Background. Several studies have found an association between indicators of fetal growth and/or obstetric complications and schizophrenia but only a few studies have investigated the possible association between these factors and bipolar disorder. Furthermore, the results of these studies have been contradictory. The aim of this study was to investigate whether the risk of bipolar disorder is associated with exposure to indicators of fetal growth.

Method. A national population nested case-control study based on Danish longitudinal register databases was carried out. Conditional logistic regression was used, controlling for potential confounding factors such as parental age at birth, socio-economic indicators and psychiatric history. We identified 196 cases, and each case was time-, age- and sex-matched with 25 normal population-based controls. All cases were between the ages of 12 and 26 years at the time of diagnosis, were born between 1973 and 1983 and were admitted and diagnosed between 1987 and 1999.

Results. During the study period 1973–1983, none of the individual variables available for analyses (birthweight, birth length, gestational age and number of previous pregnancies in the mother) was associated with receiving a diagnosis of bipolar disorder.

Conclusions. None of the indicators of fetal growth under study could be identified as risk factors for bipolar disorder, suggesting that the etiologies of schizophrenia and bipolar disorder, at least in part, are different.

Background. In this study we examined the prevalence rates of post-traumatic stress disorder (PTSD), types of trauma most often associated with PTSD, the co-morbidity of PTSD with other lifetime psychiatric disorders, which disorders preceded PTSD, and gender differences in PTSD and trauma exposure in a representative sample of Chileans.

Method. The DSM-III-R PTSD and antisocial personality disorder modules from the Diagnostic Interview Schedule (DIS) and modules for a range of DSM-III-R diagnoses from the Composite International Diagnostic Interview (CIDI) were administered to a representative sample of 2390 persons aged 15 to over 64 years in three cities in Chile.

Results. The lifetime prevalence of PTSD was 4·4% (2·5% for men and 6·2% for women). Among persons exposed to trauma, rape was most strongly associated with PTSD. Onset of PTSD significantly increased the risk of developing each of the 10 other tested disorders. Among those exposed to trauma, women were significantly more likely to develop PTSD, after controlling for assaultive violence.

Conclusions. This study highlights the importance of investigating the prevalence of PTSD, patterns of co-morbidity of PTSD, and gender differences in PTSD in non-English-speaking countries.

Background. Social rhythm disruption life events are significant predictors of mood relapse in bipolar patients. However, no research has examined the relationship between these events and their hypothesized mechanism of action: disrupted sleep-wake patterns. The goal of this study was to test whether participants with major depressive disorder have a greater disruption of daily sleep and motor activity following disrupting life events when compared to normal controls.

Method. Over the course of 2 weeks, 39 normal controls and 39 individuals with major depressive disorder completed life events interviews and wore actigraphs to obtain estimates of sleep/wake activity.

Results. Statistically significant interactions indicated that the presence of at least one disrupting life event in the previous 4 months correlated with elevations in the amount of time spent awake after sleep onset [β=0·45, ΔF(1,73)=4·80, p<0·05], and decreases in the percentage of time spent asleep [β=−0·53, ΔF(1,73)=6·57, p<0·05], in depressed individuals but not in normal controls.

Conclusions. The results indicated that depressed individuals may be more susceptible to the effects of life events on sleep than normal controls. This is the first study to date to correlate life events with objective measures of sleep. However, prospective longitudinal research is necessary to clarify the temporal relationship among these variables.

Background. Despite voluminous research on the role of hopelessness and depression in suicidality, a systematic examination of various causal models pertaining to these variables is conspicuous in its absence.

Method. The directions of relationships between the three variables were examined by means of a prospective-longitudinal, cross-lagged, three-wave design in a severely suicidal young adults.

Results. Structural Equation Modeling (SEM) analyses revealed synchronous, but not longitudinal, associations between hopelessness, depressive symptoms, and suicidal ideation.

Conclusions. In severely suicidal young adults, the three clinical constructs appear to constitute a single depressive syndrome.

Background. Assessing illness perceptions has been useful in a range of medical disorders. This study of people with a recent relapse of their psychosis examines the relationship between illness perception, their emotional responses and their attitudes to medication.

Method. One hundred patients diagnosed with a non-affective psychotic disorder were assessed within 3 months of relapse. Measures included insight, self-reported illness perceptions, medication adherence, depression, self-esteem and anxiety.

