اثربخشی و تحمل پذیری الانزاپین در درمان اختلال شخصیت

Abstract Background: Few treatment studies of schizotypal personality disorder (SPD) have investigated the new, atypical antipsychotic drugs. This study examined the efficacy and tolerability of olanzapine, an atypical antipsychotic drug, in a series of patients with DSM-IV diagnosed schizotypal personality disorder. Method: This was a 26-week, open-label study with flexible dose design in 11 subjects with a diagnosis of schizotypal personality disorder based on Structured Clinical Interview for DSM-IV (SCID) and Personality Disorder Examination (PDE Journal of Psychiatric Disorders 1 (1987) 1). Subjects were treated with a low dose (average 9.32 mg/day) of olanzapine. Psychopathology was assessed at baseline and at the end of the study and analyzed with last observation carried forward analysis. Results: Patients showed significant improvements in psychosis and depression ratings, as well as in overall functioning. Olanzapine was well tolerated, though significant weight gain was observed. Conclusion: This study provides preliminary data regarding olanzapine efficacy and tolerability in schizotypal personality disorder subjects. These data need to be confirmed in larger controlled clinical trials

. Introduction Schizotypal personality disorder (SPD), which affects 3–5% of population, is characterized by pervasive social and interpersonal deficits, and subtle, psychotic-like symptoms (Gunderson and Phillips, 1995). Observations that first-degree relatives of subjects with SPD have a higher risk for schizophrenia-related disorders Baron et al., 1985 and Siever et al., 1990b suggests that SPD is a schizophrenia related disorder. Similarly, neurobiological markers such as deficits in prepulse inhibition, P50 suppression, and antisaccade paradigms reported in schizophrenic subjects are also observed in subjects with SPD Cadenhead et al., 2002 and Siever et al., 1990a. Patients with SPD also show many of the same cognitive deficits as seen in schizophrenia, though such deficits are less severe; deficits are seen in working memory, attention, and executive functioning (Park and McTigue, 1997). Additionally, up to 40% of patients with SPD may go on to develop schizophrenia as compared to about 1% in the general population (Fenton and McGlashan, 1989). Thus, both genetic, clinical and neurobehavioral data support the hypothesis that SPD may be a schizophrenia-spectrum disorder. This provides the rationale for treating SPD with antipsychotic drugs (APDs), similar to those used in the treatment of schizophrenia and related psychotic disorders. Only a few studies have examined treatment of psychotic symptoms in subjects with SPD. All of these studies have employed low doses of high potency conventional APDs to avoid extra pyramidal symptoms (EPS) Soloff et al., 1986, Soloff et al., 1989 and Stein, 1992. For example, in a predominantly SPD population, thiothixene clearly showed a greater efficacy as compared to placebo (Goldberg et al., 1986). Similarly, haloperidol was significantly effective in the treatment of mixed SPD and Borderline Personality Disorder (BPD) inpatient population Soloff et al., 1986 and Soloff et al., 1989. In an open-label study with amoxapine (an atypical antidepressant with the neuroleptic metabolite, loxapine), BPD and SPD subjects were treated for 3 weeks and only subjects with SPD reported any beneficial effects (Jensen and Andersen, 1989). Despite the fact that atypical APDs are replacing conventional APDs as a first line of treatment for psychotic disorders, few studies have investigated atypical APDs in the treatment of SPD. Clozapine has been clearly demonstrated to have significant superiority in treating psychotic symptoms in BPD subjects over conventional APDs (Frankenburg and Zanarini, 1993). However, since clozapine has a significant risk of agranulocytosis and lowering of the seizure threshold, the advent of newer and better-tolerated atypical APDs such as olanzapine has offered a fresh perspective in the treatment of personality disorders with psychotic symptoms. Olanzapine, like clozapine, has potent affinity for D1, D2, D4, 5HT2a, 5HT2c, 5HT3, muscarinic, alpha1-adrenergic, and histamine H1 receptors (Bymaster et al., 1999), but unlike clozapine is not associated with agranulocytosis or lowering of the seizure threshold. Thus, olanzapine seemed to be a likely choice to be studied in the treatment of personality disorders. Indeed, olanzapine has been found to be effective in BPD (Frankenburg and Zanarini, 2001; Schulz et al., 1999). However, no study has examined the efficacy of olanzapine in SPD. The purpose of this study was to examine the effectiveness and safety of low-dose olanzapine in 11 subjects with SPD and to find the optimal dosing range for olanzapine to design a placebo-controlled, double-blind trial as the next step in this investigation. In addition, the relative benefits and tolerability of olanzapine in the treatment of SPD was assessed in view of the safety issues, such as weight gain and metabolic syndrome associated with the use of atypical APDs.

Results Out of 11 subjects enrolled in this study, 8 completed the 26 weeks, 2 subjects declined follow-up after weeks 8 and 4, respectively, due to unclear reasons and one subject was dropped by the investigators at week 3 due to the need for multiple medications to stabilize the psychiatric condition. The post-treatment total scores in 11 patients on BPRS, HRSD24, OAS and GAS were significantly better than the baseline scores (Table 1). Significant improvements were seen in positive and negative symptoms, depressive symptoms and in overall level of functioning. Using LOCF analysis, there was an average of 31% and 28% decrease in total BPRS and GAS scores from baseline to the end of the study, respectively. Seven out of eleven study subjects started to have a ≥20% improvement in their BPRS scores within 2 weeks of olanzapine treatment. However, two study subjects did not respond to the olanzapine treatment. No statistically significant difference was observed on the EPSE scores, suggesting no or a low incidence of extrapyramidal symptoms (Table 1). With the exception of OAS, the findings remained significant when the data were reanalyzed excluding the two subjects with comorbid axis I disorders (psychotic disorder not otherwise specified and bipolar disorder type II). Table 1. Change in clinical assessments after olanzapine treatment in schizotypal subjects Variable Baseline Final Paired difference t df P value BPRS 18 total 44.8±7.4 30.3±7.8 14.5±7.5 5.578 10 0.001a HRSD24 total 19.7±6.9 11.9±6.4 7.8±8.4 2.928 10 0.035 GAS 45.6±11.5 59.6±13.4 −14.0±9.0 3.1 9 0.005a OAS 7.4±5.6 2.1±3.9 5.2±6.0 2.5 7 0.09 EPSE 0.65±1.2 1.4±2.2 −0.75±1.8 −1.3 9 0.29 df=degree of freedom. For details of the abbreviations, see Methods. a Significant after Bonferroni correction. Table options Liver function tests and complete blood counts in study subjects were either within normal limits, or if not, findings were not clinically significant. Twelve-lead EKGs were also within normal limits in all subjects except one, who showed sinus bradycardia with sinus arrhythmia but without any clinical symptoms. Concomitant medications, i.e. acetaminophen, doxepin, sertraline, zolpidem and divalproex sodium were used in six patients to address comorbid symptoms such as insomnia, depression, hypomania, anxiety and headache. Sertraline and divalproex sodium were only used in one subject with comorbid diagnosis of bipolar disorder II. The dosages of most concomitant medications were held stable. Olanzapine was well tolerated and no serious adverse effects were reported, including extrapyramidal symptoms as reflected by no significant change in EPSE scores from baseline. However, an average weight gain of 16.12 lb+21.2 was observed in eight subjects who completed 26-week study. Five out of eight subjects gained more than 7% body weight. While two subjects lost 5 and 10 lb, respectively. The range of weight gain was 11–57 lb.