International Journal of Psychiatry in Clinical Practice, 2007; 11(2): 123 128
ORIGINAL ARTICLE
Efficacy and tolerability of quetiapine in cluster B personality disorder: an open-label study
YVES LE BLOC’H1, PIERRE BAUMANN2, MICHAEL STIGLER3, CHIN B. EAP2 & DANIELE F. ZULLINO4* ˆ ge Avance´, Site de Cery, De´partement Universitaire de Psychiatrie Adulte et Service Universitaire de Psychiatrie de l’A 2 Prilly-Lausanne, Switzerland, Unite´ de Biochimie et Psychopharmacologie Clinique, De´partement Universitaire de Psychiatrie Adulte, Centre de Neurosciences Psychiatriques, Site de Cery, Prilly-Lausanne, Switzerland, 3Unite´ de Recherche en Epide´miologie Psychiatrique, De´partement Universitaire de Psychiatrie Adulte, Site de Cery, Prilly-Lausanne, Switzerland, and 4De´partement Universitaire de Psychiatrie Adulte, Site de Cery, Prilly-Lausanne, Switzerland 1
Abstract Objective . The aim of this open-label 8-week study was to assess the effectiveness of quetiapine on aggressive behaviour and social dysfunctions in patients suffering from a cluster B personality disorder (DSM-IV). Methods . The visits were performed at baseline and at days 14, 28 and 56. After a standard titration schedule, the patients received a dose augmented or reduced dose, within a range from 50 to 400 mg/day during the visits, depending on efficacy and tolerance. Assessment of efficacy was based on the French version of the Social Disability and Aggression Scale SDAS (SDAS-21). Response was defined as a decrease of ]/50% reduction of the total scores compared to baseline. Tolerability was assessed with the CGI, UKU, EPS-scales. Results and conclusion . Eight of the 12 patients included received 200 mg/day quetiapine after titration (all patients: 50 400 mg/day). At week 8, five out of 12 patients were responders based on the SDAS-21 scores for the average expression of the symptoms, and six out of 12 on the basis of SDAS-21 scores for the peak expression. There was a significant correlation between weight change and total SDAS variation (Kendall’s tb / /0.644; p /0.02). These findings should be reexamined in further studies.
Key Words: Quetiapine, cluster B personality disorder, weight, SDAS, plasma concentrations
Introduction Antipsychotic drugs have long been a widespread approach for treating patients with personality disorders. Data on conventional antipsychotics have suggested some utility against psychoticism, whereas there is less evidence for their efficacy against depressive, suicidal and anxious symptoms [1 3]. Despite this, conventional antipsychotics are associated with an important risk of adverse drug reactions, especially extrapyramidal side effects (EPS), and cluster B personality disorder patients have been described to be particularly sensitive to EPS [2]. There has recently been an increasing interest in the use of atypical antipsychotics in this type of patient. Two open-label trials have studied the efficacy of the atypical antipsychotic drug clozapine in patients presenting borderline personality disorder. In a
study [4] of 15 borderline outpatients, meeting concomitantly DSM-III-R criteria for psychotic disorder, clozapine significantly decreased positive, negative and general symptoms, and improved psychosocial functioning when followed up for 2 9 months. In a 16-week trial including 12 inpatients with DSM-IV borderline personality disorder and severe psychotic-like symptoms, clozapine significantly improved psychotic symptoms, depression, impulsivity, and affective lability [5]. Several studies have investigated olanzapine for patients with cluster B personality disorder. In an 8-week open study [6], 11 patients with borderline personality disorder and dysthymic disorder were included. Significant reductions were found with regard to obsessive-compulsive symptoms, interpersonal sensitivity, depression, anger-hostility, phobic anxiety, paranoia, psychoticism and impulsivity. No
Correspondence: Professor P. Baumann, Ph.D., Unite´ de Biochimie et Psychopharmacologie Clinique, De´partement Universitaire de Psychiatrie Adulte, Centre de Neurosciences Psychiatriques, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland. Tel: /41 21 643 6434. Fax: /41 21 643 6444. E-mail: [email protected] *Present address: Service de Toxicologie, Hoˆpitaux Universitaires de Gene`ve, 1200 Gene`ve, Switzerland.
(Received 9 March 2006; accepted 27 June 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500600885556
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significant decline was found on a measure of aggression. In an open series of 10 patients presenting cluster B personality disorder [7], using a mirror-image design anchored to the start date of olanzapine treatment and extending 8 weeks in either direction, found depressive and anxious symptoms as well as impulsive/aggressive behaviours to be improved. In five of the 10 patients, the improvements were particularly rapid, described as occurring within 1 week after the introduction of olanzapine. In several other studies [810], olanzapine showed interesting results (in monotherapy or in combination with fluoxetine) in patients with borderline personality disorder on different characteristic symptoms, namely aggression. Besides two other case reports [11,12], risperidone was studied in an 8-week open-label trial [13]. Six out of 15 patients meeting DSM-IV criteria for borderline personality disorder improved significantly on six of the study’s eight outcome measures. In terms of symptom areas, subjects reported significantly less severe general psychopathology, anergia, hostility and suspicion, depression and aggression. Measures of anxiety and depression, as well as thought disturbance, did not demonstrate significant change over time. Quetiapine is a novel, atypical antipsychotic drug, with a broad spectrum of in vitro receptor affinity similar to that of clozapine, although with lower absolute affinities for most important receptor subtypes. The report of improvement of impulsive behaviour and severe self-mutilation in two female patients with the diagnoses of borderline personality disorder [14] has suggested its possible interest for this indication. Expanding the indication on another cluster B personality disorder, a recent series of four patients with antisocial personality disorder [15] showed some efficacy of quetiapine in treating impulsivity, hostility, aggressiveness, irritability and rage reactions at doses between 600 and 800 mg/day. In a 12-week case series study with patients suffering from borderline personality disorder and psychosis, a mean dose of 537 mg/day quetiapine improved symptoms of depression, psychosis and impulsivity, and the treatment was well tolerated [16]. Another sample of patients with a borderline personality disorder, but with few psychotic symptoms, was treated with a mean dose of 251 mg/day (range 175 400 mg/day) quetiapine. The authors reported on a strong positive clinical impact after already 2 weeks, and in particular, impulsivity was reduced by the treatment [17]. Clinical studies on the treatment of personality disorders were based mostly on the use of scales of general psychopathology including some aggressionrelated questions, such as the Brief Psychiatric Rating Scale or used self-rating scales such as the Buss and Durkee Hostility Inventory, which have, as a major drawback, their reliance on patient