Results. Illness perceptions about psychosis explained 46, 36 and 34% of the variance in depression, anxiety and self-esteem respectively. However, self-reported medication adherence was more strongly associated with a measure of insight.

Conclusions. Negative illness perceptions in psychosis are clearly related to depression, anxiety and self-esteem. These in turn have been linked to symptom maintenance and recurrence. Clinical interventions that foster appraisals of recovery rather than of chronicity and severity may therefore improve emotional well-being in people with psychosis. It might be better to address adherence to medication through direct attempts at helping them understand their need for treatment.

Background. Implicit learning through motor sequencing tasks is sensitive to basal ganglia dysfunction. Consequently, it is ideally suited for testing elements of the frontostriatal model of major depression and performance can be related to key clinical, neuropsychological, vascular and biochemical data.

Method. Twenty-one subjects with moderate to severe unipolar depression and 21 age-, sex- and education-matched controls were recruited. Clinical, vascular and biochemical data were recorded. Subjects were administered a battery of neuropsychological tests that assessed speed of processing, working memory, learning, memory, language, perceptual organization and executive functioning. Additionally, subjects were administered a motor sequencing implicit learning task. Implicit learning is assumed when reaction times improve during the sequenced condition as compared to the pseudo-random baseline condition.

Results. The rate of implicit learning in persons with depression was only half that of control subjects (3·6% v. 7·3%). Lower rates of implicit learning in patients were associated with poorer performance on neuropsychological tests of visuomotor speed and mental flexibility, longer duration of depressive episode and severity of acute stress. In a small number of subjects, poorer performance was also related to past suicide attempt.

Conclusions. Impaired implicit learning in persons with depression is consistent with frontostriatal dysfunction. Performance is related to some clinical characteristics and to neuropsychological functioning on tests of visuomotor speed and mental flexibility.

Background. Our objective was to estimate the lifetime prevalence of psychopathology in a sample of youth with and without attention deficit hyperactivity disorder (ADHD) through young adulthood using contemporaneous diagnostic and analytic techniques.

Method. We conducted a case-control, 10-year prospective study of ADHD youth. At baseline, we assessed consecutively referred male, Caucasian children with (n=140) and without (n=120) DSM-III-R ADHD, aged 6–18 years, ascertained from psychiatric and pediatric sources to allow for generalizability of results. At the 10-year follow-up, 112 (80%) and 105 (88%) of the ADHD and control children, respectively, were reassessed (mean age 22 years). We created the following categories of psychiatric disorders: Major Psychopathology (mood disorders and psychosis), Anxiety Disorders, Antisocial Disorders (conduct, oppositional-defiant, and antisocial personality disorder), Developmental Disorders (elimination, language, and tics disorder), and Substance Dependence Disorders (alcohol, drug, and nicotine dependence), as measured by blinded structured diagnostic interview.

Results. The lifetime prevalence for all categories of psychopathology were significantly greater in ADHD young adults compared to controls, with hazard ratios and 95% confidence intervals of 6·1 (3·5–10·7), 2·2 (1·5–3·2), 5·9 (3·9–8·8), 2·5 (1·7–3·6), and 2·0 (1·3–3·0), respectively, for the categories described above.

Conclusions. By their young adult years, ADHD youth were at high risk for a wide range of adverse psychiatric outcomes including markedly elevated rates of antisocial, addictive, mood and anxiety disorders. These prospective findings provide further evidence for the high morbidity associated with ADHD across the life-cycle and stress the importance of early recognition of this disorder for prevention and intervention strategies.

Background. Theory of Mind (ToM) refers to the ability to infer another person's mental state based upon interactional information. ToM deficits have been suggested to underlie crucial aspects of social interaction failure in disorders such as autism and schizophrenia, although the development of paradigms for demonstrating such deficits remains an ongoing area of research. Recent studies have explored the use of sarcasm perception, in which subjects must infer an individual's sincerity or lack thereof, as a ‘real-life’ index of ToM ability, and as an index of functioning of specific right hemispheric structures. Sarcastic detection ability has not previously been studied in schizophrenia, although patients have been shown to have deficits in ability to decode emotional information from speech (‘affective prosody’).

Method. Twenty-two schizophrenia patients and 17 control subjects were tested on their ability to detect sarcasm from spoken speech as well as measures of affective prosody and basic pitch perception.

