Biomedical subjects

W Coryell

Publications and source records attributed to W Coryell.

At least 19 recordsLinked to original sources

PubMed1996

Familial alcoholism in manic-depressive (bipolar) disease.

A previous analysis found a relatively high rate of alcoholism in a cohort of bipolar I subjects, and a trend for increased rates of alcoholism in relatives of subjects with both bipolar I disorder and alcoholism, compared to relatives of subjects with bipolar I disorder and no alcoholism. The sample of subjects with bipolar I disorder has been enlarged through continued follow-up, permitting new analyses to address the association and heritability of bipolar I disorder with alcoholism. Probands with bipolar I disorder were followed for 10 years as part of the NIMH Collaborative Depression Study. The rate of alcoholism in relatives of probands with both bipolar I disorder and alcoholism was compared to the rate of alcoholism in relatives of probands with bipolar disorder and no alcoholism. The prevalence of alcoholism in relatives of subjects with bipolar I disorder was compared to the rate of alcoholism in relatives of control subjects. Relatives of probands with bipolar I disorder showed a higher rate of alcoholism than relatives of controls. Relatives of probands with bipolar I disorder and alcoholism showed a higher rate of alcoholism than relatives of probands with bipolar I disorder without alcoholism. These data suggest that familial alcoholism may contribute to a vulnerability to bipolar I disorder, and that there is a shared heritability for the two disorders.

Adult↗

PubMed1996

Recovery after 5 years of unremitting major depressive disorder.

BACKGROUND: The long-term course of depression in patients who present for treatment carries prognostic and therapeutic implications. This study presents prospective data on the time to recovery from an episode of major depressive disorder of 5 years' duration among patients followed up since 1978 in the National Institutes of Mental Health Collaborative Program on the Psychobiology of Depression. METHODS: Survival analysis was used to examine the 10-year course of the 431 probands with major depressive disorder with a specific focus on the 35 probands who were observed to be continuously ill for the first 5 years. Univariate analytic techniques were used to describe the demographic and clinical variables in the group that recovered and the group that did not. By study design, somatic treatment was assessed but not controlled by the investigators. RESULTS: By year 10, 93% (Kaplan-Meier estimate) of probands had recovered from their intake episode of major depressive disorder. In those ill for the first 5 years, 38% had recovered within the next 5 years. Shorter duration of illness prior to intake and being married were associated with the group that recovered. Pharmacological treatment dosages averaged 100 mg of imipramine hydrochloride equivalent in the chronically ill group. CONCLUSIONS: Despite lengthy periods of illness, people continued to recover from major depressive disorder for up to 10 years of prospective follow-up. Few demographic and clinical variables distinguished those who recovered from those who did not. Treatment, as observed in this naturalistic study, was at a low level despite lengthy illness.

Adult↗

PubMed1996

Importance of psychotic features to long-term course in major depressive disorder.

OBJECTIVE: Most efforts to describe the prognostic significance of psychotic features in depression have been limited to single assessments 1 year or less after the initial evaluation. However, the various biological and treatment response differences between patients with psychotic and nonpsychotic depression suggest that prognostic differences may be very long-term. METHOD: The 787 patients described here entered the study as they sought treatment at one of five academic medical centers; they had either RDC major depressive disorder or schizo-affective depression (other than the mainly schizophrenic subtype) and completed at least 6 months of follow-up. Of these, 144 (18.3%) had psychotic depression as defined here. Patients provided follow-up interviews at 6-month intervals for 5 years and annually thereafter; 98 of those with psychotic depression and 434 of those with non-psychotic depression were followed for 10 years. RESULTS: Those who began follow-up with psychotic depression had fewer weeks with minimal symptoms in each of the 10 years of follow-up and reported more psychosocial impairment at both 5 and 10 years. Both the index episode and the first recurrence of psychotic depression lasted longer than nonpsychotic episodes, but nonpsychotic episodes among previously psychotic individuals were relatively brief. Intervals between episodes were significantly shorter for patients who had ever been psychotic. CONCLUSIONS: Together with evidence that psychotic features are highly recurrent, these data show 1) that psychotic features denote a lifetime illness of greater severity and 2) that within individuals, psychotic features may emerge in only the more severe episodes.

