Weight loss in overweight patients maintained on atypical antipsychotic agents.

BACKGROUND: Weight gain and associated medical morbidity offset the reduction of extrapyramidal side effects associated with atypical antipsychotics. Efforts to control weight in antipsychotic-treated patients have yielded limited success. METHODS: We studied the impact of an intensive 24-week program of diet, exercise, and counseling in 17 chronically psychotic patients (10 women, seven men) who entered at high average body weight (105.0+/-18.4 kg) and body mass index (BMI) (36.6+/-4.6 kg/m(2)). A total of 12 subjects who completed the initial 24 weeks elected to participate in an additional 24-week, less intensive extension phase. RESULTS: By 24 weeks, weight-loss/patient averaged 6.0 kg (5.7%) and BMI decreased to 34.5 (by 5.7%). Blood pressure decreased from 130/83 to 116/74 (11% improvement), pulse fell slightly, and serum cholesterol and triglyceride concentrations changed nonsignificantly. With less intensive management for another 24 weeks, subjects regained minimal weight (0.43 kg). CONCLUSIONS: These findings add to the emerging view that weight gain is a major health problem associated with modern antipsychotic drugs and that labor-intensive weight-control efforts in patients requiring antipsychotic treatment yield clinically promising benefits. Improved treatments without weight-gain risk are needed.

Impact of hormone replacement therapy on the body mass and fat compositions of menopausal women: a cross-sectional study.

OBJECTIVE: The purpose of the study was to compare the body mass and fat compositions of menopausal women who were taking conventional doses of hormone replacement therapy (HRT) with that of menopausal women who were not taking any hormones. DESIGN: The body fat composition of 169 healthy postmenopausal women was measured using a noninvasive handheld machine, the Electrolipograph (BioAnalogics ELG, Beaverton, OR, USA). Impedance to electrical flow in tissues is lower with increasing water content of the tissue. Information on HRT, lifestyle, diet, smoking, and alcohol was obtained from the medical record and by a telephone interview before women were invited to participate. HRT and non-HRT groups were compared. Multivariate linear regression, which included age, years since menopause, type of menopause, and use of HRT, was performed for each of the two major outcomes: body mass index (BMI) and percentage of body fat. RESULTS: Comparisons between subgroups showed a large number of significant differences reflecting differences in age since menopause, baseline BMIs, and baseline waist to hip ratios. In the regression model, however, the only factor significantly associated with lower fat and BMI was the use of HRT. Women who were taking HRT had significantly lower percentages of body fat (-4.8%; p < 0.001) and BMI (-2.6 kg/m2; p < 0.001) compared with nonusers. Age and duration and type of menopause were not significant predictors of weight and BMI in this group of postmenopausal women. CONCLUSIONS: In this study, HRT seems to be associated with a significant reduction in postmenopausal weight and fat mass gains. This may be an important mechanism by which HRT exerts its beneficial long-term effects on cardiovascular health.

Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects.

BACKGROUND: Neurobehavioral symptoms have been reported anecdotally with aspartame. OBJECTIVE: This study sought to determine whether aspartame can disrupt cognitive, neurophysiologic, or behavioral functioning in normal individuals. DESIGN: Forty-eight healthy volunteers completed a randomized, double-blind, placebo-controlled, crossover study. The first month was aspartame free. Subjects then consumed sodas and capsules with placebo, aspartame, or sucrose for 20 d each. Order was randomized and subjects were assigned to either a high- (45 mg x kg body wt(-1) x d(-1)) or low- (15 mg x kg body wt(-1) x d(-1)) dose aspartame group. Neuropsychologic and laboratory testing was done on day 10 of each treatment period to determine possible acute effects and on day 20 for possible chronic effects. RESULTS: Plasma phenylalanine concentrations increased significantly during aspartame treatment. Neuropsychologic results; adverse experiences; amino acid, insulin, and glucose values; and electroencephalograms were compared by sex and by treatment. No significant differences were found for any dependent measure. CONCLUSION: Large daily doses of aspartame had no effect on neuropsychologic, neurophysiologic, or behavioral functioning in healthy young adults.