Results. Despite normal overall intelligence, patients performed substantially worse than controls in ability to detect sarcasm (d=2·2), showing both decreased sensitivity (A′) in detection of sincerity versus sarcasm and an increased bias (B″) toward sincerity. Correlations across groups revealed significant relationships between impairments in sarcasm recognition, affective prosody and basic pitch perception.

Conclusions. These findings demonstrate substantial deficits in ability to infer an internal subjective state based upon vocal modulation among subjects with schizophrenia. Deficits were related to, but were significantly more severe than, more general forms of prosodic and sensorial misperception, and are consistent with both right hemispheric and ‘bottom-up’ theories of the disorder.

Background. Research suggests high levels of depression and low levels of service use among older adults from UK minority ethnic groups. This study aimed to explore older adults' attitudes and beliefs regarding what would help someone with depression, and to consider how these may facilitate or deter older people from accessing treatment.

Method. In-depth individual qualitative interviews were conducted with older adults with depression (treated and untreated) and the non-depressed older population. A multi-cultural approach was used that incorporated the perspectives of 32 black Caribbean, 33 South Asian and 45 white British older adults.

Results. Participants felt that the responsibility for combating depression was an internal and individual task with support considered secondary. However, the majority expressed a willingness and desire to discuss psychosocial problems. Within the black Caribbean group, conversing with God through prayer was seen as an effective means of overcoming depression, while a large proportion of South Asian and white British participants identified families as an important source of help. There was wide variation in how older adults construed the role of the general practitioner (GP) and many expressed acute awareness of the demands on GPs' time.

Conclusions. Efforts to socialize and remain active may provide a useful and acceptable adjunct to clinical interventions. However, there is a need to communicate that depression often necessitates formal help, and that it is acceptable to voice concerns regarding emotional states in a GP consultation. The findings suggest that older adults would welcome the opportunity to discuss their feelings with health-care professionals.

Background. Deliberate self-harm (DSH) is a significant public health problem, representing a major burden in terms of morbidity to the individual and health-service utilization. While clinical guidelines suggest good practice for the short-term hospital management of DSH, there remains considerable variability in the way that services are provided.

Method. A systematic review of the literature was undertaken to examine the current evidence on hospital resource use and costs involved in the short-term hospital management of adults following DSH and to elucidate the factors that influence these differences, in terms of clinical characteristics and service provision.

Results. Twenty-one papers reporting on 17 studies met the inclusion criteria for review. Clinical characteristics associated with an increase in resource use included overdose with tricyclic antidepressants (TCAs) compared with selective serotonin re-uptake inhibitors (SSRIs) (weighted ratio 2·6[ratio ]1) and co-ingestion of alcohol with SSRIs. Variations in service provision, including medical admissions policy and provision of a specialist liaison service, affected resource utilization independently of the clinical needs of patients.

Conclusions. Overdoses of TCAs incur substantially greater hospital costs than overdoses of SSRIs. Variations in the medical seriousness of DSH, and in the structure of service provision, affect the resources used in its short-term hospital management, with little evidence about the impact these differences have on clinical outcome. Research is needed to evaluate the impact of different styles of service provision on outcome, and to incorporate these factors into the trial design of future cost-effectiveness studies of interventions following DSH.

Background. The purpose of the study was to examine whether the addition of a brief individual self-help package to standard primary-care treatment of depression with antidepressants is associated with any additional improvements in clinical outcome.

Method. Individuals with major depressive disorder who were prescribed an antidepressant were recruited through their general practitioner (GP) and allocated randomly to standard treatment alone or standard treatment plus self-help. Assessments of symptoms, social adjustment, global functioning, satisfaction with treatment and knowledge about the management of the disorder were completed at three time points over 26 weeks.

Results. One hundred and twelve individuals agreed to participate and 96 met criteria for inclusion in the randomized controlled trial. Subjects in both treatment conditions improved substantially over the study period; the mean Beck Depression Inventory (BDI) score fell from 27·3 to 13·9 in the intention-to-treat analysis. There were no between group differences in outcome on any of the primary outcome measures, nor did these approach even marginal significance. Patients and GPs were highly satisfied with the self-help programme, and the intervention as compared to the control group reported significantly greater improvements in knowledge about depression and satisfaction with information received about depression.

