Mania in the Nordic countries: Patients and treatment in the acute phase of the EMBLEM study

Transcription

1 Mania in the Nordic countries: Patients and treatment in the acute phase of the EMBLEM study JENS KNUD LARSEN, VIBEKE PORSDAL, TROND F. AARRE, HANNU J. KOPONEN, JORMA AARNIO, OLE KRISTIAN KLEIVENES, THE EMBLEM ADVISORY BOARD Larsen JK, Porsdal V, Aarre TF, Koponen H, Aarnio J, Kleivenes OK, and the EMBLEM Advisory Board. Mania in the Nordic countries: Patients and treatment in the acute phase of the EMBLEM study. Nord J Psychiatry 2009;63: In bipolar disorder, mood stabilizers and second-generation antipsychotics have a central role in pharmacotherapy. There are, however, substantial differences in how the treatment is realized in different countries. The aim of this paper was to compare the treatment of acute mania in the Nordic countries with other European countries during the first 12 weeks of the EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) study. Adult patients with bipolar disorder were enrolled within standard course of care as in/outpatients if they initiated/ changed oral medication with antipsychotics, anticonvulsants or lithium for treatment of acute mania. Five hundred and thirty European psychiatrists including 23 Nordic psychiatrists enrolled 3459 patients including 79 Nordic patients eligible for analysis using the same study methods assessing demographics, psychiatric history, clinical status, functional status and pharmacological treatment. Psychiatric status at inclusion measured by the Young Mania Rating Scale (YMRS) and the Clinical Global Impression*Bipolar Disorder (CGI-BP) were similar in the Nordic and European patient groups, which is surprising as 73% of the Nordic patients compared with 38% of the European patients were inpatients. In the Nordic group of patients, more patients were living independently. Before inclusion in the study more patients in the Nordic group had combination therapy, but after inclusion in the study the prescription pattern of psychopharmacy was similar in the Nordic and the European patient groups. This study indicated differences in admission patterns, patient social functioning and medical treatment in the Nordic patients compared with the European patients. Bipolar disorder, mood stabilizers, observational study, psychoactive medication, social functioning. Jens Knud Larsen, M.D., Gentofte Psychiatric Centre, Niels Andersensvej 65, DK-2900 Hellerup, Denmark, jela@geh.regionh.dk; Accepted 4 December Bipolar disorder has a lifetime prevalence of 12% (1, 2) and is a major cause of lost disability-adjusted life years (DALY s) in industrialized societies (3). In most individuals the disorder runs a chronic course with multiple relapses. Patients are symptomatic for more than 40% of the time, mostly with depressive symptoms (4, 5). Although bipolar disorder is among the most heritable of mental disorders (6), social and psychological factors are nonetheless of great importance for determining the onset and course of the disorder (7). While medication is the cornerstone of therapy, social factors such as availability of social support and access to adequate housing, work opportunities, and specialized care will truly influence the course of the illness. In recent years there has been an outstanding increase in our knowledge on the treatment of mania on the basis of randomized clinical trials (8). Many of these studies investigated combination therapy with mood stabilizers and second-generation antipsychotics in the treatment of mania in bipolar disorder (9). There is, however, quite limited knowledge on the actual use of antimanic agents in routine clinical conditions, and large observational studies are rare. Observational studies are more likely to be challenged for their internal validity than randomized clinical trials, but they provide relevant data about the actual use of therapies either as monotherapy or combination therapy in real world patients, that is, without excluding comorbidities, suicide risk, with flexible and broader dose ranges, and across all ranges of illness severity (10, 11). EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a large-scale observational # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis As) DOI: /