cooperation. Two newer scales were developed in the 1980s measuring aggressive behaviour: the Overt Aggression Scale and the Staff Observation Aggression Scale. These instruments measure direct aggressive behaviour but are not aimed to assess aggressive behaviour other than obvious violence and assaults. More subtle vexatious, reactive or irritable behaviour may, however, also have a socially disturbing effect and make care and rehabilitation more troublesome and discouraging for the patients as well as for their caregivers. The Social Dysfunction and Aggression Scale (SDAS-21) has been developed to cover the total range of mild, moderate and severe aggressiveness [18]. The objective of the present open study was to evaluate the impact of quetiapine on outward and inward aggressive behaviour as well as social dysfunctions in patients with cluster B personality disorder. Methods This was an open-label 8-week study, performed in the section of personality disorders of the Psychiatric University Hospital of Lausanne, Switzerland. To be included, patients had to be at least 18 years of age and satisfy the DSM-IV criteria for a cluster B personality disorder, i.e. borderline, histrionic, narcissistic, or antisocial personality disorder. Exclusion criteria were a diagnosis of schizophrenia or bipolar affective disorder, the presence of an organic mental disorder, a history of seizures, the presence of a serious somatic disease, pregnancy, lactation, or childbearing potential without effective contraception. Whereas dependence from drugs other than nicotine was an exclusion criterion, drug abuse was not. The study was approved by the local ethics committee. Informed consent was obtained from each patient before study-related procedures were initiated. Quetiapine treatment was introduced using the standard titration schedule recommended by the Swiss Medical Compendium [19]. The patients received on day 1, 25 mg b.i.d.; on day 2, 50 mg b.i.d.; from day 3 to 14, 100 mg b.i.d. Thereafter, the dose could be increased or reduced during the visits depending on efficacy and tolerance, within a range from 50 to 400 mg. From day 29 on, any dose change was prohibited. Concomitant somatic treatments were allowed without restrictions, and concomitant psychotropic drugs had to be maintained at the same dosage (9/30% allowed) throughout the study. However, concomitant treatment with antipsychotic medications was excluded. The primary assessment of efficacy was based of the French version of the Social Disability and Aggression Scale SDAS (SDAS-21) [20]: this
Quetiapine in cluster B personality disorder instrument measures specifically some symptoms which are pivotal for the treatment of cluster B personality disorders, such as irritability, dysphoria, interpersonal difficulties, aggressive behaviour and addictive behaviour. The items 1 15 of the 21-item version of the SDAS are observer-rated and the items 16 21 patient-rated. SDAS ratings are usually based on the totality of information pertaining to the previous week. Two scores for each item are determined, one indicating the average expression of the concerning symptom over the preceding week, and a further score representative of peak episodes. Besides the total score of the 21 items, two subscales are defined: The SDAS-9, including nine items, represents outward aggression. The SDAS-6, including six items, labels inward aggression. Response was considered for this study to have occurred in the case of a 50% reduction of the total scores compared to baseline. Tolerability was evaluated with the UKU scale [21], the Barnes Akathisia Scale, the Abnormal Involuntary Movement Scale and the Simpson Angus Rating Scale for Extrapyramidal Side-Effects. General clinical chemical and hematological tests and drug screenings were carried out at baseline and on day 56. At screening and/or at baseline, and at each visit under treatment (days 14, 28 and 56), clinical exams including SDAS, CGI, UKU, EPSscales were applied and comedication as well as body weight were recorded. Quetiapine plasma levels were measured at each visit under treatment. As a rule, blood had to be drawn 12 h after the last quetiapine medication, but frequently the patient was requested to delay drug intake until after the visit in order to avoid peak levels. Analysis was carried out using an unpublished HPLC MS method, using the API-ES positive polarity mode, after the compounds were extracted from plasma using a liquid liquid extraction procedure (Eap et al. in preparation). Quetiapine was monitored at m /z: 384.2. Limit of quantification (LOQ) was 0.4 ng/ml, and the calibration curve was linear within the range 5 300 ng/ml. Intra- and interday coefficients of variation were below 2% for quetiapine concentrations between 10 and 250 ng/ ml. Statistics Where appropriate, data are presented as means9/ SD. They were analyzed using the last-observationcarried-forward (LOCF) method for missing data. The principal measures (SDAS scores) were subjected to repeated measures of analysis of variance (ANOVA) using the GLM procedure of SPSS 12.0. Heterogeneity of covariance was tested with the Mauchly sphericity test and degrees of freedom modified using the Greenhouse/Geisser adjustment, where appropriate. Contrast analysis (simple) was
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performed, in which each post-baseline measure was compared to baseline. In order to test for bivariate correlations, Kendall’s tb was computed. Statistical significance was set at the p B/0.05 level.
Results Characterization of the subjects Twelve patients, seven men (28.99/12.5 years) and five women (39.19/5.1 years) were enrolled. The mean number of prior hospitalizations (7.79/14.0) and the history of suicide attempts (2.39/2.1) are indicative of a rather severe problem. Eleven patients were diagnosed as presenting borderline personality disorder (301.83) and one patient presented narcissistic personality disorder as the primary diagnosis (301.81). In addition, the following secondary diagnoses were noted: alcohol dependence in two patients (303.90), cocaine dependence in one patient (304.20), and impaired intelligence in one participant (V62.89). Even if some depressive symptoms were seen in several patients, none met the criteria for a major depressive disorder. Seven patients completed the 8-week study period. Five patients dropped out prematurely from the study, one patient due to somnolence, another because of violent behaviour, and three participants repeatedly did not turn up to visits. Doses and plasma levels In eight patients, the standard target dose of 200 mg/ day was maintained from day 3 until the last day of observation. In one patient, non-compliant on day 14 as demonstrated by the absence of measurable quetiapine plasma levels, sleepiness motivated a dose reduction to 100 mg/day on day 14, and to 50 mg/ day on day 28, respectively. In another patient, the dose was increased to 200 and 400 mg/day, on days 14 and 28, respectively. On day 14, four patients were without co-medication. Other patients were co-medicated with usual doses of zolpidem (n /2), oxazepam (n /1), alprazolam (n /1), disulfiram (n /1), zopiclone (n /1), escitalopram (n /1), valproate (n /1), paroxetine (n /3), medroxyprogesterone (n /1), lorazepam (n /2), mirtazapine (n /1) and amlodipine (n /1). On day 14, blood was drawn between 07:30 and 16:30 h after the last medication (the time was unknown in one patient), while one patient was non-compliant. Quetiapine plasma concentrations were (mean, sd) 50.59/57.7 ng/ml (n /11) (range: 9165 ng/ml; median value: 26 ng/ml), while all patients were treated with 200 mg/day quetiapine. On days 28 and 56, drug plasma concentrations were between 5 and 253 ng/ml (n /6; dose 200 mg/day)
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Y. le Bloc’h et al. df /1.650; within-subject effect (F /3.897; p /0.046) (Table I). In a supplementary analysis, a repeated contrast was computed in order to test for the BMI change from one visit to the next. The difference between baseline and week 2 resulted to be significant (p /0.025), indicating that most of the observed weight gain during the observation period occurred at the beginning of the treatment. To test the correlation between weight gain and response, the difference of BMI at baseline and at week 8 were computed against the response at week 8. Although weight was not significantly correlated to the response based on the average symptom expression (Kendall’s tb /0.461; p /0.74), the correlation was significant with the response based on peak symptom expression (Kendall’s tb /0.517; p /0.045). There was a significant correlation between weight change (between baseline and week 8) and total SDAS variation (between baseline and week 8) (Kendall’s tb / /0.644; p /0.02). The non-compliant patient was excluded from these calculations (Figure 1), but there was no significant correlation between the quetiapine plasma concentrations and the variables presented in Figure 1.
