Interaction between the BDNF gene Val/66/Met polymorphism and morning cortisol levels as a predictor of depression in adult women.

BACKGROUND: Common genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression. AIMS: To determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women. METHOD: We recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva. RESULTS: There were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U-shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels. CONCLUSIONS: Morning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression.

Morning cortisol as a risk factor for subsequent major depressive disorder in adult women.

BACKGROUND: Whether individual differences in cortisol contribute to subsequent major depressive disorder (MDD) is unknown. AIMS: To determine whether premorbid levels of salivary cortisol and dehydroepiandrosterone (DHEA) were associated with subsequent MDD and how these related to psychosocial factors known to increase the risk for MDD. METHOD: Adult women (n=116) were recruited from general practices. None was currently depressed; 83 were 'psychosocially vulnerable' to MDD, 33 were not. Salivary steroids (cortisol and DHEA at 08.00 h and 20.00 h), recent life events, current mood and social support were assessed at entry. Onset of MDD was recorded during 13 months' follow-up. RESULTS: There were no associations between salivary cortisol or DHEA and recent life events or vulnerability. Twenty-eight onsets of MDD occurred during the follow-up period. This was associated with: severe adverse life events and difficulties during the follow-up period; mean morning cortisol levels at entry; and the presence of any of three vulnerability factors. CONCLUSIONS: Individual differences in morning salivary cortisol levels may represent an independent risk factor for subsequent MDD. The origin of these differences in cortisol is not yet understood.

Social factors and comorbidity of depressive and anxiety disorders.

Differences in rates of depression across and between populations can be considerable and are largely determined by psychosocial factors. Such findings have important implications for comorbidity. On the basis of multiplying independent probabilities, the proportion of comorbid conditions increases as base rates of the disorders increase in a population. If such a chance combination has clinical implications, it would appear to be a "fact" of significance irrespective of biological underpinnings. In a recent survey of 404 women living with at least one child in an inner-city area, the rate of both anxiety and depression was highly related to the childhood experiences of neglect and abuse. However, adversity in adult life (e.g. widowhood or divorce), which might be expected to relate to current stressors, was only related to the rate of depression. The two risk factors had a considerable impact on comorbidity by increasing the rate of each disorder and thus the probability of their occurring together. They had a lesser impact as "common antecedents". If both influences are considered, such adversity explains around half of the comorbidity. This is a conservative estimate of the impact of psychosocial factors.

Biological activities of staphylococcal enterotoxin type A mutants with N-terminal substitutions.

The purpose of this study was to examine the importance of certain N-terminal amino acid residues of staphylococcal enterotoxin type A (SEA) for biological activity. The results confirm our previous observation that Asn-25, Phe-47, and Leu-48 are important for SEA's emetic and superantigen activities. Substitutions at six other sites (Leu-12, Lys-14, Ser-16, Asp-45, Gln-46, and Thr-51) did not reveal any additional residues required for biological activity. Mutant SEAs with substitutions at 25, 47, or 48 all had decreased T-cell stimulatory activity, with the mutants at position 47 being the most defective. Results of a competition assay for binding to the major histocompatibility complex (MHC) class II-expressing cell line Raji suggested that the decreased superantigen activities of the mutants with substitutions at positions 47 and 48 are due to poor interactions with MHC class II molecules, whereas the defects of the mutants at position 25 are a consequence of faulty interactions with T-cell receptors. With respect to emetic activity in rhesus monkeys, the mutants at position 25 or 48 exhibited decreased but significant activity. Interestingly, the two mutants at position 47 had different emetic activities; SEA-F47G was nonemetic when administered intragastrically at 500 micrograms per animal, whereas SEA-F47S was emetic at this dosage. Since the mutants at position 47 were equally defective for superantigen activity, this further supports our previous suggestion of an incomplete correlation between SEA's emetic and superantigen activities.

Methodological aspects of life events research in people with learning disabilities: a review and initial findings.

A review of the life events studies relevant to people with learning disabilities is discussed. Issues surrounding the collection of information by using a structured interview method as set out in the Life Events and Difficulties Schedule Manual and the adjustment of threat rating to accommodate the perspective of people with learning disabilities are presented as a result of conducting a pilot study. The importance of using a probing interview style in contrast to a checklist method and eliciting the parents/carers' perception of events is emphasized.