2 JK LARSEN ET AL. study carried out in 14 European countries. With more than 3600 patients enrolled, it is one of the largest studies ever conducted in bipolar disorder. Baseline data from EMBLEM have been used for identification of clinical subgroups of mania, for describing patients undergoing involuntary admission in acute mania, and for understanding the functional impairment in patients with mania (1214). Using the baseline and acute phase data from EMBLEM, we aimed to explore how the clinical and demographic variables and treatment scheme of the patients from Finland, Norway and Denmark differed from the patients from other European countries participating in the study. The Nordic countries are societies with universal mental health service coverage in the public sector, with high average income, and high level of education. We hypothesized that this would lead to the Nordic patients being better socially integrated and having less severe illness at inclusion as compared with the total European sample. In particular we wanted to learn whether specific sociodemographic variables and treatment strategies were different in the Nordic countries compared with other European countries. Methods The EMBLEM study is a prospective, observational study of the outcome of treatment of manic and mixed episodes in bipolar disorder. Psychiatrists in 14 European countries enrolled patients in the study, among these, psychiatrists in the three Nordic countries Finland, Norway and Denmark. The other countries were France, Italy, Germany, Greece, the Netherlands, UK and Ireland, Belgium, Spain, Portugal and Switzerland. EMBLEM was divided into an acute phase from baseline to 12 weeks and a maintenance phase up to 24 months. The study methodology has been previously reported (12). This paper describes the acute phase only. The inclusion criteria were as follows: adult patients presented within the standard course of care with manic or mixed bipolar episode, they initiated or changed oral medication for treatment of acute mania with antipsychotics, anticonvulsants and/or lithium, and they did not, at the same time, participate in an interventional study. Psychiatric diagnosis of an acute manic/mixed episode was made by standard diagnostic criteria (15, 16) and/or clinical judgment. Both inpatients and outpatients could participate in the study. At the sponsor s request, participating investigators were asked to roughly recruit half of the sample from among those patients starting treatment with olanzapine or any combination of olanzapine with other drugs. The rest of the patients could be taking any other (or any other combination) of treatment(s). The decision to oversample the olanzapine group was to have sufficient power for specific analyses on olanzapine treatment of mania. In countries where such a targeted selection of patients was not possible within the legal definition of observational studies, e.g. Denmark, patients were selected by the investigators with no requests regarding treatment. Participating investigators were asked to make treatment decisions, including the initial oral treatment change, independently from participation in the EMBLEM study. All treatment decisions throughout the observational period (doses of treatments, treatment changes etc.) were made by the treating psychiatrist and no instructions regarding treatment were included in the study description. Observations were scheduled collected at baseline, and at 1, 2, 3, 6 and 12 weeks after baseline. Observations only occurred if the patient was seen as part of the normal clinical care. Basic socio-demographic and psychiatric history data were collected to characterize the patient sample including age, gender, educational status, onset of first affective symptoms, first contact with psychiatric services and first hospital stay as inpatient because of psychiatric symptoms, history of substance abuse, history of suicide attempts, frequency of manic and depressive episodes during previous 12 months and use of psychiatric healthcare during the previous 12 months. Functional status was assessed by collecting information on living conditions, level of education and social activity pattern. Impairment in work activities over the previous 12 months was rated by the investigators. The patients were assessed by means of the following scales: The Clinical Global Impression*Bipolar Disorder (CGI-BP) scales on overall, mania and depression (17), CGI hallucinations/delusions and the Young Mania Rating Scale (YMRS) (18) Time to improvement and number of patients achieving recovery were evaluated by means of the CGI-BP scales. Information on medication for bipolar disorder (antipsychotics, anticonvulsants, lithium and antidepressants), their respective doses and mode of intake as well as information on concomitant medication was collected at baseline and at each subsequent visit. Information on compliance and reason to prescribe a new medication was also collected. The reasons to prescribe a new medication were categorized as: no previous medication, lack