Efficacies of dexfenfluramine and fluoxetine in preventing weight gain after smoking cessation.

We tested whether 14 wk of dexfenfluramine (30 mg) or fluoxetine (40 mg) treatment would prevent weight gain after subjects quit smoking. Normal-weight women (n = 144) were randomly assigned to drug or placebo on a double-blind basis for 2 wk before quitting smoking and 12 wk thereafter. The fluoxetine group had more dropouts (28/49, 57.1%) than the dexfenfluramine group (17/47, 36.2%), with an intermediate number of dropouts from the placebo group (21/48, 43.8%). All groups gained weight during treatment, but their amount and pattern of weight gain differed. In the first month after quitting smoking, the placebo group gained more weight than either the dexfenfluramine or fluoxetine group (P < 0.05). By 2 mo postcessation, dexfenfluramine still suppressed weight gain in comparison with placebo (P < 0.05); weight gain with fluoxetine was not differentiable from either dexfenfluramine or placebo. By 3 mo postcessation, the dexfenfluramine group had gained 1.0 +/- 0.7 kg, significantly less than either the placebo (3.5 +/- 0.7 kg) or fluoxetine (2.7 +/- 0.5 kg) groups. Three months after drug discontinuation, formerly medicated, but not placebo patients, showed additional weight gain, eliminating differences between groups. Results indicate that weight gain, an adverse accompaniment of smoking cessation, can be minimized to some degree by serotoninergic drugs, although only for the duration of drug treatment.

Effects of hormone replacement therapy on weight, body composition, fat distribution, and food intake in early postmenopausal women: a prospective study.

OBJECTIVE: To evaluate the effects of hormone replacement therapy (HRT) on body weight and composition, fat distribution, and food intake in women entering the climacteric. DESIGN: Prospective clinical study. SETTING: Outpatient menopause clinic at a tertiary medical center. PARTICIPANTS: Sixty-three early postmenopausal women (44 to 54 years old) were prospectively studied for 1 year. They consisted of two groups: group A, 34 subjects who initiated continuous estrogen and progestin treatment (daily oral conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg), and group B, 29 women who refused hormonal therapy and served as controls. The age, menopausal status, initial anthropometric measurements (weight, body mass index [BMI], fat mass, and waist-to-hip girth ratio), and daily food intake (total caloric intake and food composition) were similar in both groups. INTERVENTIONS: Anthropometric measurements were performed before commencement of HRT use and after 12 months. MAIN OUTCOME MEASURES: Anthropometric measurements included BMI, waist-to-hip girth ratio, and body composition (the percentage of body fat and water) estimated by means of infrared interactance. Daily food intake was also recorded. RESULTS: The body weight and fat mass increased significantly in both the treatment (73.22 +/- 2.01 [mean +/- SE] to 75.57 +/- 1.12 kg) and the control group (71.45 +/- 3.11 to 73.51 +/- 1.23 kg). However, a significant shift from gynoid to android fat distribution was observed only in the control group (waist-to-hip ratio shifted from 0.80 +/- 0.01 to 0.85 +/- 0.01), whereas no significant change was observed in the treatment group (0.81 +/- 0.01 to 0.82 +/- 0.01). Caloric and macronutrient intake did not change in either group. CONCLUSIONS: These results indicate that continuous daily estrogen and progestin replacement therapy neither prevents nor increases early postmenopausal weight gain and fat accumulation. However, it does minimize the shift from gynoid to android fat distribution.

Brain serotonin, carbohydrate-craving, obesity and depression.

