This issue of Psychological Medicine carries a number of papers on the neurobiology of major depression. Those acquainted with the field will recognize some familiar topics and while familiarity can be comforting, it can also raise a sense of unease; as the millennium approaches should we still be enquiring about the role of decreased serotonin and increased cortisol in the pathophysiology of depressive disorders?

In our defence we can maintain that there is, in fact good evidence that serotonin and cortisol are implicated in the biology of depression. Our failure to tie down exactly how they are involved in the manifestation of the depressive syndrome does not reflect their lack of importance but rather the problems we have in asking the right questions and the technical difficulties we have answering them. So how far do the papers in this issue take us into this difficult territory ?

Background. Deficiencies in brain serotonin function are believed to play an important role in the pathophysiology of seasonal affective disorder/winter type (SAD). However, no direct evidence has been reported so far that lowered brain serotonin activity causes the symptoms of SAD.

Methods. We studied 11 SAD patients who had suffered recurrent winter depressive episodes of SAD and were fully recovered and off treatment during the summer. In a randomized, balanced, double-blind crossover design patients received two amino acid beverages, one containing tryptophan and the other containing no tryptophan but otherwise identical. Behavioural ratings and plasma total and free tryptophan concentrations were assessed at baseline before administration of the amino acid beverages and at several time points afterwards.

Results. The tryptophan-free amino acid beverage induced significant decreases of plasma total and free tryptophan levels and both levels increased during sham depletion (condition×time interaction: P<0·001). Tryptophan depletion, but not sham depletion caused a transient return of depressive symptoms (condition×time interaction: P<0·001).

Conclusions. The present study demonstrates that SAD patients in remission during the summer are vulnerable to a return of depression when depleted of tryptophan. This finding supports the importance of serotonergic mechanisms in the pathophysiology of SAD.

Background. An investigation of the association between diurnal changes in cortisol and DHEA levels, or in the cortisol/DHEA ratio at five different time points at presentation, and the occurrence of undesirable life events (losses, dangers to self and others, disappointments) during follow-up, and the outcome of major depression at 36 weeks were investigated.

Methods. Psychosocial and endocrine assessment of a consecutive cohort (N=68) of 8- to 16-year-old subjects with first episode major depression reassessed 12 months after presentation using a repeat measures design.

Results. Higher cortisol/DHEA ratios at 20.00 or 24.00 h predicted persistent major depression. Basal levels of either hormone alone or cortisol/DHEA ratios at the other three time points (08.00, 12.00 or 16.00 h) did not. High cortisol/DHEA ratios (i.e. values greater than the 60th percentile) at both evening points (20.00 and 24.00 h) also predicted the occurrence of subsequent disappointing life events but no other category of undesirable event. Both high evening cortisol/DHEA ratio at 20.00 h and one or more severely disappointing life events between presentation and follow-up predicted persistent major depression: 86% of subjects with both of these factors were still depressed at 36 weeks whereas 81% with neither factor were not.

Conclusions. The finding that it is depressed subjects with high cortisol/DHEA ratios at presentation who are specifically at risk for subsequent disappointing life events suggests a putative role for these adrenal steroids in abnormal cognitive or emotional processes associated with disturbed interpersonal behaviour.

Background. The aim of the study was to search for the existence of, and define, a possible relationship between performance in neuropsychological tests and baseline concentrations of plasma cortisol, vasopressin and oxytocin in medication-free patients with a major depressive episode.

Methods. Measures of depression and anxiety were obtained and a neuropsychological battery was presented. Blood for neuropeptide analysis was drawn by venepuncture at 8.00, 16.00 and 23.00 h.

Results. The melancholic patients performed less well on the neuropsychological battery than did the non-melancholic patients, but these differences could be accounted for by the severity of the illness. Global intellectual functioning was negatively correlated with mean baseline plasma concentrations of cortisol. Patients with high mean plasma vasopressin concentrations remembered more auditory presented words in the delayed recall test and produced more intrusions in the visual word learning list than did patients with low or normal mean plasma vasopressin concentrations. No association was found between neuropsychological performance and plasma concentrations of oxytocin.

