Mira A. Dalal

Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study.

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale0-6: clozapine, 36.6 ± 8.8 to 15.9 ± 13.7; olanzapine, 36.7 ± 9.9 to 19.1 ± 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 ± 0.6 to 2.5 ± 1.5; olanzapine, 4.5 ± 0.6 to 2.3 ± 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Normal plasma levels of orexin A (hypocretin-1) in narcoleptic patients

Deficient orexin signaling has been shown to cause narcolepsy-like conditions in animals. In human narcolepsy, CSF levels of orexin A (hypocretin-1) were reported to be low in most cases. The authors measured CSF and plasma orexin A levels in patients with narcolepsy and in controls. Confirming earlier studies, they found CSF orexin A levels to be extremely low in patients with narcolepsy. However, plasma orexin A levels did not differ from those observed in controls. These results suggest that orexin deficiency in patients with narcolepsy is a phenomena restricted to the CNS.

Diurnal variations of interleukin-6 plasma levels are confounded by blood drawing procedures

Recent findings suggest that inflammatory cytokines are involved in sleep regulation. In part, this idea is based on studies showing that systemic levels of interleukin-6 (IL-6) are affected by sleep and sleep deprivation. However, intravenous (IV) catheters used for repetitive blood sampling were reported to increase local IL-6 production, which might confound sleep-dependent or circadian changes in the plasma concentrations of this cytokine. To further examine the effects of blood drawing procedures on IL-6 plasma levels, 12 healthy young male subjects participated in a 24-h cross-over study protocol involving sleep and sleep deprivation. Blood was collected half-hourly through an IV line and one additional sample was taken by a simple needle stick from the contralateral arm in parallel to the last sample from the catheter. Difficulties in blood sampling, the plasma levels of IL-6, cortisol and subjective sleepiness were quantified. In samples from the IV line there was a linear increase in IL-6 levels in both conditions, whereas the amount of IL-6 detected in the needle stick sample at the end did not differ from baseline. IL-6 levels were significantly higher in samples rated as difficult and those difficulties were more frequent during sleep compared to nocturnal wakefulness. IL-6 levels did not correlate to variations in sleepiness or cortisol levels. We conclude that variations in IL-6 plasma levels measured in samples from an IV catheter are caused, at least in part, by changes in local cytokine production rather than by physiological changes in circulating IL-6 levels.

Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapines and olanzapines similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapines differential effects on interleukin-6.

Increased body mass index (BMI) in male narcoleptic patients, but not in HLA-DR2-positive healthy male volunteers

BACKGROUND There is growing evidence that hypocretin deficiency plays a pivotal role in human narcolepsy. Based on the physiological role of hypocretins in the regulation of food intake, one might suspect that narcoleptic patients should display reduced energy intake and as a consequence a reduced body weight compared to healthy controls. METHODS The body mass indices (BMIs) of 30 male narcoleptic patients were compared with large community-based reference samples. Because it is unclear whether increased BMI is an acquired consequence of the disease or a genetically determined premorbid feature of narcolepsy, we additionally examined the influence of the HLA-DR2 antigen, strongly associated with narcolepsy, on the BMI in a group of 117 healthy male volunteers. RESULTS Narcoleptic patients displayed higher age- and gender-specific BMI percentiles compared to a community-based sample from the German (normal) population. Within the patient sample, BMI distribution did not significantly differ between subjects who had previously received pharmacological treatment compared to drug-naive patients, or between the HLA-DR2 positive and negative healthy subjects. CONCLUSIONS The results of the present study suggest that an increased BMI in narcolepsy is neither associated with the HLA-DR2 antigen per se nor with medication, but is more likely to be a consequence of disease-associated neuroendocrine abnormalities.