Adult↗

PubMed1996

Psychotic depression.

The presence of delusions or hallucinations in major depressive disorder indicates a severe form of that disorder. Compared with patients with nonpsychotic depression, those with psychotic depression have depressive symptoms that are individually more severe. They also are more likely to have hypothalamic-pituitary-adrenal axis hyperactivity and increased ventricular-to-brain ratios. The short- and long-term outcomes for such patients are poor. Findings that this prognostic disadvantage may be permanent and that psychotic features recur at high rates in subsequent episodes indicate that these symptoms in major depressive disorder have a lifelong significance. Although monotherapy with antidepressants may be effective, recovery is more rapid when antidepressants are combined with antipsychotics. Electroconvulsive therapy is particularly effective for psychotic depression. The importance of combination therapy for prophylaxis is unknown.

Antidepressive Agents↗

PubMed1995

The likelihood of recurrence in bipolar affective disorder: the importance of episode recency.

These analyses used a high-intensity follow-up of of patients with bipolar affective disorder to describe the immediate and long-term risks for recurrence and the importance of sustained recovery to those risks. At the baseline evaluation, all patients were in episodes of Research Diagnostic Criteria major depressive disorder, mania or schizoaffective disorder (excluding the mainly schizophrenic subtype); those who were depressed at intake had a history of mania or schizoaffective mania. Raters re-evaluated these patients at 6-month intervals for 5 years and annually for the remainder of a 10-year follow-up. The following report describes relapse risks for the 186 patients observed to recover from their index episodes. Survival analyses quantified the likelihood of relapse over time, beginning after symptom-free periods of 4 months and 1, 2 and 3 years. Further survival analyses used treatment status as a censoring variable to estimate the eventual likelihood of recurrence among those who reported sustained compliance with lithium prophylaxis; the prophylaxis group remained under observation until they relapsed, were lost to follow-up or ceased taking lithium. Progressively longer symptom-free periods were clearly associated with lower relapse risks over the subsequent 4 years. Thereafter, however, this effect dissipitated. 7 years after recovery, the cumulative likelihood of recurrence was four in five for all bipolar patients and two in three for those whose index episode had been followed by at least 3 years without symptoms. Even with sustained lithium prophylaxis, the likelihood of at least one recurrence exceeded 70% within 5 years of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients.

BACKGROUND: Given the therapeutic and prognostic importance of the unipolar-bipolar dichotomy, predicting which patients will become bipolar subsequent to index diagnosis of major depressive disorder (MDD) is of paramount clinical significance. We sought to characterize the profile of patients with MDD who would convert to the more subtle bipolar subtype (known as BPII) on the basis of clinical and personality variables obtained during MDD episodes. METHODS: A total of 559 patients, comprehensively evaluated with the Schedule of Affective Disorders and Schizophrenia and "unipolar" MDD at entry, were administered 17 self-report personality measures. Hypomanic and manic episodes were systematically recorded over a prospective observation period of up to 11 years. We compared 48 converters to BPII (8.6%) with 22 converters to bipolar I (BPI) (3.9%) and the remaining larger group of unipolar patients. RESULTS: Except for greater acuteness, severity, and psychotic symptomatology, BPI converters were essentially similar to MDD nonconverters. By contrast, BPII converters were robustly distinguished from those with MDD who remained unipolar on the basis of self-report measures along the newly derived factors of Mood Lability, Energy-Activity, and Daydreaming. This profile was associated with early age at onset of MDD and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Overall, BPII switchers had a more protracted and tempestuous course with shorter well intervals. "Habitual self" descriptions of temperamental instability during MDD episodes provided useful clinical information for predicting which depressed patients will switch to BPII, attaining a sensitivity of 91% for all three factors combined (23 items); Mood Lability alone (nine items) was the most specific predictor (86%), though of lower sensitivity (42%). CONCLUSIONS: The BPII subtype is best understood by such lability intruding into, and possibly its accentuation during, depressive episodes, thereby creating an intimate interweaving of trait and state. Clinicians must note that the foregoing temperamental profile appears more fundamental in defining the affective dysregulation of the BPII subtype than hypomanic episodes emphasized in DSM-IV.