Serotonin-releasing brain neurons are unique in that the amount of neurotransmitter they release is normally controlled by food intake: Carbohydrate consumption--acting via insulin secretion and the "plasma tryptophan ratio"--increases serotonin release; protein intake lacks this effect. This ability of neurons to couple neuronal signaling properties to food consumption is a link in the feedback mechanism that normally keeps carbohydrate and protein intakes more or less constant. However, serotonin release is also involved in such functions as sleep onset, pain sensitivity, blood pressure regulation, and control of the mood. Hence many patients learn to overeat carbohydrates (particularly snack foods, like potato chips or pastries, which are rich in carbohydrates and fats) to make themselves feel better. This tendency to use certain foods as though they were drugs is a frequent cause of weight gain, and can also be seen in patients who become fat when exposed to stress, or in women with premenstrual syndrome, or in patients with "winter depression," or in people who are attempting to give up smoking. (Nicotine, like dietary carbohydrates, increases brain serotonin secretion; nicotine withdrawal has the opposite effect.) It also occurs in patients with normal-weight bulimia. Dexfenfluramine constitutes a highly effective treatment for such patients. In addition to producing its general satiety-promoting effect, it specifically reduces their overconsumption of carbohydrate-rich (or carbohydrate-and fat-rich) foods.

The effect of a carbohydrate-rich beverage on mood, appetite, and cognitive function in women with premenstrual syndrome.

OBJECTIVE: To test the efficacy of a specially-formulated, carbohydrate-rich beverage (one known to increase the serum ratio of tryptophan to other large neutral amino acids) on the mood, cognitive, and appetitive disturbances of premenstrual syndrome (PMS). METHODS: Twenty-four women with confirmed PMS were enrolled in a double-blind, crossover study to test the efficacy of the specially-formulated beverage compared with two other isocaloric products on PMS symptoms. The study was conducted over three menstrual cycles preceded by a 1-month placebo run-in. Patients were tested at home or work using an interactive computer-telephone system. Standardized measurements of mood, cognitive performance, and food cravings were made before and 30, 90, and 180 minutes after consumption of active and placebo beverages during the late luteal phase of the menstrual cycle. RESULTS: The experimental carbohydrate intervention significantly decreased self-reported depression, anger, confusion, and carbohydrate craving 90-180 minutes after intake. Memory word recognition was also improved significantly compared with scores obtained during the placebo run-in month (P < .05). The isocaloric placebo interventions had no significant effect on any of these measures. CONCLUSION: The results suggest that the psychological and appetitive symptoms of PMS can be relieved after consuming a specially-formulated, carbohydrate-rich beverage known to increase serum tryptophan levels.

Aberrant snacking patterns and eating disorders in patients with obsessive compulsive disorder.

BACKGROUND: Appetitive symptoms, particularly carbohydrate craving, have been shown to occur in patients whose conditions responded to treatment with drugs that enhance serotonin-mediated neurotransmission. This suggested that patients with obsessive compulsive disorder (OCD) who also frequently respond to serotonergic drugs also might have similar distributions of appetitive and eating patterns. METHOD: A survey study of 170 OCD patients and 920 controls was conducted using a questionnaire that inquired about snacking behavior, including food preference, mood changes after eating, and previous diagnosis of eating disorders. The frequency responses in the two groups were tested for statistical significance. RESULTS: Significant differences were found between the OCD and control groups with respect to the reported incidence of eating disorders, snacking patterns, and mood response to food. CONCLUSION: This finding of different snacking patterns in OCD mirrors that found in other disorders that have been shown to be responsive to serotonergic drugs. The high incidence of carbohydrate snacking among OCD patients compared with the control group provides additional evidence that brain serotonin may be involved in this disorder.

Dexfenfluramine, fluoxetine, and weight loss among female carbohydrate cravers.