Loss, humiliation and entrapment among women developing depression: a patient and non-patient comparison.

This paper is part of a series dealing with the role of life events in the onset of depressive disorders. Women who developed depression in a general population sample in Islington in North London are contrasted with a National Health Service-treated series of depressed patients in the same area. Findings among the latter confirm the importance of a severely threatening provoking event for onset among the majority of depressed women patients. The results for the two series are similar except for a small subgroup of patients characterized by a melancholic/psychotic condition with a prior episode. The severe events of importance have been recognized for some time by the traditional ratings of the Life Events and Difficulty Schedule (LEDS). However, the full descriptive material collected by the LEDS has been used to develop a new refined measure reflecting the likelihood of feelings of humiliation and being trapped following a severely threatening event, in addition to existing measures of loss or danger. The experience of humiliation and entrapment was important in provoking depression in both the patient and non-patient series. It proved to be associated with a far greater risk of depression than the experience of loss or danger without humiliation or entrapment.

Childhood Experience of Care and Abuse (CECA): a retrospective interview measure.

The development of a retrospective, investigator-based interview measure of Childhood Experience of Care and Abuse (CECA) used with two community samples of adults in London is described. The component ratings are shown to have satisfactory inter-rater reliability and also validity as determined by agreement between sisters' independent accounts. The association between the different childhood scales is explored as well as the relationship of childhood experiences to adult depression. Methodological issues concerning investigator-based versus respondent-based measures of childhood are discussed and a case made for use of the former. Advantages of using the CECA, a retrospective, time-based measure of childhood, are outlined.

Clinical and psychosocial origins of chronic depressive episodes. II. A patient enquiry.

BACKGROUND: We consider how well the psychosocial and clinical factors found to predict a chronic course for depressive episodes in the community, held for female psychiatric patients. METHOD: A consecutive series of depressed patients, aged 18 to 60, treated as in-patients, out-patients or day-patients at psychiatric departments of two London hospitals, were interviewed initially and at follow-up two years later. RESULTS: Indices of childhood adversity and current interpersonal difficulties predicted episodes taking a chronic course (of more than 12 months' duration). Half of the episodes associated with one or the other factor were chronic, compared with 22% of those with neither. The patients were at higher risk than the community series (75% v. 34%) and this explains their much greater rate of chronicity. There was also some evidence that social support reduced risk. Clinical features and the presence of a personality disorder were unrelated to chronicity. CONCLUSIONS: Similar psychosocial factors are important for predicting chronicity in both community and patient series.

Life events and endogenous depression. A puzzle reexamined.

BACKGROUND: Research has failed to find the expected clear-cut difference in the presence of events provoking onset in endogenous and nonendogenous depression. METHODS: A longitudinal study of 127 depressed female patients from two psychiatric departments were studied using the Present State Examination and the Life Event and Difficulty Schedule. Two earlier patient series using the same measures were employed to check findings, and two general population series were used to estimate the expected rate of life events. RESULTS: A large proportion of patients experienced a severely threatening event before onset, with the exception of a group defined by a British diagnostic category (a relatively small group of patients with melancholic/psychotic depression who were not experiencing their first episode). The results were broadly replicated in the two other patient series. The proportions of patients who experienced ongoing major difficulties did not differ between the groups. CONCLUSIONS: The relative size of this melancholic/psychotic group of patients with a prior onset may well have varied markedly from study to study in previous research, and this may help to explain the puzzling variability in findings concerning the role of stressful events in endogenous depression.

Lack of complete correlation between emetic and T-cell-stimulatory activities of staphylococcal enterotoxins.

