J Neural Transm (2007) 114: 1091–1095 DOI 10.1007/s00702-007-0663-2 Printed in The Netherlands
Clozapine==olanzapine-induced recurrence or deterioration of binge eating-related eating disorders S. Gebhardt1;2 , M. Haberhausen1 , J.-C. Krieg2 , H. Remschmidt1 , M. Heinzel-Gutenbrunner1;3, J. Hebebrand4 , F. M. Theisen1 1
Clinical Research Group, Department of Child and Adolescent Psychiatry, University of Marburg, Marburg, Germany Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany 3 Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany 4 Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Duisburg, Germany 2
Received: August 9, 2006 = Accepted: February 9, 2007 = Published online: March 20, 2007 # Springer-Verlag 2007
Summary Objective. To explore the association between eating disorders (EDs) prior to the use of clozapine=olanzapine (pre-clozapine=olanzapine EDs) and after initiation of these antipsychotics (post-clozapine=olanzapine EDs). Method. Sixty-four consecutively admitted patients receiving clozapine= olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine=olanzapine EDs (DSM-IV criteria). We investigated post-clozapine=olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment. Results. Post-clozapine=olanzapine EDs were significantly more frequent in patients with pre-clozapine=olanzapine EDs (5 of 6) when compared to patients without pre-clozapine=olanzapine EDs (4 of 58) [w2 ¼ 26.29; df ¼ 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3–725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n ¼ 1) or probably (n ¼ 4) related to the intake of clozapine=olanzapine. Conclusion. Clozapine=olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs. Keywords: Eating disorders, binge eating, antipsychotics, clozapine, olanzapine, recurrence, deterioration, schizophrenia
Introduction Clozapine and olanzapine are atypical antipsychotics known to cause considerable weight gain (Allison et al., 1999), possibly via increments in appetite and=or carbohydrate
craving (Leadbetter et al., 1992; Br€omel et al., 1998; Costa e Silva et al., 2001). To date, single case reports indicate an association between the use of atypical antipsychotics and both the exacerbation of bulimia nervosa (BN; Brewerton and Shannon, 1992; Crockford et al., 1997) and the onset of binge eating symptomatology in patients with anorexia nervosa (AN; Mehler et al., 2001). In a prospective study of 12 patients with schizophrenia (Br€omel et al., 1998) we found clozapine to induce binge eating episodes with a sense of lack of control as specified for binge eating disorder (BED; Spitzer et al., 1993). In another study comprising 74 adolescent and young adult patients treated with clozapine or olanzapine (Theisen et al., 2003), we found a broad spectrum of binge eating symptomatology; 12.2% of the patients fulfilled criteria for BED and 4.1% for BN; patients with binge eating symptomatology showed higher weight gain during clozapine=olanzapine treatment than patients without binge eating. The current study aimed to assess whether patients who suffered from an eating disorder (ED) prior to the use of clozapine or olanzapine may develop recurrence or deterioration of binge eating symptomatology or full-blown EDs after initiation of these antipsychotics. Material and methods
Correspondence: Frank M. Theisen, M.D., Clinical Research Group, Department of Child and Adolescent Psychiatry, University of Marburg, Hans-Sachs-Str. 6, 35033 Marburg, Germany e-mail:
[email protected]
Subjects Patients were ascertained between March 2002 and June 2003 at the Departments of Psychiatry and Child and Adolescent Psychiatry of the
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University of Marburg using the following inclusion criteria: 1) duration of treatment with either clozapine or olanzapine for at least 4 weeks, 2) treatment of psychotic symptoms in the context of a schizophrenia spectrum disorder or other psychiatric disorders [per DSM-IV], 3) no other medical or neurological disorders or pregnancy. Out of 107 consecutively admitted patients who were screened, 88 fulfilled the inclusion criteria. Among them, 24 were not able or willing to participate. Hence, 64 of 88 (72.7%) patients (34 men; mean age 30.7 13.9 years, range 13.3–64.6 years) were investigated. Thirty-three patients were treated with clozapine, 31 with olanzapine. Patients were diagnosed with schizophrenia (52.3%), another schizophrenia spectrum disorder (12.3%), mood disorders (18.5%), substance abuse (7.7%), personality disorder (3.1%) or other diagnoses (7.7%). Patients and in case of minors additionally their