Conclusions. An individualized self-help package improved perceived knowledge about depression but did not have identifiable effects on outcome when offered to patients treated in primary care. The study was sufficiently well powered to detect relatively small effects.

Background. Schizophrenia is a debilitating chronic mental illness. However, the annual prevalence of schizophrenia is not well understood because of under-representation of schizophrenia patients in epidemiological surveys. This study used multiple administrative claims databases to estimate the annual prevalence of diagnosed schizophrenia in the USA.

Method. The annual prevalence of diagnosed schizophrenia in the USA was estimated for different health insurance coverage groups. The prevalence for privately insured individuals was calculated from an administrative claims database of approximately 3 million privately insured beneficiaries covering the period 1999–2003. The prevalence for Medicaid enrollees was calculated from California Medicaid claims covering the period 2000–2002. The prevalence for Medicare and Medicaid/Medicare dual eligibles was estimated using a combination of both databases. Published statistics were used to estimate the prevalence of schizophrenia in the uninsured and veteran populations and to weight the prevalence rates obtained to the population of the USA.

Results. The 12-month prevalence of diagnosed schizophrenia in the USA in 2002 was estimated at 5·1 per 1000 lives. The Medicaid population was identified with the highest prevalence rate among the populations studied. Sensitivity analyses taking into consideration the Veterans Affairs population only changed the estimate slightly to 5·3 per 1000 lives.

Conclusion. Analyses of administrative claims data contribute to the understanding of the prevalence of diagnosed schizophrenia.

Background. Although memory deficits are consistently reported in schizophrenia and bipolar disorder, the mechanisms underlying these impairments are poorly understood. Clarifying the nature and degree of overlap in memory deficits between the two illnesses could help to distinguish brain systems disrupted in these illnesses, and indicate cognitive remediation strategies to improve patient outcomes.

Method. We examined performance on a non-verbal memory task in clinically stable out-patients with bipolar disorder (n=40), schizophrenia (n=40), and healthy comparison subjects (n=40). This task includes conditions in which distinct mnemonic strategies – namely, using context to organize familiar stimuli or using holistic representation of novel stimuli – facilitate performance.

Result. When compared to a reference condition, bipolar patients had deficits consistent with organizational dysfunction and poor detection of novel information. Although patients with schizophrenia performed worse than the other groups, they were only differentially impaired when organizational demands were significant. Task performance was not correlated with severity of clinical symptomatology.

Conclusions. This pattern of distinct memory impairments implies disturbances in partially overlapping neural systems in bipolar disorder and schizophrenia. Evidence of impairment in detection of novel stimuli that is unique to bipolar disorder suggests that, while the absolute level of cognitive dysfunction is less severe in bipolar disorder as compared to schizophrenia, subtle disruptions in memory are present. These findings can be used to plan targeted cognitive remediation programs by helping patients to capitalize on intact functions and to learn new strategies that they do not employ without training.

Background. The purpose of the study was to estimate the proportion of alcohol abuse and dependence (AAD) among suicides and controls, and to compare the incidence of AAD documented by clinicians with diagnoses derived from a research protocol.

Method. AAD according to DSM-IV was diagnosed on the basis of interviews with relatives of people who committed suicide and with controls. A total of 427 people who committed suicide during one year were paired by region, gender, age and nationality with controls randomly selected from general practitioners' lists.

Results. Alcohol abuse was found in 10% and alcohol dependence in 51% of suicide cases. The corresponding figures for controls were 7% and 14% respectively. AAD was a statistically significant predictor of completed suicides, while abstinence was a significant predictor for female suicides and former use a significant predictor for older male suicides. AAD was diagnosed in 68% of male and 29% of female suicides. Middle-aged (35–59 years) males who committed suicide had the highest risk of alcohol dependence. Among suicide cases only 29% had received a lifetime diagnosis of AAD, against 23% of controls.

Conclusions. AAD was significantly more prevalent among suicides than controls. Overall, the proportion of male suicides affected by alcohol was the same in the present psychological autopsy study as in our previous findings for Estonia on the aggregate level, while the share of female suicides with an AAD diagnosis was dramatically higher on the individual level. AAD is markedly underdiagnosed by general practitioners and clinicians.