(interval between last medication and blood sampling: 10:30 23:30 h), and between 5 and 477 ng/ml (n /5; dose 200 mg/day) (11:30 14:45 h), respectively. On day 14, there was no evidence for a significant relationship between therapeutic response and quetiapine plasma concentrations. Efficacy The changes of SDAS scores are presented in Table I.
Outward aggression. Although the within-subject effect for the average SDAS-9 score was not significant (F /1.671; df /1.859; p /0.214), peak outward aggression (SDAS-9 scores) was significantly (F /5.404; df /1.696; p /0.018) improved at weeks 2, 4 and 8 compared to baseline. However, the effect was already observed after 2 weeks, with no further improvement.
Inward aggression. Significant within-subject effects were found for both inward aggression scores, i.e. average expression (F /4.890; df /3; p /0.006): there was a significant improvement of inward aggression at weeks 4 and 8 compared to baseline.
Tolerability For the following adverse events, the UKU severity score reached at least degree 2, and the causal relationship was rated as at least possible (number of cases are given in parentheses): concentration difficulties (3), asthenia (5), sleepiness (7), increased duration of sleep (4), augmentation of dream activity (2), decreased salivation (3), emotional indifference (2), sweating (2), diminished sexual desire (1), erectile dysfunction (1), ejaculatory dysfunction (1), orgasmic dysfunction (1), hyperglycemia (1), paradoxal augmentation of aggressive impulses (1).
SDAS-21 total score. Both for average expression (F /7.089; df /1.666; p /0.007) and peak expression (F /12.019; df /3; p B/0.001) of the symptoms, the within-subject effect was significant, in that the total scores were significantly reduced at all visits compared to baseline. At week 8, five out of 12 patients were considered to be responders based on a ]/50% reduction of the SDAS-21 scores for the average expression of the symptoms, and six out of 12 on the basis of SDAS21 scores for the peak expression.
Discussion The primary objective of the present open-label study was to test the efficacy of quetiapine against some of the most pivotal symptoms of cluster B personality disorder, i.e. outward and inward
Weight change A continuous increase of the BMI was observed under quetiapine treatment, with a significant
Table I. SDAS scores and BMIs before and during a quetiapine (200 mg/day) treatment in patients. Day 14 (n /12)
Day 0 (n /12)
Day 28 (n /9)
Day 56 (n /7)
SDAS scores
mean
SD
mean
SD
mean
SD
mean
SD
SDAS_21 average expression SDAS_21 peak expression SDAS_9 average expression SDAS_9 peak expression SDAS_6 average expression SDAS_6 peak expression
32.91 43.09 12.64 18.73 11.7 14.2
13.6 12.81 7.39 7.86 6.17 5.49
23.83 27.58 9.25 10.67 8.92 9.91
13.68 15.8 7.3 8.41 5.48 6.58
23.67 26.75 7.78 10.89 7.25 8.88
12.65 12.49 5.67 6.99 3.85 4.42
15 18.14 6 7.29 5.17 6.33
10.63 12.46 6.56 7.67 3.06 3.78
BMI
22.95
3.63
23.35
3.58
22.76
2.49
23.38
3.02
BMI LOCF
22.95
3.63
23.35
3.58
23.43
3.58
23.62
3.51
Variation of SDAS-Score % (LOCF - Baseline)
Quetiapine in cluster B personality disorder
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40 20 0 -4
-2
9 ng/ml
0 ng/ml 165 ng/ml
0 20 ng/ml -20
2
4
6
8
10
42 ng/ml Drop-outs Completers
-40
14 ng/ml -60 -80
26 ng/ml 10 ng/ml
163 ng/ml 42 ng/ml
49 ng/ml
-100 Variation of BMI % (LOCF - baseline)
Figure 1. Correlation between the variation of the BMI (between baseline and week 8) and the total SDAS-score change (between baseline and week 8) (Kendall’s tau-b: /0.644; p /0.02). Individual plasma concentrations of quetiapine measured on day 14 are also indicated. The non-complaint (0 ng/ml) patient was excluded from the statistical analysis.
