A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia.

OBJECTIVE: The primary purpose of this 8-week double-blind, placebo-controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine-treated subjects with schizophrenia with insulin resistance. METHOD: Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. RESULTS: Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non-significant improvement in SG (0.016 +/- 0.006-0.018 +/- 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 +/- 2.8-7.8 +/- 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low-density lipoprotein cholesterol (LDL-C) particle number (987 +/- 443-694 +/- 415, effect size = 0.30, P = 0.04). CONCLUSION: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.

A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain.

UNLABELLED: This study sought to examine the effectiveness of sibutramine, a weight loss agent, on clozapine-associated weight gain. METHOD: This was a 12-week double-blind, placebo controlled, randomized trial of sibutramine for weight loss in obese clozapine-treated schizophrenia or schizoaffective disorder subjects. RESULTS: Ten patients were enrolled into the placebo group and 11 patients into the sibutramine group. There were no significant baseline differences between the two groups on age, gender, education, ethnicity, diagnosis, weight, body mass index (BMI), and blood pressure. At week 12, there were no significant differences in changes in weight, BMI, abdominal and waist circumferences, Hba1c, fasting glucose, or cholesterol levels. CONCLUSION: Sibutramine treatment did not show significant weight loss compared with placebo in clozapine-treated patients with schizophrenia or schizoaffective disorder. Further research with a larger sample size and longer follow-up duration is warranted.

Homocysteine levels and glucose metabolism in non-obese, non-diabetic chronic schizophrenia.

OBJECTIVE: We studied a sample of schizophrenia out-patients to test the hypotheses that serum homocysteine concentrations would correlate positively with measures of glucose metabolism. METHOD: Subjects underwent a nutritional assessment and fasting plasma, serum insulin and homocysteine tests. RESULTS: Males had a significantly higher homocysteine levels than females (7.69 +/- 1.42 microM vs. 6.63 +/- 1.40 microM; P = 0.02). Comparing subjects with normal fasting glucose (NFG) (glucose < 100 mg/dl) and impaired fasting glucose (IFG) (> or = 100 mg/dl) subjects with IFG (mean 8.2 +/- 1.5 microM) had significantly higher homocysteine levels than those with NFG (mean 7.2 +/- 1.4 microM, P = 0.03). IFG was also associated with greater mean values for a Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.002) and diastolic blood pressure (P = 0.045). CONCLUSION: The group with IFG had higher fasting serum homocysteine concentrations than those with NFG which supports a connection to an important cardiovascular risk factor.

Two cases of therapeutic failure associated with levothyroxine brand interchange.

OBJECTIVE: To report the loss of therapeutic control in 2 hypothyroid patients and remind clinical pharmacists and other healthcare professionals to remain cognizant of possible product quality differences within or bioequivalency differences between levothyroxine products. CASE SUMMARIES: Two patients with stable hypothyroidism experienced symptoms of hypothyroidism with increased serum thyroid-stimulating hormone (TSH) concentrations after switching from 1 levothyroxine product to another. One tablet from 1 of the patient's levothyroxine prescriptions was assayed, and its levothyroxine content was 74.5% of the label claim, a value outside of the United States Pharmacopeia requirements of 90-110%. DISCUSSION: Two patients with hypothyroidism had remained euthyroid and stable while receiving 1 levothyroxine product, but became symptomatic with dramatically increased serum TSH concentrations while receiving what were thought to be comparable dosages of another levothyroxine product. Therapeutic control was reestablished in both patients after therapy with the original levothyroxine product was reinstated. CONCLUSIONS: Clinical pharmacists and other healthcare professionals should remain cognizant of possible product quality differences within or bioequivalency differences between levothyroxine products. These differences necessitate close monitoring of hypothyroid patients, counseling these patients about the clinical signs of sub- and supratherapeutic levothyroxine dosages, and prudence when switching patients with stable hypothyroidism to alternative levothyroxine products. If there are inconsistencies between levothyroxine products, resultant deleterious effects on the therapeutic stability of patients with hypothyroidism may undermine cost savings that might be incurred by such a change. If these patients are switched to alternative levothyroxine products, it is recommended that thyroid function tests be repeated after equilibration to the new product.

Longitudinal follow-up of amenorrhea in eating disorders.