This study examined the emetic activity of several staphylococcal enterotoxin type A and B (SEA and SEB, respectively) mutants that had either one or two amino acid residue substitutions. New sea gene mutations were constructed by site-directed mutagenesis; gene products were obtained with glycine residues at position 25, 47, 48, 81, 85, or 86 of mature SEA. Culture supernatants from Staphylococcus aureus RN4220, or derivatives containing either sea or a sea mutation, were analyzed for the ability to stimulate proliferation of murine splenocytes, as determined by incorporation of [3H]thymidine. Culture supernatants containing SEA-N25G (a SEA mutant with a substitution of glycine for the asparagine residue at position 25), SEA-F47G, or SEA-L48G did not stimulate T-cell proliferation, unlike supernatants containing the other substitution mutants. Purified preparations of SEA-N25G had weak activity and those of SEA-F47G and SEA-L48G had essentially no activity in the T-cell proliferation assay. All mutants except SEA-V85G, which was degraded by monkey stomach lavage fluid in vitro, were tested for emetic activity. SEA-C106A and two SEB mutants, SEB-D9N/N23D and SEB-F44S (previously referred to as BR-257 and BR-358, respectively), whose construction and altered immunological properties have been reported previously, were also tested in the emetic assay. Each mutant was initially administered intragastrically at doses of 75 to 100 micrograms per animal; if none of the animals responded, the dose was increased four-to fivefold. SEA-F47G, SEA-C106A, and SEB-D9N/N23D were the only mutants that did not induce vomiting at either dose tested; these three mutants had reduced immunological activity. However, there was not a perfect correlation between immunological and emetic activities; SEA-L48G and SEB-F44S retained emetic activity, although they had essentially no T-cell-stimulatory activity. These studies suggest that these two activities can be dissociated.

Staphylococcal enterotoxin type A internal deletion mutants: serological activity and induction of T-cell proliferation.

Previous findings indicate that the N-terminal region of staphylococcal enterotoxin type A (SEA) is required for its ability to induce T-cell proliferation. To better localize internal peptides of SEA that are important for induction of murine T-cell proliferation, SEA mutants that had internal deletions in their N-terminal third were constructed. A series of unique restriction enzyme sites were first engineered into sea; only one of these changes resulted in an amino acid substitution (the aspartic acid residue at position 60 of mature SEA was changed to a glycine [D60G]). Because the D60G substitution had no discernible effect on serological or biological activity, the sea allele encoding this mutant SEA was used to construct a panel of mutant SEAs lacking residues 3 to 17, 19 to 23, 24 to 28, 29 to 49, 50 to 55, 56 to 59, 61 to 73, 68 to 74, or 74 to 85. Recombinant plasmids with the desired mutations were constructed in Escherichia coli and transferred to Staphylococcus aureus. Staphylococcal culture supernatants containing the mutant SEAs were examined. Western immunoblot analysis with polyclonal anti-SEA antiserum revealed that each of the recombinant S. aureus strains produced a mutant SEA of the predicted size. All the mutant SEAs exhibited increased sensitivity to monkey stomach lavage fluid in vitro, which is consistent with these mutants having conformations unlike that of wild-type SEA or the SEA D60G mutant. In general, deletion of internal peptides had a deleterious effect on the ability to induce T-cell proliferation; only SEA mutants lacking either residues 3 to 17 or 56 to 59 consistently produced a statistically significant increase in the incorporation of [3H]thymidine. In the course of this work, two monoclonal antibodies that had different requirements for binding to SEA in Western blots were identified. The epitope for one monoclonal antibody was contained within residues 108 to 230 of mature SEA. Binding of the other monoclonal antibody to SEA appeared to be dependent on the conformation of SEA.

Aetiology of anxiety and depressive disorders in an inner-city population. 1. Early adversity.

A survey of an inner-city population of working-class and single mothers is described and the prevalence of anxiety and depression reported using two related diagnostic schemes, Bedford College caseness and DSM-III-R. This acts as an introduction to an analysis which indicates that adverse experiences in childhood and adolescence (involving parental indifference, and sexual and physical abuse) considerably raise risk of both depression and anxiety conditions (with the exception of mild agoraphobia and simple phobia) in adult life.

Aetiology of anxiety and depressive disorders in an inner-city population. 2. Comorbidity and adversity.

An earlier paper documented that adverse experiences in childhood and adolescence considerably raise risk of both depressive and anxiety conditions (with the exception of mild agoraphobia and simple phobia) in adult life. This paper deals with the same inner-city women with children at home. Consideration of adverse experiences throughout adulthood as a whole (excluding the period just before onset) particularly involving major prior losses suggests that rather different aetiological processes may be involved. Depression appears to be often linked to experiences of major loss in adulthood as a whole and to be particularly susceptible to shortcomings in the quality of ongoing social support. For anxiety only early adverse experiences appeared to be critical. (However, the onset of both conditions is often provoked by a severely threatening event in the most recent period--particularly 'loss' in depression, and 'danger' in anxiety.) Finally the critical role of early experience for both anxiety and depression explains to a considerable extent why they so often occur together; and social factors not studied in the present enquiry may account for some of the remaining unexplained comorbidity.