of compliance, ineffectiveness, patient s request, intolerability and other causes. The purpose of this paper is to describe the disease characteristics and the treatment prescriptions of the Nordic group of the patients, using the European group of patients as a reference population. Because of this approach, only descriptive statistics are presented, and statistical tests are not performed as differences between groups with respect to one characteristic may be due to differences in other characteristics rather than to differences in country. The Nordic group of patients and the European group of patients are presented as two separate groups. Median time to change of medication 286 NORD J PSYCHIATRY VOL 63 NO

3 THE NORDIC EMBLEM PATIENTS and median time to improvement, defined as a decrease of at least 2 points from baseline on the CGI-BP overall score, were measured using KaplanMeier survival analyses approach. Recovery, defined as having a score of less than 3 on the CGI-BP overall where the score then remained at less than 3 for the two following assessments, was summarized as all other categorical variables by frequency and percentages. YMRS and CGI-BP scores were treated as continuous measurements and summarized by mean, median and standard deviation (s). All participating patients gave written informed consent. Ethical committees approved the study according to national guidelines. Results Demographics and clinical variables A total of 79 Nordic patients and 3380 patients from the other European countries were enrolled in the study between December 2002 and June 2004 and were eligible for analysis. Age at onset of illness and age at inclusion in EMBLEM were similar for the Nordic and the other European patients (Table 1). The mean numbers of manic/mixed and depressive episodes in the previous 12 months for the Nordic and the other European patients were 1.7 and 1.6 for manic/mixed episodes, and 0.9 and 0.8 for depressive episodes respectively. The severity of illness at inclusion in EMBLEM, measured with YMRS and CGI-BP, was also similar for the Nordic and the European patients even though 73% (58/79) of the patients in the Nordic sample were recruited during a hospital admission, compared with 38% (1299/3380) in the European sample. The other patients in the study were treated as outpatients, and in some of the European countries nearly all the included patients were outpatients. The share of inpatients admitted non-voluntarily was the same in the Nordic countries and in Europe, 40% in the Nordic group of patients and 41% among the European patients. Psychotic symptoms were common; almost half of the patients had hallucinations and/or delusions at inclusion. In the Nordic group more patients were living independently during the previous 4 weeks before entering the study compared with the European patients. Also, more of the Nordic patients had five or more social activities during the previous 4 weeks. The Nordic group of patients had a higher level of education than the European group measured as the proportion of patients educated above secondary lower level. However, the Nordic study investigators rated more patients as being unable to carry out work activities during the previous year than the European psychiatrists (Table 1). Use, abuse and dependence on alcohol in the previous 3 months was more common in the Nordic patients, but Table 1. Psychiatric history, clinical and social functioning. Nordic patients (n79) European patients (n3380) Age at inclusion in 46.9 years (14.00) 44.6 years (13.39) EMBLEM (mean, s) Age at first experience of 34.7 years (13.22) 31.4 years (11.68) manic/mixed episode (mean, s) Age at first experience of 32.0 years (11.77) 31.0 years (11.55) depressive episode (mean, s) First episode 11% (8/73) 7% (216/3156) Suicide attempt ever 14% (11/79) 28% (904/3291) YMRS at inclusion 25.8 (8.20) 26.4 (10.01) (mean, s) YMRS at inclusion, 21.1 (6.96) 23.6 (8.80) outpatients YMRS at inclusion, 27.6 (7.98) 30.9 (10.19) inpatients CGI-BP mania at 4.7 (0.95) 4.8 (0.97) inclusion (mean, s) Hallucinations/delusions 41.9 (26/62) 49.5 (1449/2929) at inclusion (%, n/n) Use, abuse and dependence 63% (48/76) 42% (1367/3226) on alcohol in the previous 3 months Use, abuse and 4% (3/69) 12% (375/3155) dependence on cannabis in the previous 3 months Living independently 76% (60/79) 58% (1949/3371) during the previous 4 weeks 5 or more social activities 53% (42/79) 37% (1230/3367) during previous 4 weeks Education above 74% (53/72) 56% (1852/3316) secondary lower level Rated as being unable to work 45% (32/71) 22% (694/3211) EMBLEM, European Mania in Bipolar Longitudinal Evaluation of