The authors recruited 229 treatment-seeking anorexic and bulimic women for a prospective, longitudinal study. Telephone interviews were arranged every 3 months for at least 1 year for 225 patients. At intake, 132 subjects were menstruating, 34 subjects were taking oral contraceptives, 5 subjects had an organic cause for amenorrhea (e.g., hysterectomy), and 58 subjects were amenorrheic. Each patient met Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R) criteria for anorexia nervosa (AN, N = 41), bulimia nervosa (BN, N = 98), or AN/BN (N = 90). All subjects were interviewed with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version, which was modified to include a section for DSM-III-R eating disorders, the Longitudinal Interval Follow-Up Evaluation, and the Structured Interview for DSM-III Personality Disorders. It was found that body weight was associated with menstrual status: those with amenorrhea had a mean percent ideal body weight (IBW, Metropolitan Life criteria) of 74 +/- 1% compared with 102 +/- 19% for menstruating patients (p < .01). Affective illness was more prevalent among patients with amenorrhea than among menstruating patients (75% vs. 56%, p < .05). Menses were regained within 1 year by 33% of amenorrheic patients. These patients gained an average of 7.3% of their IBW. Longer duration of eating disorder (p < .03) and the presence of an anxiety disorder (p < .05) were associated with persistent amenorrhea. Menses were lost within 1 year by 8% of menstruating patients. These patients lost an average of 5.0% of their IBW.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal failure associated with laxative abuse.

Eating disorder patients often abuse laxatives in an attempt to purge excess food. Laxative abuse can cause hypokalemia and volume depletion. Hypokalemia, in turn, can lead to rhabdomyolysis. Laxative-induced hypokalemia and volume depletion have been previously reported to cause renal insufficiency, but not severe enough to require hemodialysis. A 27-year-old woman with a long history of laxative abuse presented with severe renal failure associated with hypokalemia and volume depletion. She required acute hemodialysis for worsening acidosis (pH 7.05) despite assisted ventilation. A prior episode of hypokalemic rhabdomyolysis at age 23 had resulted in only mild renal insufficiency. Her later episode of severe renal failure was linked to profound volume depletion (blood urea nitrogen 135 mg/dl). This patient calls attention to a potentially life-threatening complication of laxative abuse and indicates that volume depletion can exacerbate laxative-associated renal failure.

Neurochemical abnormalities of anorexia nervosa and bulimia nervosa.

The authors review the research on anorexia nervosa and bulimia nervosa, emphasizing the neurotransmitters and neuromodulators that regulate eating behavior. Anorexia nervosa is associated with changes in the noradrenergic, serotonergic, and opioid systems; bulimia nervosa is accompanied by marked alterations in serotonin and norepinephrine activity. These neurochemical changes may perpetuate pathological eating behavior and may be responsible for several associated psychiatric symptoms, including anxiety and depression. The authors also summarize studies of several drugs that are used in the treatment of eating disorders and are known to modify neurotransmitter activity. Understanding the neurochemistry of eating disorders seems crucial for the rational development of both psychopharmacological and behavioral treatments.

Diuretic abuse and central pontine myelinolysis.

Patients with eating disorders often use diuretics to eliminate fluid to achieve lower body weight. Diuretic abuse can lead to severe hyponatremia. Central pontine myelinolysis, a disruption of the myelinated neurons of the pons, has been associated with rapid correction of severe hyponatremia. A case is presented of a 35-year-old woman who was brought to the emergency service by ambulance complaining of vomiting for 7 days and that she could not hear well because she was 'worn out'. Initial laboratory values included serum Na 91 mEq/l, K 1.6, Cl 46, bicarbonate 33, BUN 4 mg/dl, glucose 306 mg/dl. After 32 h of intravenous fluids, the serum Na was 126, K 4.0, Cl 89, bicarbonate 25, glucose 118 mg/dl. On the 3rd hospital day the serum Na was 139. On the 4th hospital day she was alert and appropriate. On the 5th hospital day, however, she was confabulating and chatty. The serum Na was 139. She progressed to develop a spastic quadriparesis, speech and swallowing difficulties. A magnetic resonance imaging scan showed central pontine myelinolysis. She acknowledged taking 400 mg daily of furosemide and drinking much water. She had a past history of anorexia nervosa. She had a residual weight phobia and strove to keep her weight below 106 lb. Her height was 5 feet, 6 inches. As illustrated by this case, diuretic abuse can cause severe hyponatremia and the subsequent risk of central pontine myelinolysis. In patients with severe chronic or subacute hyponatremia, a safe restoration rate for serum Na has been less than 0.55 mEq/l/h. Serum Na should be below 135 within the first 48 h and hypernatremia should be avoided.

Effect of dexamethasone on cortisol and prolactin responses to meals in bulimic and normal women.