Depression and situational helplessness/mastery in a sample selected to study childhood parental loss.

This paper continues the investigation of differential states of depression in a sample of 225 women selected for different experiences of parental loss in childhood by introducing a measure of the cognitive-behavioural set of situational helplessness/mastery which uses actual rather than hypothetical situations as the basis for scoring. The measure is also specifically designed to take account of differences according to the time of its completion (before, during or after a psychiatric episode). The relationship is explored between this attribute and, on the one hand, depressive disorder, and on the other, parental loss in childhood. Rates of current depression increased progressively with the degree of helplessness rated not only for the current period but also, in instances where there was a current depressive episode, for the time immediately prior to its onset. For those with depression the degree of helplessness was often found to be higher during the episode than just before it. A measure of helplessness in childhood was associated not only with current depression but with previous episodes. Continuity between childhood and adult helplessness was apparently considerable, and both were associated with loss of mother in childhood. A rating of helplessness shown in the past just before onset of a prior depressive episode suggested a similar raised rate compared to those never depressed. The failure to find an association between prior episodes of depression and current helplessness among those currently not depressed is discussed in terms of the likely durability of long-term cognitive-behavioural sets and the possibility that with improved social circumstances and relationships, helplessness may decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Childhood loss of parent, lack of adequate parental care and adult depression: a replication.

A study of women living in Islington has confirmed earlier findings that the loss of a mother before the age of 17 (by death or separation) is associated with an increase in clinical depression in adulthood. Lack of adequate parental care following the loss accounted for the increase in disorder and there was some evidence that it acted as a 'vulnerability factor' increasing risk of onset of depression during a 1-year follow-up period, in the presence of a severe life event or major difficulty. Premarital pregnancy, marital separation/divorce and negative evaluation of self were identified as factors intervening between childhood lack of care and adult depression.

Life events, vulnerability and onset of depression: some refinements.

A prospective study of 400 largely working-class women with children living at home has once again demonstrated the major importance of long-term severe threatening life events in provoking caseness of depression. However, it again shows that only about one out of five women experiencing such an event go on to develop depression at a case level. This paper demonstrates that more sensitive characterisation of severe events can greatly increase the size of this association. This is done both by improving the description of the event itself and by taking into account various ways in which the event can 'match' characteristics of the women present at the first interview, well before the occurrence of the event or any onset of depression.

Depression: distress or disease? Some epidemiological considerations.

Surveys using clinical-type interviews have documented a high rate of depression among working-class women, and this is discussed in the light of a recent survey in an inner-city area. While women with caseness of depression contacting a psychiatrist did not differ in number of core depressive symptoms from those who did, they did in certain characteristics that would make them worrying for a general practitioner to deal with. It is concluded that there is a considerable overlap in the severity of depressive conditions between those seen by psychiatrists and those defined as cases in population surveys; any differences that do exist may relate more to the way symptoms are expressed than to the severity of the depressive disorder as such.

Psychotic and neurotic depression. Part 3. Aetiological and background factors.

Patients receiving diagnoses of 'psychotic' and 'neurotic' depression do not differ significantly in their pre-morbid experience of life events and difficulties of aetiological significance. Some aetiological differences emerge when the two groups are subdivided into their more and less extreme halves along a distribution of discriminant function scores, but these differences are not substantial. Reallocation of the extreme 20% of each diagnostic group (who are likely misclassifications) into the other group tends to enlarge these 'aetiological' differences but they are still slight. Comparison of 'endogenous' patients (those without severe life events or major difficulties) with 'reactive' patients reveals a slight tendency for the 'endogenous' group to have a higher frequency of psychotic-type symptoms. Apart from age and experience of 'past loss', no further significant differences were found in the background characteristics of depressed patients diagnosed as 'psychotic' and those diagnosed 'neurotic'.