Medication; s, standard deviation; YMRS, Young Mania Rating Scale; CGI-BP, Clinical Global Impression*Bipolar Disorder. use, abuse and dependence on cannabis was less common among the Nordic patients compared with the European patients (Table 1). Suicide and suicide attempts were rare events during the 12-week follow-up period; however, more patients in the European sample had a history of suicide attempts than in the Nordic sample. Symptom severity at 6 and 12 weeks after inclusion in EMBLEM measured with the YMRS and CGI-BP scales were similar in the Nordic and European populations (Fig. 1a and 1b, Fig. 2a and 2b). Median time to improvement was around 24 days after baseline for the patients in the Nordic group (median survival time) and 22 days in the European group; 17% of the Nordic patients and 26% of the European patients achieved recovery. NORD J PSYCHIATRY VOL 63 NO

4 JK LARSEN ET AL. Fig. 1. Young Mania Rating Scale (YMRS) scores at baseline, week 6 and week 12 for (a) the Nordic patients and (b) the European patients excluding the Nordic patients. Pharmacotherapy Before any change in antimanic prescription at baseline, about one in four of the Nordic patients used no antimanic medication (Table 2). Approximately one in three used one medication, and 43% of the Nordic patients used two or more antimanic medications at inclusion. In comparison 35% of the other European patients used two or more antimanic medications at inclusion. Only 10 of the 79 Nordic patient used lithium or anticonvulsants as monotherapies. Typical antipsychotics and atypical antipsychotics were used with similar frequency, both as monotherapy and combination therapy, among the Nordic patients. In total 33% of the patients from the Nordic countries got atypical antipsychotics, compared with 22% for the rest of Europe. At inclusion, we identified seven different monotherapies and 11 different combination regimens used by the Nordic patients. In addition, 29% (23/78) of Nordic patients used antidepressants. The use of antidepressants was not different from the total European sample. Fig. 2. Clinical Global Impression*Bipolar Disorder (CGI- BP) scores (overall, mania, depression and hallucinations/ delusions) at baseline, week 6 and week 12 for (a) the Nordic patients and (b) the European patients excluding the Nordic patients. At baseline, all patients received a new oral medication. For the Nordic patients the reasons for this change were ineffectiveness of the ongoing medication (45%), lack of compliance (16%) and intolerability (12%) in order of falling frequency. In 67% (53/79) of the Nordic patients and in 66% (2221/3380) of the European patients combination therapies were prescribed (Table 2). Combination regimens with antipsychotics were most frequently used in the Nordic as well as in the European cohort (Table 3). This finding is in agreement with the study description, which prescribed that roughly half of the patients enrolled should be patients treated with olanzapine following baseline. The most striking result after initiation of new medication was the greater proportion of antidepressant use in the European EMBLEM sample (19% vs. 13% in the Nordic sample) and the 288 NORD J PSYCHIATRY VOL 63 NO

5 THE NORDIC EMBLEM PATIENTS Table 2. Number of antimanic medications taken before and after inclusion. No medication (%) Monotherapy (%) Combination therapy (%) Before inclusion Nordic patients (n79) European patients (n3380) After inclusion Nordic patients (n79) European patients (n3380) high proportion of Nordic patients (79%) taking benzodiazepines, compared with 60% of the European sample. The median time to the following change in medication after baseline, i.e. the time period between the prescription of new medication at baseline and the next change of medication (either starting another new medication or stopping medication), was also similar in the Nordic group and in the total European group, at 16 and 17 days respectively. Table 3. Treatment following start of new antimanic medication. Treatments Nordic patients (n79) European patients (n3380) Monotherapies (%) (n26) (n1159) Atypical antipsychotics (%) Anticonvulsants (%) Lithium (%) 12 5 Typical antipsychotics (%) 4 6 Combination therapies (%) (n53) (n2221) Atypical antipsychotics anticonvulsants (%) Atypical antipsychotics lithium (%) Atypical antipsychotics 11 7 lithiumanticonvulsants (%) Typical antipsychotics 9 9 anticonvulsants (%) Antidepressants (%) Benzodiazepines (%) Discussion The EMBLEM study found interesting descriptive differences between patients from the Nordic countries and patients from the other European countries. Nordic patients had a