aggression as well as signs of social dysfunction. A significant general improvement from week 2 of treatment onwards was observed. More specifically, peak episodes of aggression (outward and inward) improved at least from week 4 on. Furthermore, an improvement of the average expression of inward aggression was observed, reaching statistical significance from week 4 on. Although not being statistically significant, a continuous improvement of average outward aggression was also noted. These data essentially confirm the results of a previous study on olanzapine treatment of cluster B personality disorder which also used the SDAS [7]. Likewise, aggressive symptoms, especially fierceness of peak episodes, improved rapidly within a few weeks. The Barnes akathisia scale showed no such adverse event. This is particularly helpful as akathisia is a confounding factor when an antipsychotic drug is assessed for aggression. Values of plasma levels are similar with data of the literature for comparable daily doses [22]. They are lower than those recommended in the AGNP-TDM Expert Group Consensus Guidelines [23] (70 170 ng/ml) for the treatment of schizophrenia, but the doses given in the present study are lower than those used in the reference paper. However, all the published studies stress the lack of correlation between daily doses and plasma levels of quetiapine [23,24]. A recent report [25] illustrates the wide inter-individual variability of quetiapine plasma concentrations and the difficulty to separate poor compliers with ‘‘rapid’’ metabolisers. For quetiapine, one of the contributing factors may be the wide dosing interval and interval from last dose to blood sampling (12 h) relative to the short half-life of the drug (B/6 h) [24,26]. CYP3A4, and to some extent CYP2D6, are the main enzymes implicated in the metabolism of quetiapine [27]. Some patients were co-medicated with drugs, which are known to inhibit CYP3A
(valproate) or CYP2D6 (paroxetine), but the number of patients was too low to draw a conclusion about their effect on the variability of the quetiapine plasma concentrations. Although the used doses, which were adapted based on clinical decisions, remained rather low compared to those usually prescribed for schizophrenic patients, confirming previous findings for other antipsychotics of low dose efficacy in the treatment of personality disorders [28,29], the doses were sufficient to be associated with weight increase, which was significant already after 2 weeks of treatment. This observation contrasts with already mentioned studies [16,30], where no significant weight increase was observed, despite the use of higher doses of quetiapine. However, an association of weight gain under antipsychotic treatment and clinical efficacy has previously been reported for schizophrenia [31], and in a previous study we found that those cluster B patients who responded well under olanzapine, gained most weight under this treatment [7]. Similarly, despite the low number of included patients and the LOCF (last observation carried forward) design, a significant correlation was found in our study between BMI increases and treatment response. The results of this study need to be viewed against their methodological limitations. This was an open, one-centre study including a low number of cases and including a rather short duration of follow-up. These two latter points are due to difficulties in recruitment, as with most studies of patients with cluster B personality disorders and rather inappropriate to be involved in a clinical trial. Although the used titration scheme is standard in the treatment of schizophrenia, it may possibly have been too rapid in patients treated for personality disorder, accounting for the rather frequent side effects related to sedation, and for some premature drop-outs. This is also suggested by the observations of other authors who carried out a more gradual dose increase in
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some patients who complained of somnolence after initiation of a quetiapine treatment [16]. In conclusion, the present data confirm the interest of quetiapine in the treatment of cluster B personality disorders. Its efficacy, as well as the correlation between treatment response and weight gain, should be evaluated in controlled studies.
[10] Bogenschutz MP, George NH. Olanzapine versus placebo in the treatment of borderline personality disorder. J Clin Psychiatry 2004;65(1):104 9. [11] Szigethy EM, Schulz SC. Risperidone in comorbid borderline personality disorder and dysthymia. J Clin Psychopharmacol 1997;17(4):326 7. [12] Khouzam HR, Donnelly NJ. Remission of self-mutilation in a patient with borderline personality during risperidone therapy. J Nerv Ment Dis 1997;185:348 9. [13] Rocca P, Marchiaro L, Cocuzza E, et al. Treatment of borderline personality disorder with risperidone. J Clin Psychiatry 2002;63(3):241 4. [14] Hilger E, Barnas C, Kasper S. Quetiapine in the treatment of borderline personality disorder. World J Biol Psychiatry 2003;4(1):42 4. [15] Walker C, Thomas J, Allen TS. Treating impulsivity, irritability, and aggression of antisocial personality disorder with quetiapine. Int J Offender Ther Comp Criminol 2003; 47(5):556 67. [16] Gruettert T, Friege L. Quetiapine in patients with bordeline personality disorder and psychosis: a case series. Int J Psychiatry Clin Pract 2005;9(3):180 6. [17] Villeneuve E, Lemelin S. Open-label study of atypical neuroleptic quetiapine for treatment of borderline personality disorder: impulsivity as main target. J Clin Psychiatry 2005;66(10):1298 303. [18] Wistedt B, Rasmussen A, Pedersen L, et al. The development of an observer-scale for measuring social dysfunction and aggression. Pharmacopsychiatry 1990;23(6):249 52. [19] Compendium Suisse des Me´dicaments 2005. Switzerland: Documed SA: Baˆle; 2005. [20] Guelfi JD. L’e´valuation clinique standardise´e en psychiatrie. BoulogneL Editions Me´dicales Pierre Fabre; 1996. [21] Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale for psychotropic drugs and a crosssectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 1987;334:81 94. [22] Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia A high- and low-dose doubleblind comparison with placebo. Arch Gen Psychiatry 1997; 54:549 57. [23] Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004;37:243 65. [24] Hasselstrøm J, Linnet K. Quetiapine serum concentrations in psychiatric patients The influence of comedication. Ther Drug Monit 2004;26:486 91. [25] Hartter S, Connemann B, Schonfeldt-Lecuona C, et al. Elevated quetiapine serum concentrations in a patient treated concomitantly with doxepin, lorazepam, and pantoprazole. J Clin Psychopharmacol 2004;24(5):568 71. [26] Gex-Fabry M, Balant-Gorgia AE, Balant LP. Potential of concentration monitoring data for a short half-life drug: Analysis of pharmacokinetic variability for moclobemide. Ther Drug Monit 1995;17:39 46. [27] DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine An atypical antipsychotic. Clin Pharmacokinet 2001;40(7):509 22. [28] Cowdry RW. Psychopharmacology of borderline personality disorder: a review. J Clin Psychiatry 1987;48(Suppl):15 25. [29] Raj A. Overview and treatment of social anxiety disorder. Manage Care 2004; 13(6 Suppl Depression):52 7. [30] Villeneuve E, Lemelin S. Open-label study of atypical neuroleptic quetiapine for treatment of borderline personality disorder: impulsivity as main target. J Clin Psychiatry 2005;66(10):1298 303. [31] Basson BR, Kinon BJ, Taylor CC, et al. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 2001;62(4):231 8. /
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Key points
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. Relatively low doses of quetiapine (200 mg/day) may be clinically effective in patients presenting a cluster B personality disorder (DSM IV), after an 8-week period of treatment . Total SDAS (Social Disability and Aggression Scale) variation correlated significantly with weight change . There was a high interindividual variability in quetiapine plasma concentrations, which did not correlate with clinical parameters . These findings should be replicated in a placebo controlled double-blind study
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Statement of interest/Acknowledgements We gratefully acknowledge the editorial assistance of Mrs V. Sari, and the bibliographic help of Mrs J. Rosselet, Mrs M. Gobin and Mrs E. Ponce. This study was sponsored by an unrestricted grant from AstraZeneca (Switzerland).