Glucose Tolerance in Patients with Narcolepsy

STUDY OBJECTIVES Obesity is a common feature of narcolepsy. In addition, an increased occurrence of non-insulin dependent diabetes has been reported. So far, it is not known whether glucose metabolism in narcolepsy is disturbed due to, or independently of obesity. DESIGN Case-control study. SETTING Sleep medicine clinic at a research institute. PATIENTS We studied 17 patients with narcolepsy/cataplexy compared to 17 healthy controls matched for age, sex, and body mass index (BMI). INTERVENTIONS A 75-g oral glucose tolerance test was performed. MEASUREMENTS Glucose tolerance was determined by computing plasma glucose curve following oral glucose challenge for 240 minutes; insulin sensitivity and insulin secretion by homeostasis model assessment and minimal model analysis. RESULTS Standard outcome measures and indices of the oral glucose tolerance test did not differ between the patient group and the group of control subjects. CONCLUSIONS In this study, no clinically relevant pathologic findings in the glucose metabolism of narcoleptic patients compared to weight matched controls were found. Thus, narcolepsy is unlikely to be a risk factor per se for impaired glucose tolerance or diabetes.

Undetectable CSF level of orexin A (hypocretin‐1) in a HLA‐DR2 negative patient with narcolepsy–cataplexy

In their recent publication about CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia, Kanbayashi et al. (2002) report that nine Japanese HLA-DR2 positive patients with narcolepsy had undetectable orexin A (hypocretin-1) levels in the CSF. Another two patients were HLA-DR2 negative and showed normal CSF orexin A (hypocretin-1) levels. None of the 11 patients had a positive family history of narcolepsy. The authors concluded that undetectable orexin A is specific for HLA-DR2 positive narcolepsy. This is in agreement with numerous other reports on orexin A levels in narcolepsy (Arii et al. 2001; Melberg et al. 2001; Nishino et al. 2000, 2001; Ripley et al. 2001; Scammell et al. 2001) because so far, no HLA-DR2 negative patients with undetectable orexin A levels have been reported. In a study of our group (Dalal et al. 2001), we had included a 61-year-old, male narcoleptic patient (body mass index: 31.3) with onset of the disease at the age of 23 years. The patient had no positive family history of narcolepsy. He suffered from clear-cut cataplexy, excessive daytime sleepiness, intermittent hypnagogic hallucinations and had shown repeatedly sleeponset REM periods during diagnostic nocturnal polysomnography and multiple sleep latency tests. His HLA-DR phenotype was positive for DR4 and DRw12, but negative for DR2. Sequence specific primer analysis (kindly performed by Dr E. Keller, Laboratory for Immunogenetics, University of Munich, Munich, Germany) revealed that the patient was positive for HLA-DRB1*0407 ⁄DRB1*1201 and HLADQB1*0301. CSF orexin A (hypocretin-1) was below the detection limit of 40 pg mL just like in narcolepsy–cataplexy patients positive for the HLA-DR2. This case report suggests that undetectable orexin A in the CSF is not restricted to HLA-DR2 positive narcolepsy patients.

Olanzapine and clozapine differently affect sleep in patients with schizophrenia: Results from a double-blind, polysomnographic study and review of the literature

Schizophrenia is associated with impaired sleep continuity. The second generation antipsychotics clozapine and olanzapine have been reported to improve sleep continuity but also to rarely induce restless legs syndrome (RLS). The aims of this randomized double-blind study were to compare the effects of clozapine and olanzapine on sleep and the occurrence of RLS. Therefore, polysomnographies were recorded and RLS symptoms were assessed in 30 patients with schizophrenia before and after 2, 4 and 6 weeks of treatment with either clozapine or olanzapine. Treatment with both antipsychotics increased total sleep time, sleep period time and sleep efficiency and decreased sleep onset latency. These changes were similar in both groups, occurred during the first 2 treatment weeks and were sustained. For example, sleep efficiency increased from 83% (olanzapine) and 82% (clozapine) at baseline to 95% at week 2 and 97% at week 6 in both treatment groups. Sleep architecture was differently affected: clozapine caused a significantly stronger increase of stage 2 sleep (44%) than olanzapine (11%) but olanzapine a significantly stronger increase of REM-sleep. Olanzapine caused an 80% increase of slow wave sleep whereas clozapine caused a 6% decrease. No patient reported any of 4 RLS defining symptoms at baseline. During treatment, 1 patient of each group reported at one visit all 4 symptoms, i.e. met the diagnosis of an RLS. In conclusion, sleep continuity similarly improved and sleep architecture changed more physiologically with olanzapine. Neither of the antipsychotics induced RLS symptoms that were clinically relevant.