Adult↗

PubMed1995

A family study of manic-depressive (bipolar I) disease. Is it a distinct illness separable from primary unipolar depression?

OBJECTIVE: To determine whether bipolar I illness is autonomous or part of a multifactorial continuum with unipolar depression. In this study, we compare familial bipolar I illness and depression among three groups: probands with bipolar I disorder; probands with primary unipolar disorder; and controls. We also examine a continuum of severity between psychotic and nonpsychotic patients with bipolar I disorder. Considerable data suggest that bipolar I illness is distinct from unipolar illness as regards epidemiology, familial psychiatric illness, course, response to treatment, and biologic findings. METHOD: Probands were separated into bipolar I and primary unipolar depressive groups. Personally interviewed family members of these patients were compared on variables of bipolar illness or schizoaffective mania and unipolar or schizoaffective depression. A personally examined control group was compared with the relatives of the two proband groups. Similar analyses were performed using data obtained by a systematic family history method. For the same familial variables, psychotic and nonpsychotic manic probands were compared. RESULTS: Familial mania is more frequent in families of patients with bipolar disease than in controls or in families of patients with primary unipolar disorder. The latter two groups did not differ in amount of mania. Unipolar depressive illness or schizoaffective depression was higher in families of probands with bipolar and unipolar disorder than in controls. Probands with bipolar disease separated into those who had psychotic symptoms (including schizoaffective mania) and no psychotic symptoms did not differ from each other in risk for familial mania or depression. CONCLUSIONS: Bipolar I illness is a separate illness from primary unipolar illness because of an increase in familial mania. Patients with primary unipolar disease and controls show the same amount of familial mania. Lack of an increase in familial illness according to the severity of bipolar disease is against an affective continuum.

Adolescent↗

PubMed1995

Familial depression versus depression identified in a control group: are they the same?

Subjects who meet the criteria for an affective syndrome possibly are aetiologically heterogeneous. An approach to this possibility involves examining affectively ill subjects obtained by different methods of ascertainment. This study compares depressed and manic subjects who are related to affectively ill probands with affectively ill subjects who were obtained from a study of a control population, and, therefore, were less likely to be familial. The subjects were identified in a large collaborative study of depression where both family members as well as controls were personally interviewed and followed up for 6 years after admission to the study. Data were obtained on subtypes of affective disorder using the Research Diagnostic Criteria and information was gathered about psychiatric hospitalizations, suicide attempts, alcoholism and psychological functioning prior to admission. Similar assessments were made for the comparison groups for the 6 year period between intake and follow-up. Relatives of bipolar I/schizoaffective manic probands were more likely to show mania than affectively ill controls or relatives of unipolar/schizoaffective depressed probands. Affectively ill controls were less likely to be hospitalized and less likely to suffer from an incapacitating depression. They were also likely to have functioned in a more healthy fashion than the affectively ill relatives of the bipolars and unipolars, in the 5 years before admission to the study. In the 6 year follow-up, both the subjects themselves and raters assessed the depressed controls as functioning better than the affectively ill relatives of the probands. Further, assessment of global adjustment during the 6 year period was worse for the relatives of affectively ill probands than for the depressed controls. Length of major depression was longer in relatives of bipolar and unipolar probands than in controls. Though all of the subjects in this study met research criteria for an affective illness, there were marked differences in the qualitative aspects of these illnesses with the relatives of affectively ill probands, who functioned less well and had longer and more severe episodes and more hospitalizations.

Adaptation, Psychological↗

PubMed1995

Affective illness in family members and matched controls.

As part of the US National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, a subset of 460 randomly chosen relatives of affectively ill probands were compared to a control group matched by the acquaintanceship method. The rate of major affective disorder in relatives was found to be 36%; the rate among controls was 28%. Relatives were also found to have significantly higher rates of bipolar II disorder, any Research Diagnostic Criteria (RDC) affective disorder and any RDC mental disorder. All of these rates were found to be significantly higher when female relatives were compared with their acquaintances, but only the rate of any RDC mental disorder was higher when this comparison was made in men. The acquaintanceship method enabled the selection of a control group that closely resembled the relatives, probably to the extent of "overmatching". When the match was evaluated to determine whether relatives tended to select comparably ill (or well) acquaintances, this was found to be the case only for alcoholic and never mentally ill relatives.

