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Importance: Few studies have estimated the lifetime incidence of mental health disorders and the association with socioeconomic functioning., Objective: To investigate whether the lifetime incidence of treated mental health disorders is substantially higher than previously reported and estimate associations with long-term socioeconomic difficulties., Design, Setting, and Participants: This nationwide population-based register linkage study includes a randomly selected sample of 1.5 million individuals from the population of Denmark from 1995 to 2018. Data were analyzed from May 2022 to March 2023., Main Outcomes and Measures: Lifetime incidence of any treated mental health disorder in the general population was estimated from birth to age 100 years taking into account the competing risk of all-cause death and associations with socioeconomic functioning. Register measures were (1) from hospitals, a diagnosis of any mental health disorder at an inpatient/outpatient hospital contact; (2) from hospitals and prescription statistics, any mental health disorder/psychotropic prescription, including a hospital-contact diagnosis, or any psychotropic medication prescribed by physicians, including general practitioners or private psychiatrists; and (3) socioeconomic functioning as indicated by highest educational achievement, employment, income, residential status, and marital status., Results: Among a sample of 462 864 individuals with any mental health disorder, the median (IQR) age was 36.6 years (21.0-53.6 years), 233 747 (50.5%) were male, and 229 117 (49.5%) were female. Of these, 112 641 were registered with a hospital-contact mental health disorder diagnosis and 422 080 with a prescription of psychotropic medication. The cumulative incidence of a hospital-contact mental health disorder diagnosis was 29.0% (95% CI, 28.8-29.1), 31.8% (95% CI, 31.6-32.0) for females, and 26.1% (95% CI, 25.9-26.3) for males. When also considering psychotropic prescriptions, the cumulative incidence of any mental health disorder/psychotropic prescription was 82.6% (95% CI, 82.4-82.6), 87.5% (95% CI, 87.4-87.7) for females, and 76.7% (95% CI, 76.5-76.8) for males. Socioeconomic difficulties were associated with mental health disorder/psychotropic prescriptions, including lower income (hazard ratio [HR], 1.55; 95% CI, 1.53-1.56), increased unemployment or disability benefit (HR, 2.50; 95% CI, 2.47-2.53), and a greater likelihood of living alone (HR, 1.78; 95% CI, 1.76-1.80) and being unmarried (HR, 2.02; 95% CI, 2.01-2.04) during long-term follow-up. These rates were confirmed in 4 sensitivity analyses with the lowest being 74.8% (95% CI, 74.7-75.0) (1) by using varying exclusion periods, (2) by excluding prescriptions of anxiolytics and quetiapine that may be used for off-label indications, (3) by defining any mental health disorder/psychotropic prescription as any hospital-contact mental health disorder diagnosis or any psychotropic medication prescribed at least 2 times, and (4) by excluding individuals with somatic diagnoses for which psychotropics may be prescribed off-label., Conclusions and Relevance: This registry study of data from a large representative sample of the Danish population showed that the majority of individuals either received a diagnosis of a mental health disorder or were prescribed psychotropic medication during their lifetime, which was associated with subsequent socioeconomic difficulties. These findings may help change our understanding of normalcy and mental illness, reduce stigmatization, and further prompt rethinking the primary prevention of mental illness and future mental health clinical resources.

