This issue features groups of papers on genetics, long-term outcome of depression, fatigue syndromes and somatization, and the neuropsychology of schizophrenia, autism and obsessive–compulsive disorder.

The two paradigms that now dominate the increasingly active field of psychiatric genetics – genetic epidemiology and gene-finding methods – are well illustrated by five papers in this issue of Psychological Medicine. Genetic epidemiology, which uses the classical ‘work-horse’ methods of family, twin and adoption studies, infers the action of genetic and environmental risk factors by observing the pattern of resemblance of traits or disorders in various classes of relatives. Methods that are utilized in genetic epidemiology can range from great simplicity, such as the odds ratio of a disorder in first-degree relatives of affected versus matched control probands, to substantial complexity, as seen in some advanced multivariate twin-family models (Truett et al. 1994). Of the quasi-experimental methods available to psychiatric geneticists that can tease apart the effects of genetic and shared-environmental factors (nature versus nurture), the twin method has become increasingly popular. This is probably due to the increasing availability of large population-based or volunteer twin registries (see the Oct 2002 issue of Twin Research on ‘Twin Registers as a Global Resource for Genetic Research’) that can be utilized to study psychiatric and drug abuse disorders. By contrast, due to changing social circumstances in most Western countries, adoption, even in the Scandinavian countries where most of the classic studies have been done, is becoming so rare that new adoption studies with younger age cohorts are hardly feasible. By contrast, gene-finding methods, which utilized variants of two different methods of linkage or association, have the goal of determining, on the human genome, the location and potential identity of susceptibility genes.

Well conducted investigations into the long-term outcome of depressive disorders are rare. This issue of Psychological Medicine publishes two important papers reporting on different cohorts of depressed patients, one series from Japan (Kanai et al. 2003) and the other from Cambridge UK (Kennedy et al. 2003). Both were ascertained in the early 1990s and have been followed for 5–6 and 8–10 years respectively. Each study demonstrates methodological advances. Both invite comparison with previous reports of the long-term outcome of depression whose follow-up periods span the last 40 years. Is the outcome of depressive disorders at last improving in the era of modern treatments? Is this merely an artefact of better research methods, or does it also reflect therapeutic advances? If there has been very little improvement in some aspects of outcome, what lessons can we learn for future research and practice development?

Background. There is a heritable component to suicidal behaviour, encouraging the search for the associated risk alleles. Given the putative role of the 5-HT (5-hydroxytryptamine; serotonin) system in suicidal behaviour, serotonergic genes are leading candidates. In particular, several studies have reported an association with variants in the tryptophan hydroxylase (TPH) gene.

Method. We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects. The polymorphisms were TPH (A779C), 5-HT transporter (5-HTT, LPR S/L), monoamine oxidase A (MAOA G941T), 5-HT1B receptor (HTR1B G861C), 5-HT2A receptor (HTR2A T102C), and 5-HT2C receptor (HTR2C Cys23Ser). Genotyping was done using polymerase chain reaction (PCR)-based assays. The primary analyses compared allele and genotype frequencies between cases and controls. There were a limited number of planned secondary analyses within the deliberate self-harm group.

Results. The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1·38, 95% CI 1·02–1·88; P=0·03). None of the other polymorphisms was associated with deliberate self-harm. Within the deliberate self-harm group there were no associations with impulsivity, suicide risk, lifetime history of depression, or family history of deliberate self-harm.

Conclusions. Our data extend the evidence that allelic variation in the TPH gene is a risk factor for deliberate self-harm. No evidence was found to implicate the other polymorphisms.

Background. Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case–control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD.

Method. One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets.

Results. No association between 5-HTTLPR and SAD was found in the new case–control material, in the combined analysis of all samples, or when only including 316 patients with controls (N=298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2·24 (1·03–4·91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set.

Conclusions. These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.

Background. The General Health Questionnaire (GHQ) is the most popular screening instrument for detecting psychiatric disorders in community samples. Using longitudinal data of a large sample of UK twin pairs, we explored (i) heritabilities of the four scales and the total score; (ii) the genetic stability over time; and (iii) the existence of differential heritable influences at the high (ill) and low (healthy) tail of the distribution.

Method. At baseline we assessed the GHQ in 627 MZ and 1323 DZ female pairs and at a second occasion (3·5 years later) for a small subsample (90 MZ and 270 DZ pairs). Liability threshold models and raw ordinal maximum likelihood were used to estimate twin correlations and to fit longitudinal genetic models. We estimated extreme group heritabilities of the GHQ distribution by using a model-fitting implementation of the DeFries–Fulker regression method for selected twin data.