The consumption of excess calories as carbohydrates (CHO)-rich, protein-poor snacks characterizes the overeating of obese CHO cravers, premenstrual women, patients with Seasonal Affective Disorder, and former smokers. This specific appetite for CHOs may involve brain serotonin, as the synthesis and release of this neurotransmitter can increase following consumption of CHO-rich foods. To examine whether weight loss produced by serotoninergic drugs involves a selective reduction in CHO intake, obese females who consumed at least 30% of their daily calories from CHO-rich snacks were treated with dexfenfluramine ([DF] 15 mg b.i.d.); fluoxetine ([FL] 20 mg t.i.d.); or placebo (PL) for 12 weeks. Weekly weight loss for 25 of 29 PL completers was 0.22 kg +/- 0.06 (mean +/- SEM); for 21 of 28 DF completers, 0.56 +/- 0.08 kg; and for 18 of 30 FL completers, 0.58 +/- 0.09 kg (PL < DF = FL; p = .039). Seven FL subjects, 2 PL subjects, and 1 DF subject withdrew from the study due to side effects; other withdrawals were due to intercurrent illness or personal problems. Prior to treatment, subjects consumed over 40% of their daily CHO intake from snacks. Both of the drugs selectively decreased CHO snack intake (p < 0.05); DF, but not FL, also decreased meal CHO intake (p < .025). These results suggest that weight loss following treatment with serotoninergic drugs may relate to a selective decrease in CHO appetite.

Depression and weight gain: the serotonin connection.

The inability to control food intake and to engage in consistent exercise may account for repetitive episodes of weight gain. Many individuals who fail to maintain a normal weight may be susceptible to daily, monthly or seasonal perturbations in mood which result in an excessive intake of carbohydrate-rich foods and resistance to engaging in physical activity. Brain serotonin appears to be involved in these disturbances of mood and appetite; recent studies have shown that dietary and pharmacological interventions which increase serotoninergic activity normalize food intake and diminish depressed mood. Preventing recurrent weight gain may require periodic or sustained interventions that maintain mood and control over food intake.

A balanced carbohydrate: protein diet in the management of Parkinson's disease.

Although restricting dietary protein is a proposed adjunct to treating Parkinson's disease (PD), the effect of carbohydrate consumption is unknown. We measured plasma levodopa and large neutral amino acid (LNAA) levels in nine PD patients treated with carbidopa/levodopa and different isocaloric meals containing high protein-low carbohydrate, low protein-high carbohydrate, and balanced 5:1 carbohydrate:protein mixtures. We found that levodopa levels increased significantly regardless of the type of diet, but that plasma LNAA levels varied less and motor performance was superior after the balanced diet than after the other two meals. We conclude that PD patients can consume nutritionally adequate meals and still maintain a stable plasma levodopa:LNAA ratio.

Weight gain and withdrawal symptoms after smoking cessation: a preventive intervention using d-fenfluramine.

Directly measured food intake in 31 overweight female smokers to test whether (a) calorie and carbohydrate intakes increase after smoking cessation and (b) double-blind d-fenfluramine (30 mg), a serotonin-releasing drug, suppresses weight gain, overeating, and dysphoric mood associated with stopping smoking. Placebo-treated patients grew dysphoric after smoking withdrawal and ate 300 kcal/day more from 2 to 28 days after, showing a 3.5-lb weight gain. Fat and protein intakes did not change, but carbohydrate intake increased (30% to 40%). D-fenfluramine prevented postcessation dysphoria. Although drug-treated patients ate more carbohydrate snacks just after quitting, they returned to baseline by 4 weeks, showing a 1.8-lb weight loss. Agents that enhance brain serotonin-mediated neurotransmission may help prevent weight gain, overeating, and dysphoric mood after smoking withdrawal.

d-Fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression.

The ability of d-fenfluramine, a drug that releases brain serotonin and blocks its reuptake, to relieve premenstrual depression and excessive calorie and carbohydrate intakes was examined in 17 women with premenstrual syndrome. Subjects received d-fenfluramine (15 mg twice daily) or placebo, in random order, during the luteal phases of six menstrual cycles; ie, for three control and three treatment cycles each. Behavior was assessed with the Hamilton Rating Scale for Depression and its Addendum, and intakes of calories and nutrients were measured by allowing subjects unlimited access to isocaloric meal and snack foods rich in carbohydrates or protein. Pre-treatment follicular scores using the Hamilton Rating Scale for Depression and its Addendum were 2.0 +/- 0.5 and 0.5 +/- 0.5 (mean +/- SEM), respectively; corresponding luteal scores were 21.2 +/- 0.8 and 10.2 +/- 0.6 (P less than .0001). Luteal phase intakes of kilocalories, carbohydrates, and fats were also increased above follicular levels (P less than .01). d-Fenfluramine decreased premenstrual Hamilton Rating Scale for Depression and Addendum scores by 62% (P less than .001) and 60% (P less than .001), respectively; placebo reduced them by only 28% (P less than .02) and 30% (P less than .02). d-Fenfluramine also fully suppressed the premenstrual rise in kilocalorie, carbohydrate, and fat intakes (P less than .01).