Background: People with schizophrenia have an increased risk of premature mortality compared to the general population. We aimed to quantify which types of causes of death contributed to the excess mortality, and to examine whether there has been an increase in the excess mortality among persons with schizophrenia in the period 1995 to 2015., Method: We used a cohort design including the entire Danish population. We calculated life years lost of the cohort members compared to a set reference-age at 95 years old. Using a decomposition model we examined differences of cause-specific death among those with schizophrenia and the general population, including calendar trends during the last two decades., Results: In the general population, as well as in persons with schizophrenia, we found improvements in life years lost during the last two decades. Men with schizophrenia lost 13.5 years more than the general population (women; 11.4 years). Compared to the general population, a large improvement in life years lost with respect to suicide and accidents was found in those with schizophrenia, but, this improvement was offset by an increasing number of life years lost in deaths from diseases and medical conditions., Conclusion: Our findings highlight the urgent need for focused treatment of general medical conditions in those with schizophrenia. Without such an investment, it is probable that the life years lost among persons with schizophrenia (compared to the general population) will continue to worsen in future decades., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Varying definitions of treatment-resistant depression (TRD) across studies make it difficult to estimate the size of the problem and to identify patients at increased risk. The aim of this cohort study was to examine the incidence of TRD, disease-related risk factors, and changes over time using different definitions of TRD., Methods: From 1996 through 2014, all patients with a first-time hospital contact for depression (ICD-10 codes F32 and F33) were identified in Danish National Patient Registries. A total of 211,689 patients were followed for shifts in antidepressant treatment in the Danish Patient and Prescription Registries. TRD was defined at the second shift in treatment during the first 12 months after diagnosis. The associations of year and type of hospital contact, depression subtype, and severity of TRD were analyzed using Cox proportional hazard regression., Results: A total of 14.0% of patients experienced a second shift in antidepressant treatment during the first year after admission. When applying 3 other common TRD definitions, the proportion varied from 13% to 31%. Psychiatric inpatients and patients with recurrent or severe depression had the highest incidence of TRD. The incidence of TRD was also slightly higher in patients diagnosed after 2001. All associations were replicated when data were reanalyzed using the alternative definitions of TRD., Conclusions: About 14% of patients with depression developed TRD during the first year after first hospital contact. The incidence was highest in patients with severe depression and was relatively stable over time. Various definitions of TRD provided different estimates of the frequency of TRD but were all associated with disease severity., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Objective: To assess whether implementing patient-controlled admission (PCA) can reduce coercion and improve other clinical outcomes for psychiatric in-patients., Methods: During 2013-2016, 422 patients in the PCA group were propensity score matched 1:5 with a control group (n = 2110) that received treatment as usual (TAU). Patients were followed up for at least one year using the intention to treat principle utilising nationwide registers. In a paired design, the outcomes of PCA patients during the year after signing a contract were compared with the year before., Results: No reduction in coercion (risk difference = 0.001; 95% CI: -0.038; 0.040) or self-harming behaviour (risk difference = 0.005; 95% CI: -0.008; 0.018) was observed in the PCA group compared with the TAU group. The PCA group had more in-patient bed days (mean difference = 28.4; 95% CI: 21.3; 35.5) and more medication use (P < 0.0001) than the TAU group. Before and after analyses showed reduction in coercion (P = 0.0001) and in-patient bed days (P = 0.0003)., Conclusion: Implementing PCA did not reduce coercion, service use or self-harm behaviour when compared with TAU. Beneficial effects of PCA were observed only in the before and after PCA comparisons. Further research should investigate whether PCA affects other outcomes to better establish its clinical value., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Alcohol-related mortality is more pronounced in lower than in higher socioeconomic groups in Western countries. Part of the explanation is differences in drinking patterns. However, differences in vulnerability to health consequences of alcohol consumption across socioeconomic groups may also play a role. We investigated the joint effect of alcohol consumption and educational level on the rate of alcohol-related medical events., Methods: We pooled seven prospective cohorts from Denmark that enrolled 74,278 men and women age 30-70 years (study period, 1981 to 2009). We measured alcohol consumption at baseline using self-administrated questionnaires. Information on highest attained education 1 year before study entry and hospital and mortality data on alcohol-related medical events were obtained through linkage to nationwide registries. We performed analyses using the Aalen additive hazards model., Results: During follow-up (1,085,049 person-years), a total of 1718 alcohol-related events occurred. The joint effect of very high alcohol consumption (>21 [>28] drinks per week in women [men]) and low education on alcohol-related events exceeded the sum of their separate effects. Among men, we observed 289 (95% confidence interval = 123, 457) extra events per 100,000 person-years owing to education-alcohol interaction (P < 0.001). Similarly, among women, we observed 239 (95% confidence interval = 90, 388) extra events per 100,000 person-years owing to this interaction (P < 0.001)., Conclusions: High alcohol consumption is associated with a higher risk of alcohol-related medical events among those with low compared with high education. This interaction may be explained by differences in vulnerability and drinking patterns across educational groups.See video abstract at, http://links.lww.com/EDE/B267.