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References
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ORIGINAL ARTICLE
Efficacy and tolerability of quetiapine in cluster B personality disorder: an open-label study
YVES LE BLOC’H1, PIERRE BAUMANN2, MICHAEL STIGLER3, CHIN B. EAP2 & DANIELE F. ZULLINO4* ˆ ge Avance´, Site de Cery, De´partement Universitaire de Psychiatrie Adulte et Service Universitaire de Psychiatrie de l’A 2 Prilly-Lausanne, Switzerland, Unite´ de Biochimie et Psychopharmacologie Clinique, De´partement Universitaire de Psychiatrie Adulte, Centre de Neurosciences Psychiatriques, Site de Cery, Prilly-Lausanne, Switzerland, 3Unite´ de Recherche en Epide´miologie Psychiatrique, De´partement Universitaire de Psychiatrie Adulte, Site de Cery, Prilly-Lausanne, Switzerland, and 4De´partement Universitaire de Psychiatrie Adulte, Site de Cery, Prilly-Lausanne, Switzerland 1
Abstract Objective . The aim of this open-label 8-week study was to assess the effectiveness of quetiapine on aggressive behaviour and social dysfunctions in patients suffering from a cluster B personality disorder (DSM-IV). Methods . The visits were performed at baseline and at days 14, 28 and 56. After a standard titration schedule, the patients received a dose augmented or reduced dose, within a range from 50 to 400 mg/day during the visits, depending on efficacy and tolerance. Assessment of efficacy was based on the French version of the Social Disability and Aggression Scale SDAS (SDAS-21). Response was defined as a decrease of ]/50% reduction of the total scores compared to baseline. Tolerability was assessed with the CGI, UKU, EPS-scales. Results and conclusion . Eight of the 12 patients included received 200 mg/day quetiapine after titration (all patients: 50 400 mg/day). At week 8, five out of 12 patients were responders based on the SDAS-21 scores for the average expression of the symptoms, and six out of 12 on the basis of SDAS-21 scores for the peak expression. There was a significant correlation between weight change and total SDAS variation (Kendall’s tb / /0.644; p /0.02). These findings should be reexamined in further studies.
Key Words: Quetiapine, cluster B personality disorder, weight, SDAS, plasma concentrations
Introduction Antipsychotic drugs have long been a widespread approach for treating patients with personality disorders. Data on conventional antipsychotics have suggested some utility against psychoticism, whereas there is less evidence for their efficacy against depressive, suicidal and anxious symptoms [1 3]. Despite this, conventional antipsychotics are associated with an important risk of adverse drug reactions, especially extrapyramidal side effects (EPS), and cluster B personality disorder patients have been described to be particularly sensitive to EPS [2]. There has recently been an increasing interest in the use of atypical antipsychotics in this type of patient. Two open-label trials have studied the efficacy of the atypical antipsychotic drug clozapine in patients presenting borderline personality disorder. In a
study [4] of 15 borderline outpatients, meeting concomitantly DSM-III-R criteria for psychotic disorder, clozapine significantly decreased positive, negative and general symptoms, and improved psychosocial functioning when followed up for 2 9 months. In a 16-week trial including 12 inpatients with DSM-IV borderline personality disorder and severe psychotic-like symptoms, clozapine significantly improved psychotic symptoms, depression, impulsivity, and affective lability [5]. Several studies have investigated olanzapine for patients with cluster B personality disorder. In an 8-week open study [6], 11 patients with borderline personality disorder and dysthymic disorder were included. Significant reductions were found with regard to obsessive-compulsive symptoms, interpersonal sensitivity, depression, anger-hostility, phobic anxiety, paranoia, psychoticism and impulsivity. No
Correspondence: Professor P. Baumann, Ph.D., Unite´ de Biochimie et Psychopharmacologie Clinique, De´partement Universitaire de Psychiatrie Adulte, Centre de Neurosciences Psychiatriques, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland. Tel: /41 21 643 6434. Fax: /41 21 643 6444. E-mail: [email protected] *Present address: Service de Toxicologie, Hoˆpitaux Universitaires de Gene`ve, 1200 Gene`ve, Switzerland.
(Received 9 March 2006; accepted 27 June 2006) ISSN 1365-1501 print/ISSN 1471-1788 online # 2007 Taylor & Francis DOI: 10.1080/13651500600885556
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significant decline was found on a measure of aggression. In an open series of 10 patients presenting cluster B personality disorder [7], using a mirror-image design anchored to the start date of olanzapine treatment and extending 8 weeks in either direction, found depressive and anxious symptoms as well as impulsive/aggressive behaviours to be improved. In five of the 10 patients, the improvements were particularly rapid, described as occurring within 1 week after the introduction of olanzapine. In several other studies [810], olanzapine showed interesting results (in monotherapy or in combination with fluoxetine) in patients with borderline personality disorder on different characteristic symptoms, namely aggression. Besides two other case reports [11,12], risperidone was studied in an 8-week open-label trial [13]. Six out of 15 patients meeting DSM-IV criteria for borderline personality disorder improved significantly on six of the study’s eight outcome measures. In terms of symptom areas, subjects reported significantly less severe general psychopathology, anergia, hostility and suspicion, depression and aggression. Measures of anxiety and depression, as well as thought disturbance, did not demonstrate significant change over time. Quetiapine is a novel, atypical antipsychotic drug, with a broad spectrum of in vitro receptor affinity similar to that of clozapine, although with lower absolute affinities for most important receptor subtypes. The report of improvement of impulsive behaviour and severe self-mutilation in two female patients with the diagnoses of borderline personality disorder [14] has suggested its possible interest for this indication. Expanding the indication on another cluster B personality disorder, a recent series of four patients with antisocial personality disorder [15] showed some efficacy of quetiapine in treating impulsivity, hostility, aggressiveness, irritability and rage reactions at doses between 600 and 800 mg/day. In a 12-week case series study with patients suffering from borderline personality disorder and psychosis, a mean dose of 537 mg/day quetiapine improved symptoms of depression, psychosis and impulsivity, and the treatment was well tolerated [16]. Another sample of patients with a borderline personality disorder, but with few psychotic symptoms, was treated with a mean dose of 251 mg/day (range 175 400 mg/day) quetiapine. The authors reported on a strong positive clinical impact after already 2 weeks, and in particular, impulsivity was reduced by the treatment [17]. Clinical studies on the treatment of personality disorders were based mostly on the use of scales of general psychopathology including some aggressionrelated questions, such as the Brief Psychiatric Rating Scale or used self-rating scales such as the Buss and Durkee Hostility Inventory, which have, as a major drawback, their reliance on patient