Adult↗

PubMed1995

Alcoholism in manic-depressive (bipolar) illness: familial illness, course of illness, and the primary-secondary distinction.

OBJECTIVE: This 5-year follow-up study was designed to explore the factors that might lead to alcoholism in patients with bipolar disorder. METHOD: The authors studied patients with bipolar illness (70 with alcoholism and 161 without), their relatives, and a comparison group composed of relatives' acquaintances. All were evaluated with versions of the Schedule for Affective Disorders and Schizophrenia, and diagnoses were made according to the Research Diagnostic Criteria. Thirty of the bipolar alcoholic patients whose affective disorder was primary were also compared with 34 whose alcoholism was primary. RESULTS: Alcoholism was more frequent in the bipolar patients than in the comparison subjects. There no significant differences between the alcoholic and nonalcoholic bipolar patients in family history of alcoholism or affective disorders, suggesting that bipolar illness with alcoholism is not explicable by a family history of alcoholism and that the alcoholism seen in bipolar illness is dissimilar to alcoholism as a primary disorder. Alcoholism associated with bipolar illness was more likely to remit than primary alcoholism. There was no significant difference in family history between the patients with primary alcoholism and those with primary bipolar disorder. The patients with primary alcoholism had significantly fewer episodes of affective disorder during followup, suggesting that their type of bipolar illness was less severe and may have needed the added insult of alcoholism to make it manifest. CONCLUSIONS: The study supports the idea that not all alcoholism is primary with a corresponding familial diathesis. Rather, alcoholism associated with bipolar disorder is often a secondary complication.

Adult↗

PubMed1995

Long-term stability of polarity distinctions in the affective disorders.

OBJECTIVE: This analysis aimed to quantify the long-term stability of distinctions between nonbipolar, bipolar II, and bipolar I affective disorders and to determine the predictors of shifts in patients' diagnoses among these categories. METHOD: Probands entered the study as they sought treatment for manic, major depressive, or schizoaffective disorder diagnosed according to the Research Diagnostic Criteria. After thorough baseline evaluations, 605 patients with nonbipolar major depressive disorder or schizoaffective disorder, depressed type; 96 with bipolar II disorder; and 231 with bipolar I disorder or schizoaffective disorder, manic type, began the follow-up study. Direct interviews took place at 6-month intervals for the first 5 years and annually thereafter. RESULTS: Only 20 (5.2%) of the 381 initially nonbipolar probands who completed 10 years of follow-up developed mania during that time, and only 19 (5.0%) developed hypomania. A slightly higher proportion of the 67 who began with bipolar II disorder developed mania during the 10 years. Although 101 (66.4%) of the 152 bipolar I or schizoaffective manic probands developed subsequent manic episodes, only 11 (7.2%) developed hypomanic episodes and no mania. Young age at intake and at onset and chronicity of the index episode predicted shifts from nonbipolar to bipolar II disorder. Psychosis and a family history of mania predicted shifts from nonbipolar to bipolar I disorder. CONCLUSIONS: The high stability of baseline distinctions between nonbipolar, bipolar II, and bipolar I disorders, in combination with previously described family study data, strongly supports the separation of these disorders for both clinical and research purposes.

Adult↗

PubMed1995

Characteristics and significance of untreated major depressive disorder.

OBJECTIVE: This study sought to describe the characteristics and consequences of untreated major depressive disorder. METHOD: As part of a family study of probands with major affective disorders, raters assessed 3,119 first-degree relatives, spouses, and comparison subjects. When 2,237 (71.7%) of these individuals were reassessed 6 years later, 547 had experienced episodes of major depressive disorder in the interval. Those who had sought any form of treatment for any episode of major depressive disorder in the interval were compared, by baseline demographic characteristics and clinical features of their worst episodes of major depressive disorder, to those who had not. Individuals who had had untreated major depressive disorder were then compared, by changes in socioeconomic status and by levels of psychosocial impairment at follow-up, to a matched group with no major depressive disorder in the interval. RESULTS: The worst episodes of 313 treated individuals, compared to those of 234 untreated individuals, were characterized by older age, symptoms of the endogenous subtype, longer durations, and the presence of disruption in role function. Each of these factors contributed independently to the distinction between treated and untreated episodes. Untreated individuals experienced significant psychosocial impairment on follow-up but did not show the economic disadvantages shown elsewhere for probands who began follow-up as they sought treatment at tertiary medical centers. CONCLUSIONS: These data suggest that illness characteristics and age determine the decision to seek treatment for major depressive disorder. Untreated depression is apparently associated with long-standing psychosocial difficulties but not with serious economic consequences.