Poisson regression is an important tool in register-based epidemiology where it is used to study the association between exposure variables and event rates. In this paper, we will discuss the situation with 'large n and small p', where n is the sample size and p is the number of available covariates. Specifically, we are concerned with modeling options when there are time-varying covariates that can have time-varying effects. One problem is that tests of the proportional hazards assumption, of no interactions between exposure and other observed variables, or of other modeling assumptions have large power due to the large sample size and will often indicate statistical significance even for numerically small deviations that are unimportant for the subject matter. Another problem is that information on important confounders may be unavailable. In practice, this situation may lead to simple working models that are then likely misspecified. To support and improve conclusions drawn from such models, we discuss methods for sensitivity analysis, for estimation of average exposure effects using aggregated data, and a semi-parametric bootstrap method to obtain robust standard errors. The methods are illustrated using data from the Danish national registries investigating the diabetes incidence for individuals treated with antipsychotics compared with the general unexposed population., (Copyright © 2015 John Wiley & Sons, Ltd.)

We examined incidence of depression after acute coronary syndrome (ACS) and whether the timing of depression onset influenced survival. All first-time hospitalizations for ACS (n = 97,793) identified in the Danish Patient Registry during 2001-2009 and a reference population were followed for depression and mortality via linkage to patient, prescription, and cause-of-death registries until the end of 2012. Incidence of depression (as defined by hospital discharge or antidepressant medication use) and the relationship between depression and mortality were examined using time-to-event models. In total, 19,520 (20.0%) ACS patients experienced depression within 2 years after the event. The adjusted rate ratio for depression in ACS patients compared with the reference population was 1.28 (95% confidence interval (CI): 1.25, 1.30). During 12 years of follow-up, 39,523 (40.4%) ACS patients and 27,931 (28.6%) of the reference population died. ACS patients with recurrent (hazard ratio (HR) = 1.62, 95% CI: 1.57, 1.67) or new-onset (HR = 1.66, 95% CI: 1.60, 1.72) depression had higher mortality rates than patients with no depression. In the reference population, the corresponding relative estimates for recurrent (HR =1.98, 95% CI: 1.92, 2.05) and new-onset (HR = 2.42, 95% CI: 2.31, 2.54) depression were stronger. Depression is common in ACS patients and is associated with increased mortality independently of time of onset, but here the excess mortality associated with depression seemed to be lower in ACS patients than in the reference population., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression., Methods: From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses., Findings: During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow-up., Conclusion: In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression.