cooperation. Two newer scales were developed in the 1980s measuring aggressive behaviour: the Overt Aggression Scale and the Staff Observation Aggression Scale. These instruments measure direct aggressive behaviour but are not aimed to assess aggressive behaviour other than obvious violence and assaults. More subtle vexatious, reactive or irritable behaviour may, however, also have a socially disturbing effect and make care and rehabilitation more troublesome and discouraging for the patients as well as for their caregivers. The Social Dysfunction and Aggression Scale (SDAS-21) has been developed to cover the total range of mild, moderate and severe aggressiveness [18]. The objective of the present open study was to evaluate the impact of quetiapine on outward and inward aggressive behaviour as well as social dysfunctions in patients with cluster B personality disorder. Methods This was an open-label 8-week study, performed in the section of personality disorders of the Psychiatric University Hospital of Lausanne, Switzerland. To be included, patients had to be at least 18 years of age and satisfy the DSM-IV criteria for a cluster B personality disorder, i.e. borderline, histrionic, narcissistic, or antisocial personality disorder. Exclusion criteria were a diagnosis of schizophrenia or bipolar affective disorder, the presence of an organic mental disorder, a history of seizures, the presence of a serious somatic disease, pregnancy, lactation, or childbearing potential without effective contraception. Whereas dependence from drugs other than nicotine was an exclusion criterion, drug abuse was not. The study was approved by the local ethics committee. Informed consent was obtained from each patient before study-related procedures were initiated. Quetiapine treatment was introduced using the standard titration schedule recommended by the Swiss Medical Compendium [19]. The patients received on day 1, 25 mg b.i.d.; on day 2, 50 mg b.i.d.; from day 3 to 14, 100 mg b.i.d. Thereafter, the dose could be increased or reduced during the visits depending on efficacy and tolerance, within a range from 50 to 400 mg. From day 29 on, any dose change was prohibited. Concomitant somatic treatments were allowed without restrictions, and concomitant psychotropic drugs had to be maintained at the same dosage (9/30% allowed) throughout the study. However, concomitant treatment with antipsychotic medications was excluded. The primary assessment of efficacy was based of the French version of the Social Disability and Aggression Scale SDAS (SDAS-21) [20]: this
Quetiapine in cluster B personality disorder instrument measures specifically some symptoms which are pivotal for the treatment of cluster B personality disorders, such as irritability, dysphoria, interpersonal difficulties, aggressive behaviour and addictive behaviour. The items 1 15 of the 21-item version of the SDAS are observer-rated and the items 16 21 patient-rated. SDAS ratings are usually based on the totality of information pertaining to the previous week. Two scores for each item are determined, one indicating the average expression of the concerning symptom over the preceding week, and a further score representative of peak episodes. Besides the total score of the 21 items, two subscales are defined: The SDAS-9, including nine items, represents outward aggression. The SDAS-6, including six items, labels inward aggression. Response was considered for this study to have occurred in the case of a 50% reduction of the total scores compared to baseline. Tolerability was evaluated with the UKU scale [21], the Barnes Akathisia Scale, the Abnormal Involuntary Movement Scale and the Simpson Angus Rating Scale for Extrapyramidal Side-Effects. General clinical chemical and hematological tests and drug screenings were carried out at baseline and on day 56. At screening and/or at baseline, and at each visit under treatment (days 14, 28 and 56), clinical exams including SDAS, CGI, UKU, EPSscales were applied and comedication as well as body weight were recorded. Quetiapine plasma levels were measured at each visit under treatment. As a rule, blood had to be drawn 12 h after the last quetiapine medication, but frequently the patient was requested to delay drug intake until after the visit in order to avoid peak levels. Analysis was carried out using an unpublished HPLC MS method, using the API-ES positive polarity mode, after the compounds were extracted from plasma using a liquid liquid extraction procedure (Eap et al. in preparation). Quetiapine was monitored at m /z: 384.2. Limit of quantification (LOQ) was 0.4 ng/ml, and the calibration curve was linear within the range 5 300 ng/ml. Intra- and interday coefficients of variation were below 2% for quetiapine concentrations between 10 and 250 ng/ ml. Statistics Where appropriate, data are presented as means9/ SD. They were analyzed using the last-observationcarried-forward (LOCF) method for missing data. The principal measures (SDAS scores) were subjected to repeated measures of analysis of variance (ANOVA) using the GLM procedure of SPSS 12.0. Heterogeneity of covariance was tested with the Mauchly sphericity test and degrees of freedom modified using the Greenhouse/Geisser adjustment, where appropriate. Contrast analysis (simple) was
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performed, in which each post-baseline measure was compared to baseline. In order to test for bivariate correlations, Kendall’s tb was computed. Statistical significance was set at the p B/0.05 level.
Results Characterization of the subjects Twelve patients, seven men (28.99/12.5 years) and five women (39.19/5.1 years) were enrolled. The mean number of prior hospitalizations (7.79/14.0) and the history of suicide attempts (2.39/2.1) are indicative of a rather severe problem. Eleven patients were diagnosed as presenting borderline personality disorder (301.83) and one patient presented narcissistic personality disorder as the primary diagnosis (301.81). In addition, the following secondary diagnoses were noted: alcohol dependence in two patients (303.90), cocaine dependence in one patient (304.20), and impaired intelligence in one participant (V62.89). Even if some depressive symptoms were seen in several patients, none met the criteria for a major depressive disorder. Seven patients completed the 8-week study period. Five patients dropped out prematurely from the study, one patient due to somnolence, another because of violent behaviour, and three participants repeatedly did not turn up to visits. Doses and plasma levels In eight patients, the standard target dose of 200 mg/ day was maintained from day 3 until the last day of observation. In one patient, non-compliant on day 14 as demonstrated by the absence of measurable quetiapine plasma levels, sleepiness motivated a dose reduction to 100 mg/day on day 14, and to 50 mg/ day on day 28, respectively. In another patient, the dose was increased to 200 and 400 mg/day, on days 14 and 28, respectively. On day 14, four patients were without co-medication. Other patients were co-medicated with usual doses of zolpidem (n /2), oxazepam (n /1), alprazolam (n /1), disulfiram (n /1), zopiclone (n /1), escitalopram (n /1), valproate (n /1), paroxetine (n /3), medroxyprogesterone (n /1), lorazepam (n /2), mirtazapine (n /1) and amlodipine (n /1). On day 14, blood was drawn between 07:30 and 16:30 h after the last medication (the time was unknown in one patient), while one patient was non-compliant. Quetiapine plasma concentrations were (mean, sd) 50.59/57.7 ng/ml (n /11) (range: 9165 ng/ml; median value: 26 ng/ml), while all patients were treated with 200 mg/day quetiapine. On days 28 and 56, drug plasma concentrations were between 5 and 253 ng/ml (n /6; dose 200 mg/day)
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Y. le Bloc’h et al. df /1.650; within-subject effect (F /3.897; p /0.046) (Table I). In a supplementary analysis, a repeated contrast was computed in order to test for the BMI change from one visit to the next. The difference between baseline and week 2 resulted to be significant (p /0.025), indicating that most of the observed weight gain during the observation period occurred at the beginning of the treatment. To test the correlation between weight gain and response, the difference of BMI at baseline and at week 8 were computed against the response at week 8. Although weight was not significantly correlated to the response based on the average symptom expression (Kendall’s tb /0.461; p /0.74), the correlation was significant with the response based on peak symptom expression (Kendall’s tb /0.517; p /0.045). There was a significant correlation between weight change (between baseline and week 8) and total SDAS variation (between baseline and week 8) (Kendall’s tb / /0.644; p /0.02). The non-compliant patient was excluded from these calculations (Figure 1), but there was no significant correlation between the quetiapine plasma concentrations and the variables presented in Figure 1.
