Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders

Summary Objective. To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs). Method. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment. Results. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [χ² = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3–725.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine. Conclusion. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.     

Binge eating disorder and depression: A systematic review

The purpose of this systematic literature review is to examine previous studies that investigated the relation between depression and binge eating disorder (BED). Medline/PubMed published data from 1980 through 2006 was tracked using the following keywords: “binge eating disorder and depression”, “periodic binge eating and depression”, “binge eating disorder” and “periodic binge eating”. The findings of 14 studies were successfully highlighted: one cohort, four cross-sectional and nine case–control studies. Most studies (7/14) were conducted in the United States, with missing data varying between 2.3 and 44.32%, and seven studies emphasizing the most important variables. The majority of the studies (10/14) showed an association between depression and binge eating disorder, but carefully designed studies are required to minimize the limitations found in these studies.     

Sleep and eating in childhood: a potential behavioral mechanism underlying the relationship between poor sleep and obesity

ObjectiveThe goal of our study was to examine the associations between sleep and eating behaviors. Specifically, we examined associations between sleep duration and continuity with behaviors that promote eating regardless of true physiologic hunger state including emotional (food intake in response to emotional distress) external (eating in response to the sight or smell of food), and restrained eating (a paradoxical behavior; food intake is initially reduced to lose or maintain body weight, but followed by increased consumption and binge eating).ParticipantsFifty-six children (29 boys; 27 girls) ages 5 to 12 years participated in the study. Mean age was 7.7 ± 1.9 years, and average body mass index (BMI) was within the healthy range (17.8 ± 4.3 kg/m²).MethodsSleep duration, continuity and schedule were assessed using actigraphy and self-reports. The Child Dutch Eating Behavior Questionnaire-modified version (DEBQ-M) was used to examine levels of emotional, external and restrained eating in the children.ResultsAssociations between the sleep and eating behaviors were examined using partial correlations and multiple regression analyses. External eating score was negatively associated with sleep duration; emotional eating score was associated with lower levels of sleep continuity; and restrained eating score were associated with a later sleep start and later bedtime.ConclusionsShort sleep duration and poor sleep continuity were associated with higher levels of eating behaviors shown to be associated with increased food intake. Therefore, sleep loss may be associated with diminished self-regulation of appetite in children, increasing the risk for overeating and obesity.     

The dual-pathway and cognitive-behavioural models of binge eating: prospective evaluation and comparison

To evaluate and compare the dual-pathway, original cognitive-behavioural, and enhanced “transdiagnostic” cognitive-behavioural models of binge eating, using prospective data from a pre-adolescent sample. Models were tested using multilevel longitudinal structural equation modelling. Participants were 236 children (48% male) aged between 8 and 13 years at baseline, who were interviewed annually over a 2-year period. Binge eating was assessed using the Child Eating Disorder Examination. The dual-pathway and enhanced cognitive-behavioural models provided an acceptable fit to the data, whereas the original cognitive-behavioural model did not. Partial support is provided for the prospective validity of the dual-pathway and enhanced cognitive-behavioural models of binge eating in childhood. Results suggest that body dissatisfaction and weight and shape over-evaluation may both contribute to dieting behaviour in youth, and that dieting and affect-related difficulties both require consideration in theories of binge eating development.     

The influence of oxytocin on risk‐taking in the balloon analogue risk task among women with bulimia nervosa and binge eating disorder

Previous theoretical models of bulimia nervosa (BN) and binge eating disorder (BED) have implicated cross‐domain risk‐taking behaviour as a significant maintenance factor in both disorders. The present study aimed to test this hypothesis by administering the Balloon Analogue Risk Task (BART) to 25 women with BN or BED and 27 healthy comparison women without a history of an eating disorder. Furthermore, we tested the effect of a divided dose of 64 IU of oxytocin on risk‐taking behaviour in the BART. Contrary to our hypothesis, women with BN or BED did not exhibit baseline differences in performance on the BART in the placebo condition (t = 1.42, df = 50, P = 0.161, d = 0.39). Oxytocin did not have a main effect on performance in the BART (F = 0.01, df = 1, P = .907, η²_partial < 0.001); however, there was an interaction, such that participants in the BN/BED participant group, compared to the healthy comparison group, demonstrated safer behaviour on the BART in the oxytocin condition, but not in the placebo condition (F = 4.29, df = 1, P = 0.044, η²_partial = 0.082). These findings cast doubt on the common assumption that individuals with BN and BED exhibit greater risk‐taking behaviour in all domains and add to the evidence that oxytocin plays a functional role in modulating behaviours that entail trade‐offs between reward approach and risk in humans. We recommend that future dose‐response studies investigate the effect of oxytocin on reward approach behaviour further in women with recurrent binge eating behaviour, as well as the clinical significance of this effect.     