greater proportion with a higher level of education, more lived independently, and had more social interaction. They were, however, reported as less able to work than their European counterparts, possibly because of more social support and government benefits in the Nordic countries. Severity of illness was comparable, although more of the Nordic patients were treated as inpatients. There were few differences in pharmacotherapy. Patients were treated with a number of different regimens, both before and after inclusion in the study. The rather high percentage of patients that continued antidepressants during the acute treatment for mania deserves further study, as it is not in line with the general recommendation that antidepressants should be discontinued in the event of onset of manic symptoms (19, 20). Observational studies have some limitations when attributing outcomes to different treatments. However, they also have many other virtues that merit consideration. While randomized controlled trials typically have inclusion criteria that make their findings hard to generalize, observational studies can enroll reallife patients who are more representative of clinical practice without imposing pre-defined treatment options as decided per protocol. Because of less strict inclusion and exclusion criteria, observational studies may include patients with different degrees of symptom severity and comorbidities and therefore have the potential of providing information on patient populations that are routinely excluded from clinical trials (10, 21). However, the less strict inclusion and exclusion criteria may also have as a consequence that study samples vary between centers. While making it hard to make causal inferences in the absence of strict treatment protocols, observational studies can inform us about the clinical course of illness as treated in ordinary care, and they may generate hypotheses for further investigation in randomized clinical trials. Thus EMBLEM has contributed to better understanding of the clinical course of bipolar disorder complicated by substance abuse (12). Rating scales used in randomized clinical trials are designed to measure symptom severity. They may be inappropriate in clinical practice, where quality of life and social outcome measures as independent living, education, employment and meaningful personal relationships are more important. One of the main findings in this study was that the Nordic patient population differed from the European sample in terms of a variety of social outcome measures. There are a number of limitations to naturalistic, observational studies: differences in treatment setting may be due to artifacts of study design and selection of patients rather than reflect true differences in treatment patterns. Clinical studies include convenience NORD J PSYCHIATRY VOL 63 NO

6 JK LARSEN ET AL. samples, and the larger proportion of inpatients in the Nordic sample may simply be explained by more eligible inpatients being accessible to the investigators in question. We would predict illness severity to be a robust predictor of treatment setting. For this reason it is intriguing that patients in the Nordic countries, of whom more were treated as inpatients, had no more severe illness at inclusion than their European counterparts. Provision of healthcare for bipolar patients in manic or mixed episodes may not be determined solely by clinical status. Societal factors, such as availability of hospital beds and insurance coverage, probably influence the choice of treatment setting. We note that Nordic patients more often were living independently and more often were considered unable to work. This may make for lack of social support and increase the probability of being treated as an inpatient. Many Health Authorities and Professional Societies have published treatment guidelines for patients with bipolar disorder (20, 22). We know little about the dissemination of guidelines or how*if at all*they are implemented. Judging from our findings, current guidelines favoring monotherapy have limited impact on the actual treatment bipolar patients receive when they are manic or in mixed episodes. Conclusion This study indicated differences in admission patterns and patient social functioning between Nordic and European patients. When it comes to treatment there did not seem to be any consensus on the treatment of acute mania and mixed episodes. Most patients were prescribed two or more medications. The acute phase data cannot tell us how long patients are going to continue the combination therapies; however, there are reasons to believe that many patients will be maintained on multiple