(interval between last medication and blood sampling: 10:30 23:30 h), and between 5 and 477 ng/ml (n /5; dose 200 mg/day) (11:30 14:45 h), respectively. On day 14, there was no evidence for a significant relationship between therapeutic response and quetiapine plasma concentrations. Efficacy The changes of SDAS scores are presented in Table I.
Outward aggression. Although the within-subject effect for the average SDAS-9 score was not significant (F /1.671; df /1.859; p /0.214), peak outward aggression (SDAS-9 scores) was significantly (F /5.404; df /1.696; p /0.018) improved at weeks 2, 4 and 8 compared to baseline. However, the effect was already observed after 2 weeks, with no further improvement.
Inward aggression. Significant within-subject effects were found for both inward aggression scores, i.e. average expression (F /4.890; df /3; p /0.006): there was a significant improvement of inward aggression at weeks 4 and 8 compared to baseline.
Tolerability For the following adverse events, the UKU severity score reached at least degree 2, and the causal relationship was rated as at least possible (number of cases are given in parentheses): concentration difficulties (3), asthenia (5), sleepiness (7), increased duration of sleep (4), augmentation of dream activity (2), decreased salivation (3), emotional indifference (2), sweating (2), diminished sexual desire (1), erectile dysfunction (1), ejaculatory dysfunction (1), orgasmic dysfunction (1), hyperglycemia (1), paradoxal augmentation of aggressive impulses (1).
SDAS-21 total score. Both for average expression (F /7.089; df /1.666; p /0.007) and peak expression (F /12.019; df /3; p B/0.001) of the symptoms, the within-subject effect was significant, in that the total scores were significantly reduced at all visits compared to baseline. At week 8, five out of 12 patients were considered to be responders based on a ]/50% reduction of the SDAS-21 scores for the average expression of the symptoms, and six out of 12 on the basis of SDAS21 scores for the peak expression.
Discussion The primary objective of the present open-label study was to test the efficacy of quetiapine against some of the most pivotal symptoms of cluster B personality disorder, i.e. outward and inward
Weight change A continuous increase of the BMI was observed under quetiapine treatment, with a significant
Table I. SDAS scores and BMIs before and during a quetiapine (200 mg/day) treatment in patients. Day 14 (n /12)
Day 0 (n /12)
Day 28 (n /9)
Day 56 (n /7)
SDAS scores
mean
SD
mean
SD
mean
SD
mean
SD
SDAS_21 average expression SDAS_21 peak expression SDAS_9 average expression SDAS_9 peak expression SDAS_6 average expression SDAS_6 peak expression
32.91 43.09 12.64 18.73 11.7 14.2
13.6 12.81 7.39 7.86 6.17 5.49
23.83 27.58 9.25 10.67 8.92 9.91
13.68 15.8 7.3 8.41 5.48 6.58
23.67 26.75 7.78 10.89 7.25 8.88
12.65 12.49 5.67 6.99 3.85 4.42
15 18.14 6 7.29 5.17 6.33
10.63 12.46 6.56 7.67 3.06 3.78
BMI
22.95
3.63
23.35
3.58
22.76
2.49
23.38
3.02
BMI LOCF
22.95
3.63
23.35
3.58
23.43
3.58
23.62
3.51
Variation of SDAS-Score % (LOCF - Baseline)
Quetiapine in cluster B personality disorder
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40 20 0 -4
-2
9 ng/ml
0 ng/ml 165 ng/ml
0 20 ng/ml -20
2
4
6
8
10
42 ng/ml Drop-outs Completers
-40
14 ng/ml -60 -80
26 ng/ml 10 ng/ml
163 ng/ml 42 ng/ml
49 ng/ml
-100 Variation of BMI % (LOCF - baseline)
Figure 1. Correlation between the variation of the BMI (between baseline and week 8) and the total SDAS-score change (between baseline and week 8) (Kendall’s tau-b: /0.644; p /0.02). Individual plasma concentrations of quetiapine measured on day 14 are also indicated. The non-complaint (0 ng/ml) patient was excluded from the statistical analysis.