Further evidence for a low body weight in male children and adolescents with Asperger's disorder

The study explores the common clinical impression and previously reported finding by Hebebrand et al. (7) of reduced body weight in male children and adolescents with Asperger's disorder (AD). Body weight and height of 36 consecutively admitted male patients with AD were retrospectively assessed for the calculation of body mass indices (BMI, kg/m²). The BMIs were transformed to percentile ranks and plotted into BMI-centiles representative for the German population. In addition, comorbid psychopathology was assessed to explore a possible relationship between associated psychopathology and body weight. The mean BMI-centile of all patients was 34.7 ± 31.8 and, thus, differed significantly from the mean centile of an age- and gender-matched psychiatric control group, which was 52.7 ± 28.3. Thirteen patients had a BMI below the 10th centile and five even below the third. Three of the latter presented with disturbed eating behaviour. Altogether four patients showed disturbed eating behaviour. They had a significantly lower mean BMI-centile than the rest of the group. The BMI-centiles of patients with other additional psychopathology did not differ significantly from the mean percentile of the whole cohort. The results clearly show an increased risk for underweight and disturbed eating behaviour in patients with Asperger's disorder which should be evaluated in further studies. Accepted: 26 January 1999     

The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication.

BACKGROUND: Little population-based data exist on the prevalence or correlates of eating disorders. METHODS: Prevalence and correlates of eating disorders from the National Comorbidity Replication, a nationally representative face-to-face household survey (n = 9282), conducted in 2001-2003, were assessed using the WHO Composite International Diagnostic Interview. RESULTS: Lifetime prevalence estimates of DSM-IV anorexia nervosa, bulimia nervosa, and binge eating disorder are .9%, 1.5%, and 3.5% among women, and .3% .5%, and 2.0% among men. Survival analysis based on retrospective age-of-onset reports suggests that risk of bulimia nervosa and binge eating disorder increased with successive birth cohorts. All 3 disorders are significantly comorbid with many other DSM-IV disorders. Lifetime anorexia nervosa is significantly associated with low current weight (body-mass index <18.5), whereas lifetime binge eating disorder is associated with current severe obesity (body-mass index > or =40). Although most respondents with 12-month bulimia nervosa and binge eating disorder report some role impairment (data unavailable for anorexia nervosa since no respondents met criteria for 12-month prevalence), only a minority of cases ever sought treatment. CONCLUSIONS: Eating disorders, although relatively uncommon, represent a public health concern because they are frequently associated with other psychopathology and role impairment, and are frequently under-treated.     

Initial test of an emotional avoidance model of restriction in anorexia nervosa using ecological momentary assessment

It has been hypothesized that restrictive eating allows individuals with anorexia nervosa (AN) to avoid contact with negative emotions; however, this presumption has not been directly tested. In this study, we conducted an initial investigation examining whether restrictive eating serves an emotional avoidance function among individuals with AN. Females with AN (n = 118) reported on negative and positive affect, anxiety/tension, and eating behaviors at multiple time points daily over a 2-week period using ecological momentary assessment methodology. Affective patterns were compared using generalized estimating equation models between days in which participants reported either: (1) relatively high restriction (without binge eating); (2) relatively low restriction (without binge eating); (3) binge eating; or (4) no restriction or binge eating. We hypothesized that, if restriction were functioning to avoid negative affect, average negative affect and anxiety/tension, as well as average negative and positive affect lability, would be lower and average positive affect would be higher on days characterized by high levels of restriction compared to other eating patterns. Contrary to hypotheses: (1) average negative affect, anxiety/tension, and positive affect were not significantly different between days characterized by high restriction and those characterized by low or no restriction; (2) Negative affect and anxiety/tension lability were higher on days characterized by high restriction compared to no restriction or binge eating days; (3) Anxiety/tension lability was higher on days characterized by high versus low levels of restriction. This patterns of findings does not support an avoidance model of restrictive eating for individuals with AN.     