Conclusions. Our findings support the hypothesis that elevated baseline plasma cortisol concentrations are related to cognitive impairment in depressed patients and the hypothesis that the neuropeptide vasopressin independently enhances memory, directly or indirectly through increasing arousal and attention.

Background. Opioidergic pathways have an inhibitory regulatory influence on the hypothalamic–pituitary–adrenal axis (HPA) in man. Previous studies have suggested impairment of pituitary–adrenal activation in chronic fatigue syndrome (CFS). We, therefore, decided to investigate the extent of opioid inhibition of HPA activity in CFS as a possible explanation for the reputed HPA hypofunctioning in patients with CFS.

Method. Thirteen patients with CFS, diagnosed according to CDC criteria, were compared with thirteen healthy subjects. Adrenocorticotropin (ACTH) and cortisol (CORT) responses were measured following the administration of the opiate antagonist naloxone.

Results. Baseline ACTH and cortisol levels did not differ between the two groups. The release of ACTH (but not cortisol) was significantly blunted in the CFS subjects compared with controls.

Conclusions. Naloxone mediated activation of the HPA is attenuated in CFS. Excessive opioid inhibition of the HPA is thus an unlikely explanation for the HPA dysregulation in this disorder.

Background. Sumatriptan, a specific agonist at 5-HT1D receptors, stimulates release of growth hormone (GH) and inhibits release of prolactin (PRL).

Methods. We gave sumatriptan (6 mg subcutaneously) to 11 patients with unipolar major depression and 11 control subjects matched for age, sex, weight and menstrual cycle phase. Serum GH and PRL were measured at 0, 15, 30, 45, 60 and 90 min after injection.

Results. The maximal rise in GH was significantly reduced in the depressed patients, with 60% showing no increase over baseline compared with 18% of controls. There were no significant differences in PRL responses.

Conclusions. These results suggest reduced sensitivity of 5-HT1D receptors in major depression. Our results and those of studies investigating 5-HT1A receptors imply that both 5-HT1A and 5-HT1D autoreceptors may show reduced function in major depression.

Background. Significant alterations in total serum protein (TSP) patterns obtained in serum protein electrophoresis and serum proteins have been reported in patients with major depression and in subjects submitted to a combination of psychological and physical stress. The aim of the present study was to examine the effects of academic examination stress, on TSP and patterns obtained in serum protein electrophoresis.

Methods. TSP and the concentrations and percentages of the major electrophoretically separated serum proteins were measured in 41 healthy biomedical students the day before a difficult academic examination (i.e. the stressful condition), as well as a few weeks before and after the stressful condition (i.e. two baseline conditions).

Results. Academic examination stress increased TSP and the α1, α2, β and γ concentrations in stress-reactors, but not in stress non-reactors (as defined by changes in the Perceived Stress Scale). Academic examination stress reduced the percentage of albumin in the stress-reactors, but not in stress non-reactors. There were significant positive relationships between the stress-induced changes in TSP and serum α2, β and γ concentrations and the stress-induced changes in the Perceived Stress Scale.

Conclusions. The results show that even mild psychological stress of short duration can lead to measurable changes in TSP and in patterns obtained in serum protein electrophoresis.

Background. Cortisol non-suppression following the dexamethasone suppression test (DST) has been found to a variable extent in schizophrenia. The aetiology is unclear but may be related to depression or negative symptoms.

Methods. The DST was administered to 64 patients with DSM-IV schizophrenia. All patients were screened for DSM-IV major depression and rated on the Hamilton Rating Scale for Depression (HRSD), Scale for Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS).