aggression as well as signs of social dysfunction. A significant general improvement from week 2 of treatment onwards was observed. More specifically, peak episodes of aggression (outward and inward) improved at least from week 4 on. Furthermore, an improvement of the average expression of inward aggression was observed, reaching statistical significance from week 4 on. Although not being statistically significant, a continuous improvement of average outward aggression was also noted. These data essentially confirm the results of a previous study on olanzapine treatment of cluster B personality disorder which also used the SDAS [7]. Likewise, aggressive symptoms, especially fierceness of peak episodes, improved rapidly within a few weeks. The Barnes akathisia scale showed no such adverse event. This is particularly helpful as akathisia is a confounding factor when an antipsychotic drug is assessed for aggression. Values of plasma levels are similar with data of the literature for comparable daily doses [22]. They are lower than those recommended in the AGNP-TDM Expert Group Consensus Guidelines [23] (70 170 ng/ml) for the treatment of schizophrenia, but the doses given in the present study are lower than those used in the reference paper. However, all the published studies stress the lack of correlation between daily doses and plasma levels of quetiapine [23,24]. A recent report [25] illustrates the wide inter-individual variability of quetiapine plasma concentrations and the difficulty to separate poor compliers with ‘‘rapid’’ metabolisers. For quetiapine, one of the contributing factors may be the wide dosing interval and interval from last dose to blood sampling (12 h) relative to the short half-life of the drug (B/6 h) [24,26]. CYP3A4, and to some extent CYP2D6, are the main enzymes implicated in the metabolism of quetiapine [27]. Some patients were co-medicated with drugs, which are known to inhibit CYP3A
(valproate) or CYP2D6 (paroxetine), but the number of patients was too low to draw a conclusion about their effect on the variability of the quetiapine plasma concentrations. Although the used doses, which were adapted based on clinical decisions, remained rather low compared to those usually prescribed for schizophrenic patients, confirming previous findings for other antipsychotics of low dose efficacy in the treatment of personality disorders [28,29], the doses were sufficient to be associated with weight increase, which was significant already after 2 weeks of treatment. This observation contrasts with already mentioned studies [16,30], where no significant weight increase was observed, despite the use of higher doses of quetiapine. However, an association of weight gain under antipsychotic treatment and clinical efficacy has previously been reported for schizophrenia [31], and in a previous study we found that those cluster B patients who responded well under olanzapine, gained most weight under this treatment [7]. Similarly, despite the low number of included patients and the LOCF (last observation carried forward) design, a significant correlation was found in our study between BMI increases and treatment response. The results of this study need to be viewed against their methodological limitations. This was an open, one-centre study including a low number of cases and including a rather short duration of follow-up. These two latter points are due to difficulties in recruitment, as with most studies of patients with cluster B personality disorders and rather inappropriate to be involved in a clinical trial. Although the used titration scheme is standard in the treatment of schizophrenia, it may possibly have been too rapid in patients treated for personality disorder, accounting for the rather frequent side effects related to sedation, and for some premature drop-outs. This is also suggested by the observations of other authors who carried out a more gradual dose increase in
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some patients who complained of somnolence after initiation of a quetiapine treatment [16]. In conclusion, the present data confirm the interest of quetiapine in the treatment of cluster B personality disorders. Its efficacy, as well as the correlation between treatment response and weight gain, should be evaluated in controlled studies.
[10] Bogenschutz MP, George NH. Olanzapine versus placebo in the treatment of borderline personality disorder. J Clin Psychiatry 2004;65(1):104 9. [11] Szigethy EM, Schulz SC. Risperidone in comorbid borderline personality disorder and dysthymia. J Clin Psychopharmacol 1997;17(4):326 7. [12] Khouzam HR, Donnelly NJ. Remission of self-mutilation in a patient with borderline personality during risperidone therapy. J Nerv Ment Dis 1997;185:348 9. [13] Rocca P, Marchiaro L, Cocuzza E, et al. Treatment of borderline personality disorder with risperidone. J Clin Psychiatry 2002;63(3):241 4. [14] Hilger E, Barnas C, Kasper S. Quetiapine in the treatment of borderline personality disorder. World J Biol Psychiatry 2003;4(1):42 4. [15] Walker C, Thomas J, Allen TS. Treating impulsivity, irritability, and aggression of antisocial personality disorder with quetiapine. Int J Offender Ther Comp Criminol 2003; 47(5):556 67. [16] Gruettert T, Friege L. Quetiapine in patients with bordeline personality disorder and psychosis: a case series. Int J Psychiatry Clin Pract 2005;9(3):180 6. [17] Villeneuve E, Lemelin S. Open-label study of atypical neuroleptic quetiapine for treatment of borderline personality disorder: impulsivity as main target. J Clin Psychiatry 2005;66(10):1298 303. [18] Wistedt B, Rasmussen A, Pedersen L, et al. The development of an observer-scale for measuring social dysfunction and aggression. Pharmacopsychiatry 1990;23(6):249 52. [19] Compendium Suisse des Me´dicaments 2005. Switzerland: Documed SA: Baˆle; 2005. [20] Guelfi JD. L’e´valuation clinique standardise´e en psychiatrie. BoulogneL Editions Me´dicales Pierre Fabre; 1996. [21] Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale for psychotropic drugs and a crosssectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 1987;334:81 94. [22] Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia A high- and low-dose doubleblind comparison with placebo. Arch Gen Psychiatry 1997; 54:549 57. [23] Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004;37:243 65. [24] Hasselstrøm J, Linnet K. Quetiapine serum concentrations in psychiatric patients The influence of comedication. Ther Drug Monit 2004;26:486 91. [25] Hartter S, Connemann B, Schonfeldt-Lecuona C, et al. Elevated quetiapine serum concentrations in a patient treated concomitantly with doxepin, lorazepam, and pantoprazole. J Clin Psychopharmacol 2004;24(5):568 71. [26] Gex-Fabry M, Balant-Gorgia AE, Balant LP. Potential of concentration monitoring data for a short half-life drug: Analysis of pharmacokinetic variability for moclobemide. Ther Drug Monit 1995;17:39 46. [27] DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine An atypical antipsychotic. Clin Pharmacokinet 2001;40(7):509 22. [28] Cowdry RW. Psychopharmacology of borderline personality disorder: a review. J Clin Psychiatry 1987;48(Suppl):15 25. [29] Raj A. Overview and treatment of social anxiety disorder. Manage Care 2004; 13(6 Suppl Depression):52 7. [30] Villeneuve E, Lemelin S. Open-label study of atypical neuroleptic quetiapine for treatment of borderline personality disorder: impulsivity as main target. J Clin Psychiatry 2005;66(10):1298 303. [31] Basson BR, Kinon BJ, Taylor CC, et al. Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone. J Clin Psychiatry 2001;62(4):231 8. /
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Key points
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. Relatively low doses of quetiapine (200 mg/day) may be clinically effective in patients presenting a cluster B personality disorder (DSM IV), after an 8-week period of treatment . Total SDAS (Social Disability and Aggression Scale) variation correlated significantly with weight change . There was a high interindividual variability in quetiapine plasma concentrations, which did not correlate with clinical parameters . These findings should be replicated in a placebo controlled double-blind study
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Statement of interest/Acknowledgements We gratefully acknowledge the editorial assistance of Mrs V. Sari, and the bibliographic help of Mrs J. Rosselet, Mrs M. Gobin and Mrs E. Ponce. This study was sponsored by an unrestricted grant from AstraZeneca (Switzerland).
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References
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