Results. Heritabilities for Somatic Symptoms, Anxiety, Social Dysfunction, Depression and total score were 0·37, 0·40, 0·20, 0·42 and 0·44, respectively. The contribution of shared genetic factors to the correlations between time points is substantial for the total score (73%). Group heritabilities of 0·48 and 0·43 were estimated for the top and bottom 10% of the total GHQ score distribution, respectively.

Conclusion. The overall heritability of the GHQ as a measure of psychosocial distress was substantial (44%), with all scales having significant additive genetic influences that persisted across time periods. Extreme group analyses suggest that the genetic control of resilience is as important as the genetic control of vulnerability.

Background. Previous twin studies investigating the heritability of schizotypy have often had limited power and have failed to measure the disorganization/social anxiety component.

Method. Seven hundred and thirty-three female twin pairs, drawn from the Institute of Psychiatry Volunteer Twin Register, completed the Oxford–Liverpool Inventory of Feelings and Experiences and the Peters et al. Delusions Inventory. Structural equation modelling was carried out on scores for MZ and DZ twin pairs.

Results. The best fitting models for all scales comprised additive genetic and unique environmental effects. Heritability was estimated at approximately 50% for most scales, although it was lower at 37% for the PDI scale. Multivariate structural equation model fitting revealed a best-fitting model in which additive genetic and unique environmental influences act through a single common pathway for Cognitive Disorganization, Unusual Experiences and the PDI, and through a separate common pathway for Cognitive Disorganization and Introvertive Anhedonia.

Conclusions. The various components of schizotypy are moderately heritable. Multivariate model fitting indicates that at least two latent factor structures are required to account for the covariation between the various components of schizotypy. The positive and negative components of schizotypy are relatively genetically independent, although each in turn may be related to Cognitive Disorganization.

Background. While the family environment can directly influence later risk for psychopathology, dysfunction in the family of origin may also moderate the impact of genetic factors on liability for psychiatric disorders. Can a similar pattern be seen for the personality trait of Neuroticism (N) – which is a risk factor for many psychiatric conditions?

Method. Our sample of 957 complete female–female twin pairs from a population-based register had measures of self-reported N and multiple reporters (twin, co-twin, mother, father) for family dysfunction (FD). Statistical analysis was conducted by traditional regression analysis and a moderator structural equation twin model operationalized in the computer program Mx.

Results. Dividing the sample into quartiles based on increasing levels of FD, the mean of N increased substantially while correlations of N in monozygotic (MZ) and dizygotic (DZ) twins were relatively constant. Regression analyses did not suggest greater twin resemblance for N with increasing levels of FD. The best-fit structural equation model was the standard un-moderated model in which the proportion of variance in N due to genetic (39%) and unique environmental effects (61%) remained constant across values of FD.

Conclusions. Although a false-negative result due to limited power cannot be excluded, these analyses do not support the hypothesis that FD moderates the impact of genetic factors on levels of N.

Background. Long-term studies of severe depression have described high rates of non-recovery, recurrence, chronic incapacity and mortality. A more recent cohort was followed-up to ascertain whether the course had improved given developments in pharmacological and psychological treatments in the last 15 years.

Method. Subjects from a cohort of 70 mainly severe recurrent depressives originally recruited to a shorter follow-up study from 1990–1992 were followed-up after 8–11 years. Data included longitudinal information on course of depression and other psychiatric disorders, pharmacological and psychological treatment and social functioning during follow-up.

Results. Sixty-nine (99%) subjects were successfully followed-up, with 61 of 66 living subjects interviewed and detailed follow-up data obtained in total on 65. Sixty (92%) of 65 subjects recovered during follow-up, with two-thirds subsequently suffering a recurrence. Eleven (17%) suffered from an episode of chronic depression of at least 2 years duration during follow-up. Social function at follow-up was good and there were high levels of pharmacological and psychological treatment. Greater severity of illness was the most consistent predictor of poor outcome. Times to recovery and recurrence and recovery and recurrence rates were very similar to older studies.

Conclusions. The long-term outcome of depression still shows high recurrence rates and does not appear to have changed in the last 20 years.

Background. Depression is a remitting but recurring disease. However, there is a paucity of prospectively recorded data on the course of depression after recovery.

Method. A multi-centre prospective serial follow-up study of an inception cohort of hitherto untreated unipolar major depression (N=95) for 6 years. We report the time to recurrence after recovery from the index depressive episode and their predictors.