Adolescent↗

PubMed1994

The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies.

BACKGROUND: Most natural history studies of affective disorders have emphasized the prediction of eventual recovery. Little is known of changes over time in the immediate probability of recovery. METHODS: To identify regularities in the timing of recovery from nonbipolar major depressive disorders, we considered only episodes that began during follow-up to increase the accuracy with which onsets were timed and to limit the study sample to individuals who had a demonstrably episodic course. Five participating centers conducted baseline assessments and followed probands (N = 605) and nonclinical subjects (relatives, controls, and spouses, N = 826) up for 6 years. During that time, 359 probands had at least one prospectively observed episode, and 181 had two episodes; corresponding numbers for the nonclinical subjects were 216 and 78, respectively. Our analyses considered the distribution of episode lengths across ascertainment source (probands vs nonclinical subjects), center, and episode number (first vs second prospectively observed episode). RESULTS: Distribution was remarkably uniform. Regardless of ascertainment source, center, or episode number, recovery occurred within 3 months in 40% of episodes, within 6 months in 60%, and within 1 year in 80%; 20% had more protracted courses. CONCLUSIONS: Once triggered, the immediate likelihood of recovery changes over time in a predictable fashion. This has practical implications for the study of antidepressant efficacy and theoretical implications for factors involved in affective dysregulation.

Adolescent↗

PubMed1994

Recurrently situational (reactive) depression: a study of course, phenomenology and familial psychopathology.

Probands with non-bipolar major depressive disorder (MDD) were grouped according to the consistency across episodes with which depression appeared to arise from situational factors. Situational depression showed significant diagnostic stability across the second and third recurrences in a 10-year follow-up. The relatives of recurrently situational probands had higher neuroticism scores, higher lifetime rates of MDD and, when depressed, fewer endogenous symptoms than did the relatives of non-situational probands. This study joins two others in finding an association between stress-related depression and high familial loadings for MDD. It also illustrates the value of diagnostic consistency across episodes as a means of refining groups for the study of diagnostic subtypes.

Adjustment Disorders↗

PubMed1994

Manic-depressive (bipolar) disorder: the course in light of a prospective ten-year follow-up of 131 patients.

For a five-year period, 131 bipolar patients were followed every 6 months; for the next 5 years, they were followed yearly. Each patient was interviewed in a systematic way that gave information about episodes, hospitalizations, cycle lengths and the presence of alcoholism. Women and men were not significantly different in the number of follow-up manic or depressive episodes or hospitalizations. Chronicity from index episode to the end of the 10-year follow-up was uncommon (4%). Alcoholism, which was common in these patients, showed a great diminution at the end of 10 years. Contrary to expectation, cycle lengths showed no systematic decrease in length over the follow-up. In this naturalistic study, treatment intensity was not related to decreasing episodes or to changes in cycle length. The number of episodes in the first 5 years of follow-up was not correlated with the number of episodes in the last 5 years. Cycle lengths in the first 5 years of follow-up were similar in length to the last 5 years of follow-up. A family history of mania in these bipolar patients was associated with more episodes in follow-up than if such a family history were absent. The patients whose alcoholism predated the onset of their affective illness were less likely to have episodes in the follow-up than the patients in whom affective illness predated the onset of the alcoholism.

Adult↗

PubMed1994

The long-term stability of depressive subtypes.