Objective: Life expectancy in patients with bipolar disorder has been reported to be decreased by 11 to 20 years. These calculations are based on data for individuals at the age of 15 years. However, this may be misleading for patients with bipolar disorder in general as most patients have a later onset of illness. The aim of the present study was to calculate the remaining life expectancy for patients of different ages with a diagnosis of bipolar disorder., Methods: Using nationwide registers of all inpatient and outpatient contacts to all psychiatric hospitals in Denmark from 1970 to 2012 we calculated remaining life expectancies for values of age 15, 25, 35 ⃛ 75 years among all individuals alive in year 2000., Results: For the typical male or female patient aged 25 to 45 years, the remaining life expectancy was decreased by 12.0-8.7 years and 10.6-8.3 years, respectively. The ratio between remaining life expectancy in bipolar disorder and that of the general population decreased with age, indicating that patients with bipolar disorder start losing life-years during early and mid-adulthood., Conclusions: Life expectancy in bipolar disorder is decreased substantially, but less so than previously reported. Patients start losing life-years during early and mid-adulthood., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Assortative mating has been demonstrated in mental disorders but the extent of cohabitation between patients with clinically diagnosed psychiatric disease has been poorly explored. Method We conducted a register-based study of all Danes between 18 and 70 years of age in a 13-year observational period, linking data on individuals' contacts with psychiatric services with data on individuals' cohabitation status. Two different Poisson regression analyses were performed: the first comparing the rates of commencing cohabitation with a psychiatric patient between individuals, depending on whether the individuals themselves had, or did not have, a psychiatric diagnosis; the second comparing the incidence rates of psychiatric diagnoses for individuals cohabitating with psychiatric patients with the similar rates for individuals living with unaffected cohabitants., Results: In total, 159 929 (5.0%) out of 3 204 633 individuals were given a psychiatric diagnosis during the study period. Diagnosed individuals had an overall rate ratio (RR) of commencing cohabitation with a psychiatric patient of 1.95 [95% confidence interval (CI) 1.90-2.00] for women and 1.65 (95% CI 1.61-1.69) for men, when compared with unaffected individuals. The overall RR of receiving a psychiatric diagnosis while cohabitating with a psychiatric patient was 2.40 (95% CI 2.31-2.49) for women and 2.91 (95% CI 2.81-3.01) for men, when compared with those cohabitating with unaffected individuals. Individuals with schizophrenia and men with bipolar disorder had the highest RR of commencing cohabitation with a cohabitant with a similar diagnosis., Conclusions: Cohabitation among individuals with severe psychiatric disorders is increased. This has implications for research and for the clinical management of patients.

Aim: Using the unique Danish psychiatric and somatic health registers, we investigated the rate of subsequent dementia in patients with late-onset acute and transient psychosis., Methods: By linkage of the psychiatric and the somatic nationwide registers of all patients with in- or outpatient hospital contact in Denmark, we included all patients with a first ever contact during the period 1 January 1994 to 31 December 2001 with one of the main index diagnoses: late-onset acute and transient psychosis or osteoarthritis. Data on the general population were also included. The first diagnosis of dementia for each individual at discharge or at outpatient contact was established. Poisson regression models were used to compare the cohorts of patients with dementia as the outcome of interest., Results: Using a cut-off age of 60 years, 8062 individuals were included. Significant associations were found between a subsequent diagnosis of dementia and the index diagnosis, age and calendar time. Overall, the rate ratio for developing dementia in late-onset acute and transient psychosis compared to osteoarthritis patients was 10.86 (95% confidence intervals, 8.42 and 14.00, respectively), however, the magnitude of the rate ratio varied according to sex, age, duration since diagnosis and calendar time. Compared to the general population, the rate ratio was 8.12 (95% confidence intervals, 6.77 and 9.74, respectively)., Conclusion: The present study has established that subjects with late-onset acute and transient psychosis are at 11 times higher risk of subsequently getting a diagnosis of dementia compared to patients with osteoarthritis, and at 8 times higher risk compared to the general population.