Effects of milnacipran on binge eating - a pilot study

Selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors are effective in the treatment of bulimia nervosa. There have been relatively few studies of the efficacy of specific serotonin and norepinephrine reuptake inhibitors in the treatment of eating disorders. Twenty-five outpatients with binge eating episodes, diagnosed as anorexia nervosa, binge-eating/purging type, bulimia nervosa/purging type, or bulimia nervosa/non-purging type, were treated with milnacipran and 20 patients completed the 8-week study. Symptom severity was evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) self-rating scale before administration of milnacipran and after 1, 4, and 8 weeks treatment. The scores improved after 8 weeks, especially drive to, and regret for, binge eating. Milnacipran was more effective in patients without purging and in younger patients, while there was no difference in the efficacy of milnacipran among subtypes of eating disorders.     

Neuroendocrine responsivities of the pituitary dopamine system in male schizophrenic patients during treatment with clozapine, olanzapine, risperidone, sulpiride, or haloperidol

Background Atypical antipsychotic drugs, in clinical doses, occupy 5-HT2 receptors near saturation, while D2 dopamine receptors, assessed usually in striatum by SPECT or PET methods, are occupied to different degrees. We hypothesized that these differences in D2 receptor occupancies may also be evaluated by a neuroendocrine approach, namely by measuring the plasma prolactin responses to i. m. administered haloperidol, since the expected elevations depend mainly on the free remaining D2 receptors in the tuberoinfundibular tract. Methods We measured the plasma prolactin levels at 0, 30, 60, 90, and 120 minutes after administration of 5 mg haloperidol i. m. in six groups of male patients with schizophrenia: a) 33 patients in a drug-free state, b) 15 patients on treatment with clozapine (range 200–600 mg/day), c) 15 patients on olanzapine (10–30 mg/day), d) 14 patients on risperidone (8–16 mg/day), e) 23 patients on haloperidol (10–40 mg/day), f) 14 patients on sulpiride (600–1600 mg/day). Data were also obtained from a group of 14 healthy male control subjects. The differences in baseline prolactin levels and in the responses to acute haloperidol of the seven groups were compared. Results The baseline prolactin levels did not differ significantly in the groups of controls (8.3±3.8 ng/ml), drug-free patients (8.0±3.6) and patients treated with clozapine (7.7±3.8), they were moderately elevated in patients treated with olanzapine (16.8±8.9), elevated in patients on haloperidol (34.4±17.3), and they were even higher in the groups of patients treated with risperidone (54.9±22.4) or sulpiride (58.8±27.0). All groups of patients gave attenuated prolactin responses to i. m. haloperidol compared to healthy controls. During treatment with haloperidol, risperidone, or sulpiride, no significant prolactin increases after i. m. haloperidol were observed. The group treated with olanzapine gave significant prolactin increases, which were lower than those obtained in the group of patients treated with clozapine, who gave responses similar to that of the drug-free patients. Conclusions Plasma prolactin levels and responses to i. m. haloperidol of patients on treatment with antipsychotic drugs, reflect the prolactin release potencies of the drugs, which are related, but not restricted, to their affinities to D2 dopamine receptors. According to the prolactin baseline levels and responses to i. m. haloperidol, the drugs of this study can be categorized for their potency to the pituitary dopamine system that controls prolactin release, as follows: sulpiride > risperidone > haloperidol > olanzapine > clozapine. This categorization is similar to that obtained by binding studies in striatal D2 dopamine receptors using brain imaging techniques. Received: 26 March 2001 / Accepted: 21 June 2001     

Clozapine,but not olanzapine,disrupts conditioned avoidance response in rats by antagonizing 5-HT<Subscript>2A/2C</Subscript> receptors