Results. DSM-IV criteria for major depression was fulfilled by 36% of the patients and 42% of patients had a history of parasuicide. Four patients had undetectable levels of dexamethasone and were excluded from the endocrine analyses. Only one remaining patient had a cortisol level above the cut-off point (>138 nmol/l), indicating escape from dexamethasone suppression. The post-dexamethasone cortisol level correlated significantly with HRSD and BPRS scores but not with the SANS. The SANS and HRSD scores were not correlated, but they were independently correlated with the BPRS score.

Conclusions. In contrast to some other work, rates of dexamethasone non-suppression were very low; together with the high rates of depression, this suggests that depression in schizophrenia may have a different neuroendocrine profile from major depressive disorders. Failure to measure dexamethasone levels can be misleading.

Background. This two-stage prevalence survey involved geographically delimited areas, four urban (Liverpool, Newcastle, Nottingham and Oxford) and two rural (Cambridgeshire and Gwynedd), including institutions.

Methods. Stratified random population samples of people in their 65th year and above, from Family Health Service Authorities were studied. The sample was stratified (65–74 years and [ges ]75) to provide equal numbers. In Liverpool equal numbers in 5 year age groups were taken. After an initial screening interview, approximately 20% were selected on the basis of age, AGECAT organicity confidence level and MMSE score to proceed to a detailed assessment interview from which the full AGECAT organicity confidence level could be derived.

Results. Major influences on MMSE were confirmed as age, sex, social class and educational level. Estimates of prevalence of AGECAT O3 and above for each centre and the entire sample according to age are given, based on 1991 Census population structure, and suggest that around half a million (543400) people in England and Wales would be defined as case level by this method. The five centres employing the same methodology showed no heterogeneity in prevalence.

Conclusions. Prevalence of cognitive impairment and dementia appear not to vary widely across the centres examined in this study, which provides stable estimates by age and sex for AGECAT O3 and above, and norms for MMSE. Using these estimates as an indication of the size of the population affected, around 550000 individuals in England and Wales would be expected to be suffering from dementia of mild or greater severity.

Background. Population-based studies suggest substantial co-morbidity between physical illness and depression in late-life. However, a causal relationship has not been established. If a relationship exists, it is important to establish which aspects of poor health determine risk for depression, and which factors confer vulnerability or resilience in the face of poor health. We investigate the role of disablement, measured as impairment, disability and handicap.

Methods. A prospective population-based cohort study, comprising an index assessment and 1 year follow-up, of all residents aged 65 years or over, of an electoral ward in London, UK (N=889).

Results. The prevalence of SHORT-CARE pervasive depression was 17·7% at index assessment. The 1 year onset rate for pervasive depression was 12·0%, and the 1 year maintenance rate 63·2%. There was a high mortality rate among the depressed. Disablement, particularly handicap was the most important predictor of the onset of depression (population attributable fraction, 0·69). Lack of contact with friends was a direct risk factor but also modified the association between handicap and depression. Marriage was protective for men, but a risk factor for women. Maintenance of depression was predicted by low levels of social support and social participation, rather than by disablement.

Conclusions. It seems likely that disablement, specifically handicap, is the chief cause of onsets of depression in late-life. Genetic predisposition, early adversity and serious life events may play a less prominent role than in earlier life. Effective prevention of late-life depression requires attention at the structural level to the sources of handicap within communities.

Background. The heterogeneity of schizophrenic and delusional syndromes by age of onset has frequently been discussed.

Methods. The age distribution of symptoms and 5 year course was studied in a population-based first-episode sample admitted to 10 psychiatric hospitals before the age of 60 (N=232) and in a clinical sample without age limit of consecutive first admissions to a single hospital (N=1109), both samples with broadly diagnosed schizophrenia.