parents gave written informed consent; the study was approved by the Ethics Committee of the University of Marburg. Assessment and instruments The 64 patients were interviewed using the standardized eating disorders module of the M-Composite International Diagnostic Interview (M-CIDI; Wittchen et al., 1998a, b). If subjects fulfilled criteria for a lifetime history of an ED, it was evaluated whether this disorder was present prior to the use of antipsychotics (pre-clozapine=olanzapine ED) as based on both information in their medical records and data obtained by the interview. We used the CIDI, with the possibility of diagnosing AN, because patients with AN may be at risk for developing a binge eating-related ED (Herpertz-Dahlmann et al., 2001). All patients were screened with the question whether they had eating binges after initiation of clozapine or olanzapine treatment during which
they ate within any two-hour period what most people would regard as an unusually large amount of food (Mussell et al., 1996). In the group of patients who screened positively, ED diagnoses were determined using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP; Spitzer et al., 1993) as face-to-face interview to diagnose BED according to DSM-IV research criteria and BN according to DSM-IV diagnostic criteria in order to identify first occurrence, recurrence or deterioration of binge eating symptomatology or full-blown EDs after initiation of clozapine=olanzapine treatment (post-clozapine=olanzapine EDs). BED was included in the current study as it represents a proposed diagnostic DSM-IV category for further study and as an example for an eating disorder not otherwise specified (EDNOS). Patients with pre- and post-clozapine=olanzapine EDs were then investigated as to whether recurrence or deterioration of binge eating symptomatology or EDs was related to the initiation of clozapine=olanzapine treatment using the adverse drug reaction (ADR) scale by Naranjo et al. (1981). The intraclass correlation coefficient of reliability (R[est] ¼ 0.92) suggests that the method can discriminate ADRs of different probabilities (‘‘definite, probable, possible, or doubtful’’). Although it was not the main topic of this study, we additionally assessed the following clinical data for exploratory analyses; these data refer to a three-month period after initiation of clozapine=olanzapine treatment. (1) Body weight gain was assessed retrospectively from records and was stated to be present if 5 kg or more had been gained within three months. (2) Increase in appetite was assessed in the face-to-face interview with the patient using a 4-point response ranging from 1 (not increased) to 4 (very much increased). (3) Treatment response was assessed as expert estimation from the treating physician using a 5-point ranging from 1 (no response) to 5 (very good response).
Table 1. Classification of reported eating behaviors according to the DSM-IV research criteria for binge eating disorder (BED) and the DSM-IV diagnostic criteria for the eating disorders (ED) anorexia nervosa (AN), bulimia nervosa (BN) and eating disorders not otherwise specified (EDNOS) in patients treated with clozapine (n ¼ 3) or olanzapine (n ¼ 3) Clozapine
Olanzapine
Patient (gender)
A (female)
B (female)
C (male)
D (female)
E (female)
F (female)
Pre -clozapine=olanzapine ED diagnosis Diagnosis=indication for the use of clozapine=olanzapine
BN EDNOS EDNOS BN borderline paranoid paranoid borderline personality schizophrenia schizophrenia personality disorder disorder
EDNOS AN paranoid major schizophrenia depressive disorder
Eating larger amounts in a discrete period of time Sense of lack of control over eating Frequency: 2 days=week Duration: 3 months=6 months Associated symptomsa Marked distressb Self-evaluation influenced by body shape and weightc Compensatory behaviors (fasting, sport, diet pills) Compensatory behaviors (vomiting, laxatives, diuretics, enemas)
þ þ þ þ=þ þ þ þ
þ þ þ þ=þ þ þ þ
þ þ þ = þ þ þ
þ þ
þ þ=þ þ
þ
þ þ
þ
Post -clozapine=olanzapine ED diagnosis
EDNOS (BED)
EDNOS (BED)
EDNOS (BN EDNOS criteria over 6 weeks)
Post -clozapine=olanzapine ED symptomatology
a
EDNOS
Criterion B of BED: at least 3 of the following 5 criteria: ‘‘eating much more rapidly than normal; eating until feeling uncomfortably full; eating large amounts of food when not physically hungry; eating alone because of being embarrassed by how much one is eating; feeling disgusted with oneself, depressed, or very guilty after overeating’’. b Criterion C of BED. c Criterion D of BN. Pre-=post- prior to=after initiation of clozapine=olanzapine treatment.