The present study was designed to assess the role of 5-HT_2A/2C receptors in the acute and repeated effect of clozapine and olanzapine in a rat conditioned avoidance response model, a validated model of antipsychotic activity. Male Sprague–Dawley rats that were previously treated with either phencyclidine (0.5–2.0 mg/kg, sc), amphetamine (1.25–5.0 mg/kg, sc), or saline and tested in a prepulse inhibition of acoustic startle study were used. They were first trained to acquire avoidance response to a white noise (CS1) and a pure tone (CS2) that differed in their ability to predict the occurrence of footshock. Those who acquired avoidance response were administered with clozapine (10.0 mg/kg, sc) or olanzapine (1.0 mg/kg, sc) together with either saline or 1-2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their conditioned avoidance responses were tested for four consecutive days. After two drug-free retraining days, the long-term repeated effect was assessed in a challenge test during which all rats were injected with a low dose of clozapine (5 mg/kg, sc) or olanzapine (0.5 mg/kg). Results show that pretreatment of DOI dose-dependently reversed the acute disruptive effect of clozapine on both CS1 and CS2 avoidance responses, whereas it had little effect in reversing the acute effect of olanzapine. On the challenge test, pretreatment of DOI did not alter the clozapine-induced tolerance or the olanzapine-induced sensitization effect. These results confirmed our previous findings and suggest that clozapine, but not olanzapine, acts on through 5-HT_2A/2C receptors to achieve its acute avoidance disruptive effect and likely its therapeutic effects. The long-term clozapine tolerance and olanzapine sensitization effects appear to be mediated by non-5-HT_2A/2C receptors.     

Validation de la version française de la Binge Eating Scale : étude de sa structure factorielle,de sa consistance interne et de sa validité de construit en population clinique et non clinique

ObjectiveThe Binge Eating Scale is a widely used scale to assess binge eating disorder in obese patients. Until now, this scale has not been validated on a French population, and no psychometrically sound tool assesses binge eating disorder in the French. This study aimed to test the psychometric properties of a French version of the Binge Eating Scale by establishing its factor structure, internal consistency, and construct validity in both a non-clinical population and a clinical population (obese patients who are candidates for bariatric surgery).MethodsA total of 553 non-clinical subjects and 63 morbidly obese patients who were candidates for bariatric surgery were assessed with the BES and the Bulimic Investigatory Test, Edinburgh or BITE (which assesses both binge eating behaviours and use of inappropriate compensatory behaviours). We tested the factor structure of the instrument, its internal consistency, its construct validity with measures of binge eating, and its construct validity with measures of inappropriate compensatory behaviours to avoid weight gain. In 47 out of the 63 obese patients, we assessed binge eating disorder (SCID).ResultsIn the non-clinical population, the BES had a one-factor structure (which accounted for 61% of the variance), excellent internal consistency (α = 0.93), and high construct validity with measures of binge eating. In this population, construct validity with measures of inappropriate compensatory behaviours was confirmed in overweight and obese subjects (P = 0.42), but not in underweight and optimal weight subjects (P < 0.001). In obese patients candidates for bariatric surgery, we demonstrated that the BES had a one-factor structure (which accounted for 46% of the variance), had high internal consistency (α = 0.88) and high construct validity with measures of binge eating and good construct validity with measures of inappropriate compensatory behaviours to avoid weight gain. In the subpopulation of 47 obese patients, sensitivity, specificity, positive predictive value and negative predictive value were respectively 75%, 88.4%, 37.5% and 97.4% (BES threshold = 18).DiscussionIn this study, we validated a psychometrically sound French version of the Binge Eating Scale, both in a non-clinical and a clinical sample. The psychometric properties of the French version of the BES are comparable to its original version with a one-factor structure. The BES is a useful tool to assess binge eating disorder in obese patients (e.g., bariatric surgery candidates), but might not differentiate between binge eating disorder and bulimia nervosa in underweight and optimal weight subjects.     

Cognitive and Symptom Profiles in High-Functioning Pervasive Developmental Disorder Not Otherwise Specified and Attention-Deficit/Hyperactivity Disorder

Age- and IQ-balanced 27 children with high-functioning (IQ≥70) pervasive developmental disorder not otherwise specified (HPDDNOS) and 27 children with attention-deficit/hyperactivity disorder (ADHD) were compared on the Japanese version of Wechsler Intelligence Scale for Children Third Edition (WISC-III) and the Childhood Autism Rating Scale-Tokyo Version (CARS-TV). Compared with the ADHD children, the HPDDNOS children scored significantly lower on verbal comprehension, vocabulary, and comprehension, but significantly higher on block design. After controlling for the total CARS-TV score, the HPDDNOS children were significantly more abnormal on “relationships with people,” “nonverbal communication,” and “general impressions,” but less abnormal on “near receptor responsiveness” and “activity level.” These differences in cognitive and autistic symptom profiles may help professionals to distinguish clinically between both conditions.     