OBJECTIVE: This study used the concept of diagnostic stability to examine the validity of three subtypes of major depression. METHOD: Patients with major depressive disorder (N = 424) were assigned baseline diagnoses according to structured interviews and the Research Diagnostic Criteria. Follow-up evaluations took place at 6-month intervals over the next 5 years and annually for an additional 3 years. During this period 424, 246, 163, and 96 of the patients who had recovered from the index episode had one, two, three, and four recurrences, respectively, of major depressive disorder. The kappa statistic was used to quantify the likelihood that patients with the psychotic, agitated/retarded, or endogenous subtype of depression in a given episode would again manifest that subtype in subsequent episodes. RESULTS: The psychotic subtype showed the most enduring diagnostic stability across multiple subsequent episodes. Even after three intervening episodes, patients with baseline psychotic major depression were five times more likely to develop a psychotic depression than were other depressed patients. For all three subtypes, diagnostic stability was greater for contiguous episodes than for noncontiguous episodes. Psychotic, agitated/retarded, and endogenous subtypes showed significant stability after control for the bipolar/unipolar and primary/secondary distinctions. The endogenous subtype was stable among patients with primary depression but not among those with secondary depression. CONCLUSIONS: The psychotic subtype was the most valid of the subtypes tested from the perspective of diagnostic stability. The fact that stability across adjacent episodes exceeded stability across more distantly spaced episodes may reflect state-dependent determinants, and these are likely to vary by subtype.

Bipolar Disorder↗

PubMed1994

Prognostic effect of the variable course of alcoholism on the 10-year course of depression.

OBJECTIVE: The purpose of this study was to examine the predictive effect of the clinical activity of patients' alcohol use on the course of major depressive disorder. METHOD: One hundred seventy-six probands with Research Diagnostic Criteria (RDC) diagnoses of both major depressive disorder and alcoholism were compared to 412 probands with major depressive disorder only by using 10 years of short-interval, prospective follow-up data collected as part of the National Institute of Mental Health Collaborative Depression Study. The course of depression was examined by using intensity analysis to represent transitions between states of major depressive disorder. The effect of patients' RDC alcoholism status on the long-term course of major depressive disorder was examined by stratifying the analyses by three levels of alcoholism--never alcoholic, not meeting criteria for current alcoholism, and current alcoholism. RESULTS: Depressed probands who were either never alcoholic or currently nonactive alcoholic had twice the likelihood of recovery from major depressive disorder than did actively alcoholic depressed probands. The three levels of alcoholism did not differentially predict recurrence of major depressive disorder. CONCLUSIONS: These findings provide long-term, empirically derived evidence for the deleterious effect of current alcoholism on recovery from depression. The lack of a differential effect of the three levels of alcoholism on recurrence of major depressive disorder suggests that other factors may have greater predictive value.

Adult↗

PubMed1993

A prospective follow-up of patients with bipolar and primary unipolar affective disorder.

OBJECTIVE: As part of the National Institute of Mental Health Collaborative Study of the Psychobiology of Depression, the comparative course of manic depressive (bipolar) and primary unipolar patients was assessed. DESIGN: Systematic evaluation using structured instruments every 6 months for a period of 5 years with the recording of remissions, new episodes, and subsequent hospitalizations. PATIENTS: The number of subjects varied somewhat depending on the analyses conducted. For a comparison of course in bipolar patients and unipolar patients, 148 bipolars were compared with 172 unipolar patients. RESULTS: Both unipolar and bipolar patients were more likely to have episodes if they had episodes prior to index admission. Likewise, prior hospitalizations predicted multiple hospitalizations in follow-up. Chronicity was significantly more prevalent among unipolar depressives but in both unipolar and bipolar patients, chronicity diminished over time. Bipolar patients were more likely than unipolar patients to have multiple episodes at the 2-year and 5-year follow-ups. In bipolar patients, there was no difference in the number of episodes in follow-up between males and females but in unipolar patients, females were significantly more likely to have subsequent hospitalizations and episodes than males. Treatment variables did not relate to these differences. A family history of mania or schizoaffective mania predicted multiple episodes in bipolar patients but not in primary unipolar depressives. A family history of all affective illness (mania, schizoaffective mania, bipolar II illness, and depression) did not predict a multiple-episode course in either bipolar or unipolar illness. In unipolar patients, the independent variables leading to multiple-episode course in follow-up are being female, an early age of onset, and prior episodes. CONCLUSIONS: As a result of this systematic follow-up study, new data add to the distinction between bipolar and primary unipolar patients both as regards number of episodes in follow-up and also as regards risk factors that are associated with the multiple-episode course.

Adult↗