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Clozapine=olanzapine-induced recurrence=deterioration of eating disorders Statistics A Chi-square test was used to explore the association between pre- and postclozapine=olanzapine EDs. Potential body weight gain, increase in appetite, treatment response, and occurrence of post-clozapine=olanzapine EDs between patient groups were studied using t-tests for continuous variables and Chi-square tests for dichotomous data. Correlations between treatment response and increase in appetite were evaluated using the Pearson correlation coefficient. T-test was used for assessing differences in treatment response among patients with and without body weight gain. P-values were two-tailed; 0.05 was the significance level. Descriptive statistics were used for all other variables. The data were analyzed using Statistical Package of the Social Sciences (SPSS 12.0 for Windows) software.
Results Six (1 male, 5 females) of 64 subjects (9.4%) diagnosed with paranoid schizophrenia (n ¼ 3), major depressive disorder (n ¼ 1) and borderline personality disorder (n ¼ 2) met DSM-IV criteria for a pre-clozapine=olanzapine ED (details in Table 1). Five of the six patients who had suffered from pre-clozapine=olanzapine EDs fulfilled diagnostic criteria for post-clozapine=olanzapine EDs (Table 1): four patients (A, B, E, F) fulfilled DSM-IV diagnostic criteria for EDNOS (two fulfilled additionally DSM-IV research criteria for BED), one patient (D) displayed EDNOS with a bulimic symptomatology, while one patient (C) did not show any ED symptomatology. Post-clozapine=olanzapine EDs were significantly more frequent in patients with pre-clozapine=olanzapine EDs (5 of 6 patients, 83%) when compared to patients without pre-clozapine=olanzapine EDs (4 of 58 patients; 6.9%) [w2 ¼ 26.29; df ¼ 1; p< 0.001; odds ratio (OR) 67.5; 95% CI: 6.3–725.8; Table 2].
Table 2. Crosstabulation on frequencies of patients with=without pre=postclozapine=olanzapine EDs Post-clozapine= olanzapine ED n ¼ 9 Pre-clozapine= olanzapine ED n ¼ 6 No pre-clozapine= olanzapine ED n ¼ 58
No post-clozapine= olanzapine ED n ¼ 55
5
1
4
54
History of an eating disorder (ED) prior to the use of clozapine= olanzapine, assessed using the M-Composite International Diagnostic Interview (M-CIDI; Wittchen et al., 1998a, b). Eating disorder (ED) which started within three months after initiation of clozapine=olanzapine treatment, assessed using the Questionnaire on Eating and Weight Patterns (QEWP; Spitzer et al., 1993).
In four of the six patients with pre-clozapine=olanzapine EDs the ED (BN, n ¼ 2; EDNOS, n ¼ 2) was followed by an interval ranging from 0.5 to 10 years, during which patients did not fulfill diagnostic criteria for an ED (patients A–D; see Fig. 1). In three of these four patients ED sympomatology recurred immediately after clozapine=olanzapine treatment initiation. Two patients with pre-clozapine=olanzapine EDs (EDNOS, n ¼ 1; AN, n ¼ 1) showed no interval until initiation of clozapine=olanzapine therapy (patients E, F; Fig. 1); however, according to the patients’ report and the results of the QEWP, ED symptomatology deteriorated immediately after initiation of clozapine=olanzapine treatment. Among the five patients with post-clozapine=olanzapine EDs, the Naranjo probability scale revealed a definite (n ¼ 1) or probable (n ¼ 4) relationship between these EDs and clozapine=olanzapine intake (see Fig. 1).