Background. There is increasing evidence that cognitive deficits are present in bipolar disorder (BP), but their neural correlates have not been fully explored. The aim of this study is to correlate structural brain abnormalities with cognitive performance in BP and to explore differences between clinical subtypes.

Method. Thirty-six BP patients (13 men, 23 women) with a mean age of 39 years (range 21–63 years) underwent neuropsychological testing and imaging. Twenty-five patients had bipolar disorder I (BP I) and 11 had bipolar disorder II (BP II). Patients with co-morbid psychiatric diagnosis, drug and alcohol abuse or systemic illness were excluded. Correlations between cognitive performance and structural brain changes were explored using high-resolution anatomical imaging and magnetization transfer imaging (MTI).

Results. In the whole BP group the difference between estimated pre-morbid IQ and current IQ was significantly correlated with left-sided reduction of the magnetization transfer ratio (MTR) in the superior temporal gyrus, uncus and para-hippocampal gyrus. In BP II patients the areas where these correlations were significant extended to the right superior and middle temporal gyri, cingulate gyrus, pre-cuneus and adjacent frontal and parietal white matter. The volume of superior temporal white matter was also correlated with IQ difference in this subgroup.

Conclusions. The study highlights the association between fronto-temporal abnormalities and decline in IQ in BP. The more extensive abnormalities present in BP II patients suggest that persistent depression, rather than mania, may be a key pathophysiological factor or that BP II represents a clinical phenotype with a higher risk of developing cognitive abnormalities.

Background. The aims of the study were to investigate whether (i) patients with lifetime presence of non-affective psychosis show an external-personal attribution bias for negative events, (ii) this attribution style can also be detected in first-degree relatives of patients with psychosis and subjects with subclinical psychotic experiences, and (iii) this attribution style is related to the presence of psychotic symptoms, in particular delusions.

Method. Participants were 23 patients with lifetime presence of non-affective psychosis, a high- risk group of 36 first-degree relatives of patients with non-affective psychosis, a high-risk group of 31 subjects with subclinical psychotic experiences and 46 normal controls. Attribution style was measured by the Internal, Personal and Situational Attribution Questionnaire. Positive symptoms were assessed with the Present State Examination (PSE) and the Scale for the Assessment of Positive Symptoms (SAPS).

Results. Relative to the controls, an externalizing bias was apparent in the patient group (β=0·20, p=0·03) but not in the two high-risk groups. There was a dose–response association between externalizing bias and the delusions subscale of the PSE (relative to lowest level: highest level of delusions: β=0·53, p=0·04; intermediate levels of delusions: β=0·23, p=0·35). No significant differences were found in personalizing bias between the four groups.

Conclusions. Patients with psychosis tend to use an externalizing bias in their explanations of negative social events, and this bias is associated with the presence of positive psychotic symptoms, in particular delusions. A deviant attribution style is not part of the vulnerability to psychosis.

Background. Cognitive models propose that auditory verbal hallucinations arise through defective self-monitoring and external attribution of inner speech. We used a paradigm that engages verbal self-monitoring to examine how deficits in this process are related to symptoms and diagnosis in patients with psychosis.

Method. We tested 45 patients with schizophrenia. Fifteen had current auditory hallucinations, 15 had a history of (but no current) auditory hallucinations, and 15 had delusions but neither current nor previous hallucinations. We also tested 10 patients with affective psychosis and current auditory hallucinations, and 20 healthy volunteers. Participants read single adjectives aloud while the source and the pitch of the on-line auditory verbal feedback was manipulated, then immediately identified the source of the speech they heard (‘self’/‘other’/‘unsure’).

Results. When reading aloud with distorted feedback of their own voice, patients with schizophrenia who had auditory hallucinations were more likely than controls to misidentify its source as ‘other’. Patients with delusions but no current hallucinations displayed a similar deficit, although there was a trend for this to be less marked. Patients with a history of hallucinations did not differ from controls. Patients with hallucinations in the context of an affective disorder made more unsure responses rather than misattributions.

Conclusions. Difficulty with source monitoring was related to the acute psychotic state rather than a predisposition to hallucinations, and was evident in patients with affective psychosis as well as schizophrenia. External misattribution of source may reflect an impairment in verbal self-monitoring and/or the appraisal of ambiguous sensory material.