In normal individuals, serum cortisol and prolactin concentrations have been shown to rise following a mid-day meal. To determine whether abnormalities of the hypothalamo-pituitary-adrenal axis in bulimics lead to a disrupted hormonal response to eating, cortisol and prolactin responses to meals (600 kcal, 30% protein, 30% fat, 40% carbohydrate) were studied on two consecutive days in six normal weight bulimics and six normal volunteers. Dexamethasone (1 mg orally) was administered at 2330 h after baseline sampling. During baseline sampling, cortisol concentrations were significantly higher in the bulimics (18.2 +/- 0.9 micrograms/dl, mean +/- SEM) than in the normals (12.1 +/- 0.4 micrograms/dl) (p less than 0.001). Post-dexamethasone cortisol concentrations also were higher in the bulimics (5.7 +/- 0.3 micrograms/dl) than in the normals (1.2 +/- 0.2 micrograms/dl) (p less than 0.001). The three bulimics with a major depressive disorder had higher peak post-dexamethasone cortisol concentrations than the nondepressed bulimics. Dexamethasone significantly enhanced the prolactin response to meals among both bulimics (at 90 min post onset of eating) and normals (at 60, 75 and 90 min post onset of eating). This enhancement of the prolactin response to meals by dexamethasone is opposite to the inhibitory effect of dexamethasone on stress-induced prolactin release and suggesting that stress-induced and meal-induced prolactin release involve different neuroendocrine mechanisms.

Hypoglycemia and death in anorexia nervosa.

Several deaths in patients with anorexia nervosa have been ascribed to 'inanition'. The proximate cause of death from inanition has not been established. There are few previous reports of life-threatening hypoglycemia in anorexia nervosa. We participated in the care of two severely cachectic women with anorexia nervosa who were in coma with serum glucose levels of 8 and 14 mg/dl, respectively. Both patients became alert after administration of intravenous glucose. Both were found to have pneumonia at the time of the hypoglycemic event. While the mechanism of the hypoglycemia is unknown, it may be related to the suppression of gluconeogenesis by infection in the setting of reduced substrate, depleted fat stores and decreased catecholamine release.

Non-bulimia: food regurgitation in a patient with self-diagnosed bulimia.

The increased prevalence of bulimia has received great publicity by the news media. Such publicity predisposes individuals to self-diagnosis. A 57-year-old man with a 10-year history of food regurgitation presented to an eating disorder clinic complaining of bulimia, which he had heard discussed on a television talk show. He proved not to have bulimia but a large pharyngoesophageal (Zenker's) diverticulum. The diagnosis of bulimia may be misattributed to various symptoms by patients. The differential diagnosis of chronic regurgitation and vomiting must be considered in such patients.

Cysteamine decreases prolactin responsiveness to thyrotropin-releasing hormone in normal men.

Cysteamine depletes pituitary and plasma prolactin in rats. It acts through a nondopaminergic mechanism to alter both immunoactive and bioactive prolactin. The effect of cysteamine on prolactin secretion is reported in normal men. Six normal subjects received a control thyrotropin-releasing hormone (TRH) test at 0900 using 200 micrograms TRH intravenously; serum prolactin and TSH were measured at -10, 0, 10, 20, 30, 60, and 90 min after administration of TRH. Serum calcium and parathyroid hormones levels were measured at -10 min. Seven or more days later, they received cysteamine hydrochloride 15 mg/kg body weight orally every 6 hours for 5 doses. One hour after the last dose, the TRH test was repeated. Peak serum prolactin levels following TRH, prolactin levels at the 10-min time point, and total area from 0 to 30 min under the prolactin secretory curve were significantly decreased by cysteamine administration. TSH levels were unchanged. Serum calcium levels were significantly decreased by cysteamine administration, but parathyroid hormone levels were unchanged. It was concluded that cysteamine reduced TRH-stimulated prolactin secretion. Cysteamine also decreases serum calcium levels and suppresses the anticipated rise in serum parathyroid hormone levels. These effects on serum calcium and parathyroid hormone are similar to those previously shown for WR2721, another sulfhydryl compound. Cysteamine should be further considered as an alternative drug in the treatment of hyperprolactinemia and as a therapeutic agent for hypercalcemia.

The incidentally discovered adrenal mass.

With the wider application of increasingly sensitive computed tomographic scans, more adrenal masses will be discovered incidentally. Because benign lesions of the adrenal are much commoner than malignant ones, an approach is needed to determine which incidentally discovered masses should be removed. The history and physical examination may guide the evaluation. Imaging studies and needle biopsies have limited value. If the history and physical findings do not suggest a diagnosis, an approach using the size of the mass, results of any cyst puncture, and a biochemical assessment may determine which patients should have surgery. This approach is based on the relative prevalence of benign and malignant clinically silent adrenal tumors.

The incidentally discovered adrenal mass.

With the wider application of increasingly sensitive computed tomographic scans, more adrenal masses will be discovered incidentally. Because benign lesions of the adrenal are much commoner than malignant ones, an approach is needed to determine which incidentally discovered masses should be removed. The history and physical examination may guide the evaluation. Imaging studies and needle biopsies have limited value. If the history and physical findings do not suggest a diagnosis, an approach using the size of the mass, results of any cyst puncture, and a biochemical assessment may determine which patients should have surgery. This approach is based on the relative prevalences of benign and malignant clinically silent adrenal tumors.