Results. Early-onset patients, particularly men, presented more non-specific symptoms and higher PSE-CATEGO total scores than late-onset patients. In men, symptom severity decreased with increasing age of onset. In women, it remained stable except for an increase of negative symptoms with late-onset. Only a few symptoms changed markedly with age: disorganization decreased, while paranoid and systematic delusions increased steeply across the whole age of onset range. Pronounced age- and sex-differences emerged in illness behaviour, socially negative behaviour and substance abuse. Within the group of late-onset psychoses there were continuous transitions in symptom profiles and no discrimination between schizophrenia and paranoid psychosis or late paraphrenia. The main determinant of social course was onset level of social development. Early-onset patients did not improve in social status, while late-onset patients, prior to retirement, suffered considerable decline in social status.

Conclusions. Gender differences in age at onset and in age trends in symptom severity support the hypothesis of a mild protective effect of oestrogen. Social course results from an interplay between biological factors (age at onset and functional impairment) and development factors (level of social development at onset and illness behaviour).

Background. Studies from several countries have shown a decline, in the last few decades, of the number of admissions with a diagnosis of schizophrenia. This could be due to a fall in the incidence of schizophrenia, but it also could be due to confounding factors. The hypothesis tested in the study is that the incidence of schizophrenia is actually falling because of a decrease in the presence of a seasonal aetiological agent.

Methods. The hypothesis was tested by analysing the dates of birth of the patients discharged with a diagnosis of schizophrenia from NHS hospitals in England and Wales and would be confirmed by an appropriate change in the seasonality of the births over time.

Results. Evidence of seasonality has been observed in the schizophrenic births, but with no significant change over time.

Conclusions. The fall in first admissions with a diagnosis of schizophrenia does not seem to be due to a change in the prevalence of a seasonal aetiological factor. Therefore, either there has been a reduction in incidence due to a change in a non-seasonal agent, or the incidence of schizophrenia is not changing and the fall in first admissions is due to confounding factors.

Background. Within the framework of developmental psychopathology the outcome of male former child and adolescent psychiatric patients at age 36 or 38 was studied in order to add to the limited knowledge in this field.

Methods. A total of 269 former child psychiatric patients of male sex and a control group of more than 2700 men, who were all born in 1952, were compared with regard to mortality, delinquency and adult psychiatric disorders. The study was based on case-file data from assessments conducted with the child and adolescent psychiatric patients and on adults, derived from either federal registers (mortality, delinquency) or army health records and records of the psychiatric facilities of the canton. The study is based on lifetime prevalence rates.

Results. The two samples did not differ with regard to mortality rates. Delinquency tended to be more prevalent and psychiatric disorders were significantly more prevalent among the former child psychiatric patients. Close to 10% of the latter group showed major delinquency, one-quarter was psychiatrically disturbed and 30% displayed one of these two indicators or maladjustment at least once during the follow-up period. A correspondence in pattern of varying between child and adult psychiatric spectrum disorders was observed. Whereas the type of child and adolescent psychiatric disorders did not predict adult maladjustment, there was some indication that deprived environments, broken homes and parental psychiatric disorders during childhood increased the likelihood of poor adult outcome.

Conclusions. This study clearly underlines the long-term negative effects of child and adolescent mental abnormalities in males.

Background. The liability to autism confers a risk for a range of more subtle autistic-like impairments, but it remains unclear whether it also confers a risk for other psychiatric disturbances.

Methods. To investigate this, we studied the pattern of familial aggregation of psychiatric disorders in relatives of 99 autistic and 36 Down's probands, using family history and direct interview measures.

Results. Family history data showed that motor tics, obsessive–compulsive (OCD) and affective disorders were significantly more common in relatives of autistic probands and that individuals with OCD were more likely to exhibit autistic-like social and communication impairments. Direct interview data confirmed the increased rate of affective disorders (especially major depressive disorder) in the first-degree relatives. There was no evidence to indicate significant co-morbidity between affective disorders and the broadly defined phenotype of autism. Moreover, the characteristics of the probands' and the relatives' that were associated with the liability to familiality of the broader phenotype of autism differed from those that predicted the liability to the familiality of affective disorders. Examination of the onset of affective disorders suggested that the increased risk was not confined to the period following the birth of the child with autism.