Fig. 1. Schematic illustration of the time course of eating disorders (EDs) in six patients with EDs prior to the initiation of clozapine=olanzapine treatment
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Among the 58 patients without pre-clozapine=olanzapine EDs, four patients (6.9%) fulfilled criteria for post-clozapine=olanzapine EDs: three patients displayed EDNOS (two fulfilled additionally DSM-IV research criteria for BED), and one developed a bulimia nervosa (purging type). The Naranjo probability scale revealed a definite (n ¼ 2) or probable (n ¼ 2) relationship between these EDs and clozapine=olanzapine intake. Body weight gain of at least 5 kg within the first three months of clozapine=olanzapine treatment was found in 56.3% of the patients. The two drugs did not differ with respect to weight gain. Increase in appetite was reported to be extreme in 12.5%, very much increased in 20.3%, slightly increased in 35.9% and not increased in 21.9% of the patients, while 9.4% could not give precise information about change in appetite. Patients reported a significantly more increased appetite with clozapine treatment when compared to olanzapine (p ¼ 0.012). Increase in appetite was higher in patients with than without body weight gain (p ¼ 0.042). Treatment response on clozapine=olanzapine was very good in 18.8%, good in 23.4%, moderate in 21.9%, slight in 17.2%, not present in 7.8% (no data in 10.9%), and did not differ between the two drugs. There were no significant correlations between treatment response and increase in appetite. Patients with and without body weight gain did not differ in their treatment response. Discussion The current study suggests that clozapine or olanzapine may either induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs. In five of six patients who reported pre-clozapine=olanzapine EDs in adolescence or young adulthood, recurrence or deterioration of binge eating episodes developed immediately after initiation of these antipsychotics. These patients fulfilled DSM-IV diagnostic criteria for EDNOS; an objective causality assessment using the Naranjo probability scale (Naranjo et al., 1981) revealed a definite (n ¼ 1) or probable (n ¼ 4) relationship between post-clozapine=olanzapine EDs and the intake of these drugs. Further, statistical analysis revealed a significant (p< 0.001) association between pre- and post-clozapine= olanzapine EDs. The odds ratio was 67.5 indicating that patients with pre-clozapine=olanzapine EDs are at considerably higher risk of developing post-clozapine=olanzapine EDs than those without pre-clozapine=olanzapine EDs. In spite of the high statistical significance the given odds ratio of 67.5 probably does not represent an exact value, which is caused by the small number of patients with pre-clozapine=
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olanzapine EDs and indicated by the large confidence interval (CI: 6.3–725.8). Our results support findings from earlier studies that reported an association between the intake of clozapine= olanzapine and either the onset of binge eating symptomatology (Br€omel et al., 1998), BED or BN (Mehler et al., 2001; Theisen et al., 2001, 2003) or the exacerbation of BN (Brewerton and Shannon, 1992). Given that clozapine and olanzapine are the most potent antipsychotics to induce weight gain (Allison et al., 1999), it could be speculated that the observed hyperphagic eating patterns represent an increase in energy intake caused by central effects on the energy homeostasis system. Clearly, this theory cannot entirely explain the complexity of an ED. However, the initiation of clozapine=olanzapine treatment was probably or definitely related to post-clozapine=olanzapine EDs in five of