Background. The global burden and large diagnostic and therapeutic deficits associated with depressive disorders call for intervention programs. The aim of the Nuremberg Alliance against Depression (NAD) is to establish and to assess the effectiveness of a four-level intervention program for improving the care of patients with depression.

Method. A 2-year intervention program was performed in Nuremberg (480000 inhabitants) at four levels: training of family doctors and support through different methods; a public relations campaign informing about depression; cooperation with community facilitators (teachers, priests, local media, etc.); and support for self-help activities as well as for high-risk groups. The effects of the 2-year intervention on the number of suicidal acts (completed suicides plus suicide attempts, main outcome criterion) were evaluated with respect to a 1-year baseline and a control region (Wuerzburg, 270000 inhabitants).

Results. Compared to the control region, a reduction in frequency of suicidal acts was observed in Nuremberg during the 2-year intervention (2001 v. 2000: −19·4%; p[les ]0·082; 2002 v. 2000: −24%, p[les ]0·004). Considering suicide attempts only (secondary outcome criterion), the same effect was found (2001 v. 2000: −18·3%, p[les ]0·023; 2002 v. 2000: −26·5%, p<0·001). The reduction was most noticeable for high-risk methods (e.g. hanging, jumping, shooting). Concerning completed suicides, there were no significant differences compared to the control region.

Conclusions. The NAD appeared to be effective in reducing suicidality. It provides a concept as well as many methods that are currently being implemented in several other intervention regions in Germany and in other countries.

Background. Clinicians have questioned the validity of depression criteria in patients with chronic medical illness, but few empirical data address this question.

Method. Computerized records identified two samples of managed care patients beginning depression treatment: 235 with diabetes, ischemic heart disease, or chronic obstructive lung disease and 204 without those conditions. Telephone assessments at baseline, 2 months, and 6 months included the Structured Clinical Interview for DSM-IV and other measures of depression severity and functional status. Item Response Theory analyses compared patterns of depressive symptoms across groups and specifically evaluated somatic symptoms (fatigue, change in weight or appetite, psychomotor agitation/retardation, and sleep disturbance) as indicators of depression. Logistic regression examined how change in somatic symptoms during treatment varied between patient groups.

Results. Overall item response analysis indicated differential item functioning between groups (χ2=33·7, df=18, p=0·017). Two of eight item-level comparisons were statistically significant; one in the predicted direction (patients with co-morbidity reported more fatigue at low levels of depression: χ2=17·9, df=1, p<0·001) and one in the opposite direction from predicted (patients with co-morbidity reported less psychomotor agitation/retardation at low levels of depression: χ2=8·0, df=1, p=0·005). Observed differences were modest: at the midpoint of the depression severity scale, patients with medical co-morbidity had a 54% probability of reporting fatigue compared to 45% in those without co-morbidity. All four somatic symptoms showed robust improvement with treatment, and this improvement did not differ significantly between patients with and without medical co-morbidity.

Conclusions. We find only limited evidence that fatigue, changes in weight or appetite, psychomotor agitation/retardation, and sleep disturbance are less valid indicators of depression in patients with chronic medical illness. DSM-IV criteria for diagnosis of depression do not require significant modification for patients with medical co-morbidity.

Background. There are a large number of factors mediating suicide. Many studies have searched for a direct causal relationship between economic hardship and suicide, however, findings have been varied.

Method. Suicide data was obtained from the Australian Bureau of Statistics for the period between January 1968 and August 2002. These were correlated with a suite of macroeconomic data including housing loan interest rates, unemployment rates, days lost to industrial disputes, Consumer Price Index, gross domestic product, and the Consumer Sentiment Index.

Results. A total of 51845 males and 16327 females committed suicide between these dates. There were significant associations between suicide rates and eleven macroeconomic indicators for both genders in at least one age range. Data was divided into male and female and five age ranges and pooled ages. Analyses were conducted on these 132 datasets resulting in 80 significant findings. The data was generally stronger for indices measuring economic performance than indices measuring consumers' perceptions of the state of the economy. A striking difference between male and female trends was seen. Generally, male suicide rates increased with markers of economic adversity, while the opposite pattern was seen in females. There were significantly different patterns in age-stratified data, with for example higher housing loan interest rates having a positive association with suicide in younger people and a negative association in older age groups.

Conclusion. Macroeconomic trends are significantly associated with suicide. The patterns in males and females are very different, and there are further substantial age-related differences.