The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective.

BACKGROUND: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. METHODS: The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. RESULTS: Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [chi(2)(1)= 8.32, p = .004; odds ratio = 3.25, 95% confidence interval 1.43, 7.41]. CONCLUSIONS: Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other.     

Safety and tolerability: How do second-generation atypical antipsychotics compare?

Previously, clinicians could only utilize antipsychotic drugs that almost invariably caused extrapyramidal side effects (EPS) at the dose at which they were clinically effective. By definition, second-generation atypical antipsychotic agents are significantly better than conventional agents with regard to EPS; that is, they are clinically effective at doses at which they are less likely to cause EPS. This advantage translates into several important clinical benefits, including better negative symptom efficacy, lesser dysphoria, less impaired cognition, and a lower risk of tardive dyskinesia; in fact, this “EPS advantage” is the principal basis of the clinical advantages provided by this class of atypical antipsychotics. Pharmacologically, “atypical” antipsychotics differ in their side-effect profiles. Six second-generation antipsychotics are currently available in the United States: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. There are meaningful differences between these agents with regard to weight gain, sedation, anticholinergic side effects, cardiovascular issues, endocrine side effects, and hepatic and sexual issues; these are considered and their clinical implications discussed.     

Dopamine transporter binding in Gilles de la Tourette syndrome

Preliminary studies in patients with Gilles de la Tourette syndrome (TS) provided evidence of presynaptic dopaminergic dysfunction, demonstrating increased reuptake sites. Therefore we investigated striatal dopamine transporter binding in 12 TS patients and 9 control subjects using single photon emission computed tomography and ¹²³I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)tropane. In TS patients we found significantly higher relative striatal activity ratios (mean ±SD 12.33±3.58) than in controls (9.36±1.35, P<0.05). Only five patients, however, showed straitum/occipital cortex ratios more than 2 SD above the normal means. Seven patients had activity ratios within the average ratio of the control group plus 2 SD. Regarding the relationship between clinical parameters and striatum/occipital cortex ratios, we found an association between binding ratios and “self-injurious behavior” and “lack of impulse control”. This study corroborates previous data suggesting an involvement of the dopaminergic system in TS pathology. Our results demonstrate that an increase in dopamine transporter capacity is a possible but not a necessary alteration, and which appears more likely when self-injurious behaviour and lack of impulse control are associated. Received: 13 September 1999, Received in revised form: 24 January 2000, Accepted: 16 February 2000     

Acute ghrelin changes food preference from a high‐fat diet to chow during binge‐like eating in rodents

Ghrelin, an orexigenic hormone released from the empty stomach, provides a gut–brain signal that promotes many appetitive behaviours, including anticipatory and goal‐directed behaviours for palatable treats high in sugar and/or fat. In the present study, we aimed to determine whether ghrelin is able to influence and/or may even have a role in binge‐like eating behaviour in rodents. Accordingly, we used a palatable scheduled feeding (PSF) paradigm in which ad lib. chow‐fed rodents are trained to ‘binge’ on a high‐fat diet (HFD) offered each day for a limited period of 2 hours. After 2 weeks of habituation to this paradigm, on the test day and immediately prior to the 2‐hour PSF, rats were administered ghrelin or vehicle solution by the i.c.v. route. Remarkably and unexpectedly, during the palatable scheduled feed, when rats normally only binge on the HFD, those injected with i.c.v. ghrelin started to eat more chow and chow intake remained above baseline for the rest of the 24‐hour day. We identify the ventral tegmental area (VTA) (a key brain area involved in food reward) as a substrate involved because these effects could be reproduced, in part, by intra‐VTA delivery of ghrelin. Fasting, which increases endogenous ghrelin, immediately prior to a palatable schedule feed also increased chow intake during/after the schedule feed but, in contrast to ghrelin injection, did not reduce HFD intake. Chronic continuous central ghrelin infusion over several weeks enhanced binge‐like behaviour in palatable schedule fed rats. Over a 4‐week period, GHS‐R1A‐KO mice were able to adapt and maintain large meals of HFD in a manner similar to wild‐type mice, suggesting that ghrelin signalling may not have a critical role in the acquisition or maintenance in this kind of feeding behaviour. In conclusion, ghrelin appears to act as a modulating factor for binge‐like eating behaviour by shifting food preference towards a more nutritious choice (from HFD to chow), with these effects being somewhat divergent from fasting.     