our patients, suggesting that at least the onset of disturbed eating behavior may be judged to be due to the direct physiological effects of the substance. Inappropriate compensatory behaviors (such as fasting and=or purging) may represent attempts to counterregulate clozapine=olanzapine induced weight gain in some patients (Theisen et al., 2003). Interestingly, drugs which are associated with weight loss, such as the anticonvulsant topiramate, may also modify hyperphagic eating patterns. Thus, topiramate has been used successfully to treat BED (McElroy et al., 2003; Shapira et al., 2000) and it may antagonize weight gain induced by clozapine (Dursun and Devarajan, 2000; Sch€uler-Springorum et al., 2002) and olanzapine (Levy et al., 2002). One recent case report suggests that topiramate might trigger AN in susceptible individuals (Rosenow et al., 2002). These findings suggest that, although the underlying mechanisms are unknown, clozapine=olanzapine and topiramate work in the opposite direction and may be involved in changes in the energy homeostasis system resulting in ED symptoms. It is important to note that numerous psychiatric disorders per se are associated with EDs. Schizophrenia is associated with EDs in 1–3% (see Joos and Steinert, 1997). Except for one large-scaled study in hospitalised male veterans (n ¼ 466, 590) which revealed high comorbidity rates of psychotic disorders in patients with AN (36%), BN (18%) or EDNOS (27%) (Striegel-Moore et al., 1999), the prevalence of schizophrenia in samples of patients with EDs is generally below 10% (Foulon, 2003). Other analyses displayed high prevalence rates of EDs in patients with (especially borderline) personality disorders (58%; Rosenvinge et al., 2000) and affective disorders (45%; Geist et al., 1998). However, the extent to which these rates are potentially influenced by medication is not clear, be-
Clozapine=olanzapine-induced recurrence=deterioration of eating disorders
cause the use of drugs has not been investigated systematically in most of these comorbidity studies. The study is limited with respect to statistical analysis by an imbalance in the number of patients with versus without pre-clozapine=olanzapine ED (n ¼ 6 vs. n ¼ 58). Additionally, only inpatients were included and the data on EDs were assessed retrospectively. However, although focusing on inpatients may provide a more homogenous sample with respect to the treatment setting, the inclusion of outpatients in further studies is warranted. Another limitation may be the usage of the QEWP, which is especially suitable to identify binge-eating related eating disorders (BED and BN; Theisen et al., 2003). To gain more information on other associated symptoms, however, further studies may refer additionally to the ‘‘Eating Disorder Examination Questionnaire’’ (EDE-Q; Fairburn and Cooper, 1994), providing subscales on bulimia, dietary restraint, and shape= weight concerns, which would allow deeper exploration of, for example, the association of antipsychotic dosage and ED symptom subscales. Altogether, the study represents a naturalistic examination and is therefore of high clinical relevance. To our knowledge, this is the first study suggesting that clozapine and olanzapine may induce either recurrence or deterioration of EDs in patients with pre-clozapine=olanzapine EDs. Further studies on systematically ascertained community populations of individuals taking these antipsychotics are warranted to investigate the relationship between drug intake and EDs. Declaration of interest This study was supported by the ,,Bundesministerium f€ur Bildung und Forschung‘‘ (BMBF: 01GS0118 and NGFN2: 01GS0482) and the ,,Deutsche Forschungsgemeinschaft‘‘ (DFG: Re 471=11-2; Th 707=1-1).
References Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156: 1686–1696 Brewerton TD, Shannon M (1992) Possible clozapine exacerbation of bulimia nervosa. Am J Psychiatry 149: 1408–1409 Br€ omel T, Blum WF, Ziegler A, Schulz E, Bender M, Fleischhaker C, Remschmidt H, Krieg JC, Hebebrand J (1998) Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry 3: 76–80 Costa e Silva JA, Alvarez N, Mazzoti G, Gattaz WF, Ospina J, Larach V, Starkstein S, Oliva D, Cousins L, Tohen M, Taylor CC, Wang J, Tran PV (2001) Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America. J Clin Psychopharmacol 21: 375–381 Crockford DN, Fisher G, Barker P (1997) Risperidone, weight gain, and bulimia nervosa. Can J Psychiatry 42: 326–327
1095 Dursun SM, Devarajan S (2000) Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry 45: 198 Fairburn CG, Cooper MJ (1994) Changes in selective information processing with three psychological treatments for bulimia nervosa. Br J Clin Psychol 33: 353–356 Foulon C (2003) Schizophrenia and eating disorders. Encephale 29: 463–466 Geist R, Davis R, Heinman M (1998) Binge=purge symptoms and comorbidity in adolescents with eating disorders. Can J Psychiatry 43: 507–512 Herpertz-Dahlmann B, M€uller B, Herpertz S, Heussen N, Hebebrand J, Remschmidt H (2001) Prospective 10-year follow-up in adolescent anorexia nervosa – course, outcome, psychiatric comorbidity, and psychosocial adaptation. J Child Psychol Psychiatry 42: 603–612 Joos A, Steinert T (1997) Comorbidity of schizophrenia and bulimic anorexia. A case with forensic implications [German]. Nervenarzt 68: 417–420 Leadbetter R, Shutty M, Pavalonis D, Vieweg V, Higgins P, Downs M (1992) Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 149: 68–72 Levy E, Margolese HC, Chouinard G (2002) Topiramate produced weight loss following olanzapine-induced weight gain in schizophrenia. J Clin Psychiatry 63: 1045 McElroy SL, Arnold LM, Shapira NA, Keck PE Jr, Rosenthal NR, Karim MR, Kamin M, Hudson JI (2003) Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebocontrolled trial. Am J Psychiatry 160: 255–261 Mehler C, Wewetzer C, Schulze U, Warnke A, Theisen F, Dittmann RW (2001) Olanzapine in children and adolescents with chronic anorexia nervosa. A study of five cases. Eur Child Adolesc Psychiatry 10: 151–157 Mussell MP, Mitchell JE, de Zwaan M, Crosby RD, Seim HC, Crow SJ (1996) Clinical characteristics associated with binge eating in obese females: a descriptive study. Int J Obes Relat Metab Disord 20: 324–331 Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30: 239–245 Rosenow F, Knake S, Hebebrand J (2002) Topiramate and anorexia nervosa. Am J Psychiatry 159: 2112–2113 Rosenvinge JH, Martinussen M, Ostensen E (2000) The comorbidity of eating disorders and personality disorders: a metaanalytic review of studies published between 1983 and 1998. Eat Weight Disord 5: 52–61 Sch€uler-Springorum M, Hebebrand J, Wehmeier PM, Remschmidt H (2002) Is topiramate effective for weight loss in neuroleptic-induced obesity? 2 case reports [German]. Z Kinder Jugendpsychiatr Psychother 30: 51–58 Shapira NA, Goldsmith TD, McElroy SL (2000) Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry 61: 368–372 Spitzer RL, Yanovski S, Wadden T, Wing R, Marcus MD, Stunkard A, Devlin M, Mitchell J, Hasin D, Horne RL (1993) Binge eating disorder: its further validation in a multisite study. Int J Eat Disord 13: 137–153 Striegel-Moore RH, Garvin V, Dohm FA, Rosenheck RA (1999) Psychiatric comorbidity of eating disorders in men: a national study of hospitalized veterans. Int J Eat Disord 25: 399–404 Theisen FM, Cichon S, Linden A, Martin M, Remschmidt H, Hebebrand J (2001) Clozapine and weight gain. Am J Psychiatry 158: 816 Theisen FM, Linden A, K€onig IR, Martin M, Remschmidt H, Hebebrand J (2003) Spectrum of binge eating symptomatology in patients treated with clozapine and olanzapine. J Neural Transm 110: 111–121 Wittchen HU, Lachner G, Wunderlich U, Pfister H (1998a) Test-retest reliability of the computerized DSM-IV version of the Munich-Composite International Diagnostic Interview (M-CIDI). Soc Psychiatry Psychiatr Epidemiol 33: 568–578 Wittchen HU, Nelson CB, Lachner G (1998b) Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychol Med 28: 109–112