For recurrent events there is evidence that misspecification of the frailty distribution can cause severe bias in estimated regression coefficients (Am. J. Epidemiol 1998; 149:404-411; Statist. Med. 2006; 25:1672-1684). In this paper we adapt a procedure originally suggested in (Biometrika 1999; 86:381-393) for parallel data for checking the gamma frailty to recurrent events. To apply the model checking procedure, a consistent non-parametric estimator for the marginal gap time distributions is needed. This is in general not possible due to induced dependent censoring in the recurrent events setting, however, in (Biometrika 1999; 86:59-70) a non-parametric estimator for the joint gap time distributions based on the principle of inverse probability of censoring weights is suggested. Here, we attempt to apply this estimator in the model checking procedure and the performance of the method is investigated with simulations and applied to Danish registry data. The method is further investigated using the usual Kaplan-Meier estimator and a marginalized estimator for the marginal gap time distributions. We conclude that the procedure only works when the recurrent event is common and when the intra-individual association between gap times is weak., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Depressive symptoms and major depression are frequent in patients with Parkinson's disease (PD). However, a systematic knowledge about the treatment with antidepressant drugs among PD patients is missing. We estimated the frequency of antidepressant drug treatment in a national sample of persons treated with antiparkinson drugs (APDs). All persons treated with APDs were identified in the national Danish Prescription database. The subsequent risk of treatment with antidepressants was estimated and compared with the risks for two large control groups. The study period was 5 years. In total, 1,029,737 persons were included. Persons who got APDs had significantly increased rate ratios (RR) of subsequent antidepressant drug treatment compared with an unexposed control group (RR: 2.10 (95% CI: 2.04-2.16)) and with persons who got anti-diabetic drugs [RR: 1.58 (95% CI: 1.51-1.65)]. Persons treated with APDs have higher frequency of antidepressant drug treatment than have controls. With the reservation that data on drug consumption cannot be directly transferred into conclusions about specific diseases, the present study supports results from other population-based studies of an association between PD and depression., ((c) 2007 Movement Disorder Society.)

Objective: To estimate the rate of treatment with anti-parkinson drugs (APD) among patients with depression., Method: In a nationwide case register linkage study, all persons with a main diagnosis of depression during 5 years were identified. A control group of persons with diagnoses of osteoarthritis was included. The subsequent risk of getting treatment with APD was estimated for the two groups. Statistical analyses involved Poisson's regression and competing risk models., Results: A total of 14 991 persons were included. The rate of getting APD was 2.57 (95% CI: 1.46-4.52) times higher for persons with depression than for persons with osteoarthritis. Overall, the rate was highest for men. However, women with depression had a 3.89 (95% CI: 1.98-7.62) times higher rate of APD treatment as women with osteoarthritis while no significant difference was found among men., Conclusion: Provided that prescription of APD reflects the presence of Parkinson's disease, results support a positive statistical association between depressive disorders and Parkinson's disease.

Findings from several studies have suggested that the risk of recurrence increases with the number of previous episodes in depressive and bipolar disorders. However, a comprehensive and critical review of the literature published during the past century shows that in several previous studies, a progressive course of episodes may have been falsely shown, mainly because of various kinds of biases and because these studies have not considered individual heterogeneity in their analyses. Nevertheless, four recent studies, including two nationwide register studies from Denmark, a prospective 15-year multicenter study from the United States, and a prospective lifelong study from Zurich, Switzerland, generally have taken these drawbacks and pitfalls into account in the design and handling of data. In all four studies, an effect of episodes was found in depressive (four studies) and bipolar (three studies) disorders. It is concluded that the average risk of recurrence increases with the number of episodes in depressive and in bipolar affective disorders. Nevertheless, the course of illness in unipolar and bipolar disorders is heterogeneous, and the effect of previous episodes and its interrelation with other risk factors on the risk of relapse and recurrence warrants additional research.

Background: Links between thyroid function and depression have been noted in many contexts. We assessed whether hospitalization with hypothyroidism was a risk factor for developing affective disorder., Methods: We conducted a prospective cohort study using historical data from Danish registers. The observational period was 1977-1999. Three study cohorts were identified: all patients with a first hospital admittance with the resulting index discharge diagnoses hypothyroidism, osteoarthritis, or nontoxic goiter. A later hospitalization with a resulting discharge diagnosis of affective disorder was used as event of interest, and rates of readmission were estimated and compared using competing risk models in survival analyses., Findings: We identified 165,307 patients discharged with an index diagnosis. In the observational period, 1041 events occurred. An index diagnosis of hypothyroidism was associated with an increased risk of hospitalization with affective disorder when compared to the control diseases. The risk of hospitalization with affective disorder was greatest in the first year after index hospitalization., Conclusion: Patients hospitalized with hypothyroidism have a greater risk of readmission with depression or bipolar disorder than control patients. This renders epidemiologic support to theories linking thyroid dysfunction with mood disturbances.