medications in long-term prophylaxis. Acknowledgements*The EMBLEM Advisory Board: (Belgium) Prof. Bernard Sabbe; (Denmark) Dr Jens Knud Larsen; (Finland) Prof. Hannu Koponen; (France) Dr Isabelle Gasquet; (France) Prof. Jean Michel Azorin; (Germany) Dr Heinz Grunze; (Italy) Prof. Giovanni Battista Cassano; (Netherlands) Prof. Willem Nolen, Prof. Jim van Os; (Norway) Dr Trond Aarre; (Portugal) Prof. Filipe Arriaga; (Spain) Dr Ana Gonzalez Pinto, Dr Josep Maria Haro, Prof. Eduard Vieta; (Switzerland) Prof. Dr med Jules Angst; (UK) Dr John Cookson, Prof. Martin Knapp; (USA) Dr. Mauricio Tohen. The EMBLEM study is funded by Eli Lilly and Company Limited, Windlesham, Surrey, UK. References 1. Kringlen E, Torgersen S, Cramer V. A Norwegian psychiatric epidemiological study. Am J Psychiatry 2001;/158:/ Kessler RCm McGonalge KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III- R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;/51:/ Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;/349:/ Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;/59: / Post RM, Denicoff KD, Leverich GS, Altshuler LL, Frye MA, Suppes TA, Rush AJ, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH Life Chart Method. J Clin Psychiatry 2003;/64: / Kieseppa T, Partonen T, Haukka J, Kaprio J, Lönnquist J. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 2004;/161:/ Post RM, Leverich GS, Xing G, Weiss RB. Developmental vulnerabilities to the onset and course of bipolar disorder. Dev Psychopathol 2001;/13:/ Vieta E, Goikolea JM. Atypical antipsychotics: Newer options for mania and maintenance therapy. Bipolar Disord 2005;/7(Suppl 4):/ Muzina DJ, Calabrese JR. Maintenance therapies in bipolar disorder: Focus on randomized controlled trials. Aust NZJ Psychiatry 2005;/39: / Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996;/312:/ Vieta E, Panicoli F, Goetz I, Reed C, Gomes M, Tohen M for the EMBLEM Advisory Board. Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12 week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study. J Clin Psychiatry 2008;106: Haro JM, van Os J, Vieta E, Reed C, Lorenzo M, Goetz I, EMBLEM advisory board. Evidence of three distinct classes of typical, psychotic and dual mania: Results from the EMBLEM study. Acta Psychiatr Scand 2006;113: Schuepbach D, Goetz I, Boeker H, Hell D. Voluntary vs. involuntary hospital admission in acute mania of bipolar disorder: Results from the Swiss sample of the EMBLEM study. J Affect Disord 2006;/90:/ Goetz I, Tohen M, Reed C, Lorenzo M, Vieta E. Functional impairment in patients with mania: Baseline results of the EMBLEM study. Bipolar Disord 2007;/9:/ American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV). Washington, DC: American Psychiatric Association; World Health Organisation. The ICD-10 classification of mental and behavioural disorders. Diagnostic criteria for research. Geneva: World Health Organisation; Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the clinical global impressions (CGI) scale for use in bipolar illness (BP): The CGI-BP. Psychiatry Res 1997;/73:/ Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry 1978;/ 133:/ Vestergaard P, Licht RW. Treatment of bipolar depression with antidepressants- a dilemma. Ugeskr Læger 2000;/162:/ Licht RW, Vestergaard P, Kessing LV, Larsen JK, Thomsen PH. Psychopharmacological treatment with lithium and antiepileptic drugs: Suggested guidelines from the Danish Psychiatric Association and the Child and Adolescent Psychiatric Association in Denmark. Acta Psychiatr Scand 2003;/108(Suppl 419):/ Haro JM, Edgell ET, Novick D, Alonso J, Kennedy L, Jones PB et al. Effectiveness of antipsychotic treatment for schizophrenia: 6-month results of the Pan.European Schizophrenia Outpatient Health Outcomes (SOHO) study. Acta Psychiatr Scand 2005;/111:/ NORD J PSYCHIATRY VOL 63 NO

7 THE NORDIC EMBLEM PATIENTS 22. American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder. Washington, DC: American Psychiatric Association; Jens Knud Larsen, M.D., Gentofte Psychiatric Centre, Niels Andersensvej 65, DK-2900 Hellerup, Denmark. Vibeke Porsdal, M.D., Ph.D., Eli Lilly Denmark, Nybrovej 110, DK Lyngby, Denmark. Trond F. Aarre, M.D., Nordfjord Psychiatric Centre, Sjukehusvegen 9, N-6770 Nordfjordeid, Norway. Hannu J. Koponen, Professor, Department of Psychiatry, Kuopio University and Department of Psychiatry, Kuopio University Hospital, PO Box 1777, FIN Kuopio, Finland. Jorma Aarnio, Chief psychologist, Hämeenlinna Prison Hospital, Pikku-Parolantie 7, Hämeenlinna, Finland. Ole Kristian Kleivenes, M.D., Eli Lilly Norge A.S, Grenseveien 99, PO Box 6090 Etterstad, N-0601 Oslo, Norway. NORD J PSYCHIATRY VOL 63 NO