwise concordance, odds ratio, tetrachoric correlations, and biometrical model fitting. Results Twin resemblance for substance use, heavy use, abuse, and dependence was substantial, and consistently greater in monozygotic than in dizygotic twins. For any drug use and for cannabis and hallucinogen use, model fitting suggested that twin resemblance was due to both genetic and familial-environmental factors. Twin resemblance for sedative, stimulant, cocaine, and opiate use, however, was caused solely by genetic factors. With 2 exceptions (cocaine abuse and stimulant dependence), twin resemblance for heavy use, abuse, and dependence resulted from only genetic factors, with heritability of liability usually ranging from 60% to 80%. No consistent evidence was found for violations of the equal environment assumption. Conclusions In accord with prior results in studies of women, the family environment plays a role in twin resemblance for some forms of substance use in men. However, twin resemblance for heavy use, abuse, and dependence in men is largely caused by genetic factors, and heritability estimates are high.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/481586/yoa9243.pdf

Illicit Psychoactive Substance Use, Heavy Use, Abuse, and Dependence in a US Population-Based Sample of Male Twins

Although stressful life events (SLEs) play a major role in many etiologic theories of major depression (MD), important questions remain about the nature of their association with the onset of depressive episodes. We assessed over the last year, in female twins ascertained from a population based registry, the occurrence of 15 classes of SLEs and the onset of DSM-III-R MD and 2-week generalized anxiety disorder (GAD). The sample contained 24,648 person-months, 316 onsets of MD, and 239 onsets of GAD. SLEs were rated on long-term contextual threat and dependence. Discrete time-survival analyses were employed. The association between SLEs and depressive onsets was usually strongest in the month of occurrence but extended for "difficulty-like" events for up to 6 months. The depressogenic effect of SLEs was strongly predicted by contextual threat level, although some low threat events significantly increased risk for MD. The risk for a depressive onset given the number of reported SLEs within one month was: no event, 0.9%; one, 3.4%; two, 6.8%; and three, 23.8%. Although a few events were relatively specifically depressogenic or anxiogenic, most SLEs increased risk for both MD and GAD. The risk period produced by SLEs range from short-lived to relatively prolonged. High threat events encompass most but not all of the depressogenic effects of SLEs. Multiple SLEs in the same month substantially increase the risk for a depressive onset. The specificity of most SLEs for depressive versus anxiety syndromes is modest.

Stressful life events and major depression : Risk period, long-term contextual threat, and diagnostic specificity

Background The nosologic structure of psychotic illness, still influenced as much by historical as empirical perspectives, remains controversial. Methods Latent class analysis was applied to detailed symptomatic and outcome assessments of probands (n=343) with broadly defined schizophrenia and affective illness ascertained from a population-based psychiatric registry in Roscommon County, Ireland. First-degree relatives (n=942) were assessed by personal interview and/or review of hospital record. Results Six classes were found, all of which bore substantial resemblance to current or historical nosologic constructs. In order of decreasing frequency, they were (1) classic schizophrenia, (2) major depression, (3) schizophreniform disorder, (4) bipolar-schizomania, (5) schizodepression, and (6) hebephrenia. These classes differed on many historical and clinical variables not used in the latent class analysis. Compared with relatives of controls, significantly increased rates of major depression were seen in relatives of depressed and schizodepressed probands. Significantly increased rates of bipolar illness were restricted to relatives of bipolar-schizomanic probands. The risks for schizophrenia and schizophrenia spectrum disorders were significantly increased in relatives of all proband classes except major depression. This increase was moderate for bipolar-schizomanic probands, substantial for schizophrenic, schizophreniform, and schizodepressed probands, and marked for hebephrenic probands. Conclusions These results suggest a relatively complex typology of psychotic syndromes consistent neither with a unitary model nor with a Kraepelinian dichotomy. The familial vulnerability to psychosis extends across several syndromes, being most pronounced in those with schizophrenialike symptoms. The familial vulnerability to depressive and manic affective illness is somewhat more specific.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/203928/yoa6346.pdf

The Structure of Psychosis: Latent Class Analysis of Probands From the Roscommon Family Study

Background. Familial factors, which are partly genetic, influence risk for phobias. Prior family and twin studies, however, were based on a single lifetime assessment, which may be only moderately reliable.Methods. We obtained, 8 years apart, two assessments of lifetime history of five unreasonable fears and phobias (agoraphobia and social, situational, animal and blood-injury phobia) from face-to-face and telephone interviews from 1708 individual female twins from a population-based registry. We also obtained, 1 month apart, test–retest reliability on 192 twins. We fitted, using the program Mx, a measurement model that estimates the role of genetic and environmental risk factors correcting for measurement error.Results. Short-term reliability of the five phobias was modest (mean κ=0·46), but higher than long-term stability (mean κ=0·30). Unreliability occurred both for subject recall of unreasonable fears and for interviewer assessment of which fears constituted phobias. Examining fears and phobias together, in a multiple threshold model, results suggested that twin resemblance was due solely to genetic factors, with estimated total heritabilities, corrected for unreliability, of: any 43%, agoraphobia 67%, animal 47%, blood/injury 59%, situational 46% and social 51%. With the exception of animal phobia, similar results were obtained analysing phobias alone.Conclusions. Lifetime histories of unreasonable fears and phobias assessed at personal interview have substantial unreliability. Correcting for unreliability, the liability to fears and their associated phobias is moderately heritable. Individual-specific environmental experiences play an important role in the development of phobias, while familial–environmental factors appear to be of little aetiological significance.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0033291799008429

Laura M. Karkowski

Papers

Causal Relationship Between Stressful Life Events and the Onset of Major Depression

Illicit Psychoactive Substance Use, Heavy Use, Abuse, and Dependence in a US Population-Based Sample of Male Twins

Stressful life events and major depression : Risk period, long-term contextual threat, and diagnostic specificity

The Structure of Psychosis: Latent Class Analysis of Probands From the Roscommon Family Study

Fears and phobias: reliability and heritability.