Results. The cumulative probability of remaining well without subthreshold symptoms was 57% (95% CI, 46 to 68%) at 1 year, 47% (95% CI, 36 to 58%) at 2 years and 35% (95% CI, 23 to 47%) at 5 years. The same without full relapse was 79% (95% CI, 70 to 88%) at 1 year, 70% (95% CI, 60 to 80%) at 2 years and 58% (95% CI, 46 to 70%) at 5 years. The median duration of well-interval from the end of the index episode to the beginning of the subthreshold episode was 19·0 months (95% CI, 2·4 to 35·7), and that to the end of the full episode was over 6 years. Residual symptoms at time of recovery predicted earlier recurrence.

Conclusions. The median length of the well-interval was much longer than previously reported in studies employing similar definitions but dealing with a more severe spectrum of patients. However, the sobering fact remains that less than half of the patients can expect to remain virtually symptom-free for 2 years or more after recovery from the depressive episode.

Background. Infectious mononucleosis (IM) is a risk factor for chronic fatigue. Reduced activity is the most consistent factor found to be associated with poor outcome following the onset of infectious mononucleosis. However, little is known about the biological mechanisms involved in the pathogenesis of chronic fatigue following IM and no study, so far, has examined the relation between certain illness beliefs and poor outcome. This study explored immunological, endocrine, behavioural and cognitive responses to the acute illness and assessed which components of these groups of risk factors predicted a chronic course.

Method. Using a prospective cohort design, 71 primary care patients with IM were enrolled onto the study and interviewed. Their recovery was explored by postal questionnaire up to 1 year later.

Results. In the univariate analysis, increased baseline levels of immune activation were associated with fatigue at baseline and 3 months. Cortisol levels were not associated with fatigue at any point. Using multivariate models of clinical and psychosocial baseline factors, severity of symptoms and illness perceptions were found to predict fatigue 3 months later. At 6 months, fatigue was best predicted by female gender and illness perceptions, and at 12 months by female gender and a symptoms–disability factor.

Conclusions. In the multivariate analysis no factors were found to predict poor outcome at all time-points. Instead the pattern of predictors changed over time, partly but not completely consistent with our a priori predictions. Larger studies are needed to explore further the predictive nature of biopsychosocial factors in the pathogenesis of chronic fatigue related to IM. The psycho-behavioural predictors found in this study are amenable to intervention. Such interventions should be tested in randomized controlled trials.

Background. Outcome studies of chronic fatigue, neurasthenia and other unexplained fatigue syndromes are few and have been carried out in developed Western countries. This paper aimed to study the outcome of unexplained fatigue syndromes in an international primary care sample and to identify risk factors for persistence.

Method. We used data from the WHO collaborative study of psychological problems in general health care, in which 3201 primary care attenders from 14 countries were followed-up for 12 months. The assessment included a modified version of the Composite International Diagnostic Interview.

Results. Unexplained fatigue persisted in one-fifth to one-third of the subjects depending on the definition of fatigue. From the factors studied only severity of fatigue and psychiatric morbidity at baseline were associated with persistence 12 months later. Outcome did not differ between countries of different stages of economic development.

Conclusions. The prognosis of fatigue syndromes in international primary care is relatively good. The study underlines the importance of psychological factors in influencing short-term prognosis.

Background. The importance of somatization among older primary care attenders is unclear. We aimed to establish the prevalence, persistence and associations of somatization among older primary care attenders, and the associations of frequent attendance.

Method. One hundred and forty primary care attenders over 65 years were rated twice, 10 months apart, on measures of somatization, psychiatric status, physical health and attendance.

Results. The syndrome of GMS hypochondriacal neurosis had a prevalence of 5% but was transient. Somatized symptoms and attributions were persistent and associated with depression, physical illness and perceived poor social support. Frequent attenders (top third) had higher rates of depression, physical illness and somatic symptoms, and lower perceived support.

Conclusion. Somatization is common among older primary care attenders and has similar correlates to younger primary care somatizers. Psychological distress among older primary care attenders is associated with frequent attendance. Improved recognition should result in benefits to patients and services.

Objective. The study was designed to determine the association between self-reported asthma and the risk, persistence and severity of panic attacks among adults in the community.

Method. Data were drawn from waves 1 and 2 of the Baltimore site of the Epidemiologic Catchment Area (ECA) Study (N=2768), which included self-report information on asthma, treatment for asthma and panic attacks in 1981 and 1982. Multiple logistic regression analyses were used to calculate odds ratios comparing the prevalence of panic attack at baseline and follow-up by asthma status at baseline. Linear regression analyses were used to examine the relationship between self-reported asthma status and the number of panic symptoms during a panic attack.