Conclusions. Overall, the results indicated that OCD, but not affective disorders, may index an underlying liability to autism. They also indicated that the increased risk of affective disorders was not solely the consequence of the stress of raising a child with autism and that further research will be required to clarify the mechanisms involved.

Background. A cardinal feature of schizophrenia is the sufferer's difficulty in interacting appropriately within the social milieu. This deficit has recently been associated with the concept of theory of mind, more commonly construed as a working model to understand behavioural patterns in autistic children. In this paper the complex relationships between theory of mind, IQ and psychoses are addressed.

Methods. Five experimental groups were used; non-psychiatric controls, affective disorder, schizophrenia with normal pre-morbid IQ, schizophrenia with pre-morbid IQ in the mildly learning disabled range, and mild learning disability with no history of psychiatric illness. All subjects were given a first order Theory of Mind Task and if successful, a second order Theory of Mind Task was then administered. All subjects were rated using the Positive and Negative Symptom Scale (PANSS).

Results. Subjects with schizophrenia and subjects with mild learning disability show impaired ability on a second order theory of mind task. However, when patients who are unable to answer reality questions are removed from the analysis specific impairment of theory of mind is only seen in subjects with schizophrenia. Furthermore, this impairment is relatively specific to particular psychopathological clusters in subjects with schizophrenia. Even though the same clusters of psychopathology are also seen in patients with affective disorder, their presence is not associated with poor second order theory of mind performance.

Conclusions. Impaired theory of mind on second order tests is specific to schizophrenia when compared to mild learning disability and affective disorder control groups. Subjects with schizophrenia and pre-morbid mild learning disability show greater impairment than subjects with schizophrenia and a pre-morbid IQ within the normal range.

Background. Children with asthma are vulnerable to negative emotions, but clinical observations and research suggest that negative emotions can also be precipitants of asthma attacks. Empirical data provided mixed results. The hypothesis was tested that negative emotions influence subjective rather than objective symptoms of asthma, breathlessness and airways obstruction, respectively.

Methods. Forty asthmatic children (aged 7 to 18 years) were randomly assigned to one of four experimental conditions: 1, viewing an emotional film of 10 min; 2, performing standardized physical exercise of modest intensity up to a heartbeat of 170 b/min; 3, combination of conditions, order conditions, 1+2; and 4, combination of conditions, order conditions 2+1. Lung function, breathlessness and state anxiety were measured pre-test and post-test. Respiration sounds were recorded continuously for assessment of emotional breathing patterns.

Results. The data and responses to exit questions, confirmed a successful induction of anxiety via increased state anxiety and respiratory rate. Viewing the emotional film did not by itself enhance airways obstruction or breathlessness. Airways obstruction and breathlessness increased significantly after exercise only. Significantly more breathlessness was reported when negative emotions preceded exercise. Breathlessness was statistically independent of lung function, severity of asthma, symptoms in the past 4 weeks, anxiety or age.

Conclusion. Negative emotions affect subjective, rather than objective symptoms of childhood asthma. It was suggested that children in a negative emotional state, uncertain about the condition of their airways, are inclined to interpret exercise-related general sensations (fatigue, heart pounding, sighing) in line with expectations as symptoms of airways obstruction. Consequently, they may report relatively high breathlessness, irrespective of actual objective symptoms of asthma.

Background. Despite a growing literature pointing to the deleterious health effects of sexual and physical abuse history, few studies provide evidence about which medical symptoms are most affected. The aim of this paper is to determine the impact of sexual and physical abuse history on a selected set of medical symptoms, and to test how such abuse, medical symptoms and functional disability may affect subsequent health care visits.

Methods. We studied 239 women from a referral-based gastroenterology clinic; follow-up data were available on 196 of these women. All women were interviewed about sexual and physical abuse history.