A few studies have suggested that the prevalence of diabetes is increased for patients with depression and for patients with bipolar disorder compared with the general population. However, no study has been published comparing the risk of getting a diagnosis of diabetes for patients with affective disorders with the risk for patients with other medical illnesses. It was the aim of the present study to investigate whether patients hospitalised for depressive or bipolar disorders are at increased risk of getting a diagnosis of diabetes at readmission compared to patients previously admitted for osteoarthritis. In a nationwide case register study, all patients who got a discharge diagnosis of depression, mania/bipolar disorder or osteoarthritis at first admission in a period from 1977 to 1997 were identified. The probability of getting readmitted and discharged with a diagnosis of diabetes was estimated with competing risks models in survival analysis. In total, 29,035 patients with a diagnosis of depression at first discharge, 6683 patients with mania/mixed episode and 108,525 patients with a diagnosis of osteoarthritis were identified. The risk of getting readmitted with diabetes was not increased for patients who had previously been admitted with depression or mania/bipolar disorder compared to patients with osteoarthritis. There was no difference in the risks of developing Type 1 and Type 2 diabetes.

Objective: To investigate the temporal relationships between a range of neurological diseases and affective disorders., Method: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two control group diagnoses were followed for up to 21 years. The incidences of affective disorders in the different groups were compared with the control groups, using competing risks to consider the risk of affective disorder and the risk of death in the same analysis., Results: We found an increased incidence of affective disorders in dementia, Parkinson's disease, epilepsy, stroke and intracerebral haemorrhage compared with control groups. The association was found to be the strongest for dementia and Parkinson's disease. In hospitalized patients, with incident multiple sclerosis, the incidence of affective disorder was lower than the incidence in the control groups., Conclusion: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases).

Background: Previous studies suggest that gender, age at onset, and marital status act as risk factors for further recurrence initially during the course of affective disorder but not at a later stage. These studies did, however, not take the individual liability to recurrence into account., Method: The effect of predictors of recurrence was estimated with the use of generalised linear mixed models in a case register study including a random sample of all patients admitted with primary affective disorder in Denmark during 1971-1993., Results: In total, 7047 first admission patients with a diagnosis of affective disorder, depressive or manic/circular type were included in the analyses. The study confirmed that the effect of the type of disorder, age at first admission, and never being married decreased during the course of illness even when the individual liability to recurrence was taken into account. No differences in the effect of gender and in the effect of a recent divorce were found between early and later episodes and the effect of a recent death of a spouse seemed to increase during the course of illness. The risk of recurrence increased with every new episode for all sub-groups of patients., Conclusion: The effect of some, but not all, predictors of recurrence decline during the course of affective illness. The number of previous episodes predicts recurrence in most subgroups of patients., Limitation: The data relate to re-admissions rather than recurrence., Clinical Relevance: The study underscores the importance of the illness process itself.

Background: The risk of recurrence has been found to increase with the number of episodes in both unipolar and bipolar affective disorder. The present study compared the effect of the number of episodes on the risk of recurrence in the two disorders., Method: A case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. The effect of the number of prior episodes on the rate of recurrence following the first discharge after 1984 was estimated. A total of 7925 unipolar patients and 2011 bipolar patients were included in the study., Results: The rate of recurrence was, on average, 1.6 times greater for bipolar patients than for unipolar patients. Nevertheless, the effect of the number of episodes was greatest for unipolar patients. Thus, the rate of recurrence increased, on average, 15% with every episode for unipolar patients and 9% with every episode for bipolar patients, when adjusted for differences in age and gender., Conclusion: The risk of recurrence increases with every new episode in affective disorder. The effect of episodes is greater for unipolar disorder than for bipolar disorder., Limitations: The data relate to re-admissions rather than recurrence., Clinical Relevance: The study shows that the prognosis worsens more for unipolar than for bipolar patients with each new episode and suggests the relevance of earlier and more sustained intervention.