Results. Self-report asthma was associated with significantly increased likelihood of having panic attacks at baseline (1981) (12·1% v. 7·3%, P<0·05) and of having panic attacks at both baseline and follow-up (15·9% v. 7·3%, P<0·05), compared to those without asthma at baseline. Adults receiving treatment for asthma at baseline had an increased risk of incident panic attacks at follow-up (OR=2·65 (1·11, 6·34)) and at baseline and follow-up (OR=5.88 (2·21, 15.62)), though untreated asthma did not appear to increase risk of incident panic at follow-up. Similarly, the risk of panic at follow-up was not increased among those with asthma at baseline who did not report asthma at follow-up, compared with those without asthma at baseline. Treated asthma was associated with having more panic symptoms during panic attacks, compared to those without asthma (P<0·001).

Conclusion. These findings are consistent with and extend previous results suggesting that self-reported asthma is associated with an increased risk of panic attacks among adults in the general population, and that there is a consistent relation between severity and persistence of asthma and panic attacks. The lack of association between remitted asthma and panic attack may reveal a need for further research to determine whether asthma may be a causal risk factor for panic attacks, or whether a third factor (genetic or environmental) may be associated with increased risk of the co-occurrence of asthma and panic attacks. Replication of these results using alternative methodology with corroborative data on asthma and panic attacks is needed next.

Background. Visual masking tasks assess the earliest stages of visual processing. This study was conducted to address: (1) whether schizophrenia patients show masking deficits after controlling for sensory input factors; (2) whether patients have relatively intact forward masking (when the mask precedes the target) compared with backward masking (when the mask follows the target); and (3) whether the masking deficits in schizophrenia reflect an accelerated age-related decline in performance.

Method. A staircase method was used to ensure that the unmasked target identification was equivalent across subjects to eliminate any confounding due to differences in discrimination of simple perceptual inputs. Three computerized visual masking tasks were administered to 120 schizophrenia patients (ages 18–56) and 55 normal comparison subjects (ages 19–54) under both forward and backward masking conditions. The tasks included: (1) locating a target; (2) identifying a target with a high-energy mask; and (3) identifying a target with a low-energy mask.

Results. Patients showed deficits across all three masking tasks. Interactions of group by forward versus backward masking were not significant, suggesting that deficits in forward and backward masking were comparable. All three conditions showed an age-related decline in performance and rates of decline were comparable between patients and controls. Two of the masking conditions showed increased rates of decline in backward, compared to forward, masking.

Conclusions. We found age-related decline in performance that was comparable for the two groups. In addition, we failed to find evidence of a relative sparing of forward masking in schizophrenia. These results suggest that: (1) early visual processing deficits in schizophrenia are not due to a simple perceptual input problem; (2) sustained channels are involved in the masking deficit (in addition to transient channels); and (3) for the age range in this study, these deficits in schizophrenia are not age-related.

Background. It has been proposed that inferences about the mental states of others are drawn after a referral to autobiographical memory. This study explored the relationship between autobiographical memory retrieval and performance on tests of theory of mind in people with schizophrenia.

Method. Fifty-nine people with a DSM-IV diagnosis of schizophrenia and 44 healthy participants matched for age, sex and estimated IQ were given the Autobiographical Memory Interview (AMI), two measures of theory of mind (ToM) and a logical memory test.

Results. There was clear evidence that the people with schizophrenia were under-performing on all tasks. Within the schizophrenia sample, robust relationships existed between the total scores achieved on the AMI and the ToM tasks. Furthermore, there was evidence that the participants with schizophrenia had a tendency to recollect odd or negative events when prompted by the standard questions of the AMI.

Conclusions. The results of this study indicate that when people with schizophrenia attempt to think about the beliefs and intentions of others they use analogical reasoning. Whether this approach is also adopted by other clinical and normal adult groups is a question for future research.

Background. Autism and schizophrenia are considered to be substantially influenced by genetic factors. The endophenotype of both disorders probably also includes deficits in affect perception. The objective of this study was to examine the capacity to detect facially expressed emotion in autistic and schizophrenic subjects, their parents and siblings.

Method. Thirty-five subjects with autism and 102 of their relatives, 21 schizophrenic subjects and 46 relatives from simplex (one child affected) and multiplex (more than one child affected) families, as well as an unaffected control sample consisting of 22 probands completed a 50-item computer-based test to assess the ability to recognize basic emotions.