Longitudinal MRI study of multiple system atrophy – when do the findings appear,and what is the course?

Several investigators have revealed features of multiple system atrophy (MSA) by magnetic resonance imaging (MRI). For use in clinical diagnosis, we determined the exact time when two main features of pontine and putaminal intensity changes appeared. Furthermore, in order to reveal the course from when the disorder first appeared and how it spread, we also investigated the course of MRI findings and differences between clinical subtypes. The cranial MRI of 42 patients with MSA were longitudinally studied including comments on the so called “cross sign” of pontine T2 high intensity, which was divided into 6 stages, and also on the linear T2 high intensity of the dorsolateral side of the putamen (“putaminal slit”) which was divided into 4 stages. Patients were classified as 16 MSA-C, 7 autonomic dominant type (MSA-A), and 19 MSA-P. The age at onset ranged from 41 to 74 years (mean, 55 ± 9). The duration of the disease in the MRI study ranged from 1 to 24 years. The pontine “cross sign” was completed (shows Cross, stage IV) earlier in MSA-C mainly before 5 years, later in MSA-P and even much later in MSA-A. Regarding the “putaminal slit”, MSA-P shows earlier bilateral changes (stage II), mostly before 3 years, compared with MSA-C, which requires 4 years to reveal even a unilateral change (stage I), or MSA-A which requires even more time. MRI findings showed a tendency to relate to clinical findings, since MSA-C exhibits “cross sign” completion earlier than bilateral “putaminal slit”; however, MSA-P shows bilateral “putaminal slit” earlier than “cross sign”, and MSA-A requires much more time to show both. Clinically, MSA-C, MSA-A, or MSA-P showed different MRI courses so that three subtypes could be defined also with MRI findings. Therefore these observations are useful not only for diagnosis of MSA itself, but also to distinguish clinical subtypes (MSA-C, MSA-A, or MSA-P) which have different rates of lesion progression. Received: 5 September 2001, Received in revised form: 10 December 2001, Accepted: 17 December 2001     

Impact of apolipoprotein A5 (APOA5) polymorphisms on serum triglyceride levels in schizophrenic patients under long-term atypical antipsychotic treatment

Abstract

Objectives. Schizophrenic patients treated with clozapine or olanzapine often develop hypertriglyceridemia. The apolipoprotein A5 gene (APOA5), which affects VLDL production and lipolysis, has been implicated in the triglyceride (TG) metabolism. This study examined the association of common APOA5 genetic variants and TG levels in chronically institutionalized schizophrenic patients, on a stable dose of atypical antipsychotic (clozapine, olanzapine or risperidone. Methods. The TG levels in 466 schizophrenic patients treated with clozapine (n = 182), olanzapine (n = 89) or risperidone (n = 195) were measured. Patients were genotyped for the three APOA5 single nucleotide polymorphisms (SNPs) rs662799 (–1131T > C), rs651821 (3A > G) and rs2266788 (1891T > C). Results. A gene × drug interaction with TG levels was observed. In single-marker-based analysis, the minor alleles of the two polymorphisms (–1131C and –3G) were observed to be associated with increased TGs in patients treated with risperidone, but not with clozapine or olanzapine. Haplotype analysis further revealed that carriers of the haplotype constructed with the three minor alleles had higher TG levels than those who did not carry this haplotype in patients taking risperidone (CGC^(+/+) vs. = 125.4 ± 59.1 vs. 82.2 ± 65.8, P = 0.015; CGC^{(–/+ )} vs. CGC^(–/–) = 113.7 ± 80.4 vs. 82.2 ± 65.8, P = 0.012). Conclusions. Our findings extend and add new information to the existing data regarding the association between APOA5 and TG regulation during long-term atypical antipsychotic treatment.