Results. Women with abuse history, particularly those with severe abuse, were much more likely to report somatic symptoms related to panic (e.g. palpitations, numbness, shortness of breath), depression (e.g. difficulty sleeping, loss of appetite), musculoskeletal disorders (e.g. headaches, muscle aches), genito-urinary disorders (e.g. vaginal discharge, pelvic pain, painful intercourse), skin disturbance (e.g. rash) and respiratory illness (e.g. stuffy nose). Furthermore, we found that the severity of abuse history, somatic symptoms and functional disability predicted 30% of the variance in health care visits during the subsequent year, and that the effect of abuse severity on visits was explained by abused women having more somatic symptoms and functional disability.

Conclusions. Patients' reports of abuse history, somatic symptoms and functional disability appear to be important factors in explaining the number of health care visits among a clinic sample of women with gastrointestinal disorders.

Background. The gatekeeper function of the general practitioner (GP) in the pathway to specialized psychiatric services was investigated in this study, which is part of the Nordic Comparative Study on Sectorized Psychiatry. The question addressed in this paper is whether different sociodemographic and clinical factors as well as factors related to service utilization are associated with referral from the GP compared with self-referrals (including referrals from relatives).

Methods. The study comprised a total of 1413 consecutive patients, admitted during 1 year to five psychiatric centres in four Nordic countries. The centres included in this study were those that accepted non-medical referrals. Only new patients (not in contact with the service for at least 18 months) were included.

Results. Increasing age was the only sociodemographic factor significantly associated with referral by the GP. The clinical factors (psychosis, being totally new to psychiatry and being in need of in-patient treatment) and some treatment characteristics (planned out-patient treatment and involuntary in-patient treatment), were all significantly associated with referral by the GP. Some indication was found that self-referred patients have shorter episodes of care.

Conclusions. The findings were remarkably stable across the different centres indicating a general pattern. This study extends previous work on the role of GPs in the pathway to specialized psychiatric services and indicates that the GP has an important gatekeeper function for the most disabled patients.

Background. Research on the subject of insight has been hampered by difficulties in definition and reliable measurement.

Methods. We compared several rating scales to measure insight on a group of 33 psychotic patients as well as assessing patients' psychopathology, clinical characteristics and cognitive functioning.

Results. Most currently used scales showed a high degree of inter-correlation. Measures of insight related strongly to the presence of delusions; grandiosity (inversely), and depression (positively). Higher insight scores correlated with indices of treatment compliance and inversely with substance abuse. Measures of pre-morbid IQ and impaired executive functioning, including the Wisconsin Card Sorting Test were not associated with poor insight.

Conclusions. The study highlights aspects of psychopathology and clinical variables particularly related to insight and supports the continued use of standardized scales in further research in this area.

Background. The validity of the concept of seasonal affective disorder and the causal link to lack of daylight in winter is controversial. There is a need for investigations in large samples of the general population at different latitudes and within general research contexts to avoid selective response bias and sensitization of the population.

Methods. During a study of health effects of the air pollution from Russia in a small community at 70° north, a self-administered questionnaire was filled in by 3736 inhabitants, 60·8% of the total population between 18 and 69 years. Three questions concerned depression, sleeping problems and other problems related to the two contrasting seasons with regard to daylight.

Results. Twenty-seven per cent reported to have some kind of problem in the dark period. Most frequently reported were sleeping problems during winter, in 19·9% of women and 11·2% of men. Self-reported depression in winter was found in 11·1% of women and 4·8%% of men. Sleeping problems increased with age, while depression was most often reported by middle-aged people. The only other reported problem in winter was fatigue. The adjusted relative risk (RR) for winter depression in women compared to men was 2·5 (95% confidence interval: 1·9–3·2). Very few had problems in summer.

Conclusions. In the high north, one-third of the women and one-fifth of the men experience problems with sleep, mood or energy related to season. The prevalence of self-reported depression was surprisingly low in winter considering the lack of daylight.