Results. The autistic subjects showed a poorer performance on the facial recognition test than did the schizophrenic and the unaffected individuals. In addition, there was a tendency for subjects from multiplex families with autistic loading to score lower on the test than individuals from simplex families with autistic loading. Schizophrenic subjects and their relatives as well as siblings and parents of autistic subjects did not differ from the sample of unaffected subjects in their ability to judge facial affect.

Conclusions. Findings corroborate the assumption that emotion detection deficits are part of the endophenotype of autism. In families with autistic children, the extent of facial recognition deficits probably indexes an elevation in familial burden. It seems unlikely that problems in emotion perception form a consistent part of the endophenotype of schizophrenia or the broader phenotype in relatives of patients with psychosis or autism.

Background. There is an ongoing debate about the nature of executive dysfunction that accompanies obsessive–compulsive disorder (OCD). One reason for this may be that state-related factors, such as use of medication or co-morbid symptoms, confound with task performance. This study tried to isolate trait- from state-dependent cognitive impairments by examining variability of cognition following treatment.

Method. Nineteen OCD patients were tested on the Cambridge Neuropsychological Test Automated Battery (CANTAB) before and after treatment with fluoxetine. Their pattern of performance was compared to the one observed in healthy volunteers (N=24).

Results. OCD patients displayed impairments in planning ability, spatial memory and motor speed that persisted after clinical improvement. With treatment, OCD performance diverged from that of controls on measures of focused attention and strategic ability. However, these effects were rather mild as they did not entail a significant deterioration of performance within the OCD sample.

Conclusions. Our data suggest that cognitive impairments in OCD are not secondary to symptoms and therefore form a trait feature of the disorder. The nature of the deficits refers to a chronic dysfunction of the dorsolateral–striatal circuit. The minor effects of treatment on task performance is in line with recent evidence that serotonin mediates cognitive functions of orbitofrontal cortex to a greater extent than those associated with dorsolateral prefrontal regions.

Background. Although prior research has demonstrated a strong association between interpersonal dependency (IPD) levels and risk for major depression (MD), the possible aetiological explanations of this association as well as any gender differences in the IPD–MD relationship need further clarification.

Method. Population-based twin samples (N=7174) were interviewed in multiple waves to assess IPD and MD as part of a larger twin study. IPD levels were assessed using the Interpersonal Dependency Inventory while MD diagnoses were derived from the SCID. Cox proportional hazard models and multiple regression techniques were utilized.

Results. IPD was strongly associated with a risk for lifetime MD. Pre-morbid IPD scores were predictive of future onsets of MD while experiencing a MD episode was also associated with a significant rise in IPD levels. While females had higher IPD scores, IPD scores were more significantly associated with risk for lifetime MD in males. Controlling for the level of IPD substantially reduced the observed association between gender and risk for MD.

Conclusion. The strong association observed between IPD and risk for MD results largely from IPD being a risk factor for MD, but state effects of MD on IPD also contribute. IPD scores in males were more predictive of lifetime MD than for females. The higher levels of IPD in women than in men may contribute meaningfully to the sex differences in risk for MD.

Background. The goal of this study was to determine associations between the age of first menstrual period (menarche) and adverse childhood experiences in a random community sample of New Zealand women. Previous reports have linked early menarche to absence of a live-in father figure and to family conflict, as well as genetic determination of early puberty and adiposity.

Method. Two groups of women randomly selected from the community on their responses to a mailed screening questionnaire on childhood sexual abuse (CSA) were interviewed in detail. Data about their childhood experiences, including age of menarche, were collected on two occasions, 6 years apart. Early menarche was defined as first menstruation occurring before the age of 12 years.

Results. Univariate analyses identified a number of adverse childhood experiences preceded early menarche, which was reported by 20·3% of this sample. These included low family socio-economic status, absence of father, a number of variables showing family conflict, poor relationships between the girl and either/both parents, a self-rated childhood personality style as a loner, childhood physical and sexual abuse. Sequential modelling showed parental rows, being a loner and the duration of CSA to be most important, although lack of a father and any CSA were each also independently associated with early menarche. No variables survived the modelling exercise as predictors of early menarche for those women who did not report childhood sexual abuse.

Conclusions. The identified variables statistically interacted with each other in a highly complex manner. The attempt to rank their importance was only partially successful, for methodological reasons (half the sample reporting CSA). Chronic or protracted CSA needs to be added to the list of factors associated with early menarche in future studies.