Carbohydrate craving. Relationship between carbohydrate intake and disorders of mood.

Common to repetitive episodes of weight gain or failures to succeed on weight loss regimens is the excessive consumption of carbohydrate-rich foods in association with dysphoria. The brain neurotransmitter, serotonin, seems to be involved in the abnormal regulation of mood and food intake that underlies diet failures or weight gain in individuals who suffer from carbohydrate craving obesity (CCO), premenstrual syndrome (PMS) and seasonal affective disorder (SAD). All 3 syndromes are characterized by episodic bouts of increased carbohydrate consumption and depressed mood. Studies with dietary treatment or drugs that enhance serotoninergic neurotransmission have found that increased serotonin neurotransmission is associated with normalised food intake and mood. These results suggest that periodic intervention with dietary or drug treatment that increases serotonin availability may help sustain weight or assist in weight loss.

Effect of nutrient intake on premenstrual depression.

We examined the occurrence and coincidence of depressed mood and excessive carbohydrate intake in 19 patients who claimed to suffer from severe premenstrual syndrome and in nine control subjects, all as inpatients, during the early follicular and late luteal phases of their menstrual cycles. Mood was assessed with the Hamilton Depression Scale and an addendum that evaluated fatigue, sociability, appetite, and carbohydrate craving. Calorie and nutrient intakes were measured directly. The subjects with premenstrual syndrome significantly increased calorie intake during the late luteal phase (from 1892 +/- 104 to 2395 +/- 93 kcal, mean +/- SEM); carbohydrate intake increased by 24% from meals and by 43% from snacks. Protein intake failed to change, whereas intake of fat, a fixed constituent of all of the test foods, rose in proportion to calorie intake. The Hamilton Depression Scale and addendum scores rose from 2.0 +/- 0.5 to 21.2 +/- 0.8 (Hamilton Scale) and from 0.5 +/- 0.5 to 10.2 +/- 0.6 (addendum) among subjects with premenstrual syndrome during the luteal phase but failed to change among the controls (2.1 +/- 0.8 to 2.4 +/- 0.8, and 0.4 +/- 0.3 to 0.6 +/- 0.3). Consumption of a carbohydrate-rich, protein-poor evening test meal during the late luteal phase of the menstrual cycle improved depression, tension, anger, confusion, sadness, fatigue, alertness, and calmness scores (p less than 0.01) among patients with premenstrual syndrome. No effect of the meal was observed during the follicular phase or among the control subjects during either phase. Because synthesis of brain serotonin, which is known to be involved in mood and appetite, increases after carbohydrate intake, premenstrual syndrome subjects may overconsume carbohydrates in an attempt to improve their dysphoric mood state.

Treatment of seasonal depression with d-fenfluramine.

Eighteen patients with seasonal affective disorder (SAD) participated in a double-blind, placebo-controlled crossover study in 1986-1987. Each received, in random order, d-fenfluramine (15 mg p.o. twice daily)-a serotonin-releasing drug previously shown to suppress carbohydrate craving-or a placebo; these were given for 4 weeks separated by a 2-week washout period. Symptoms were assessed by means of clinical interviews and the Hamilton Rating Scale for Depression (HAM-D) with a special SAD addendum (AAD). Patients were also weighed. Depression scores (mean +/- SE) were identical before treatment with drug (20.9 +/- 1.3, HAM-D; 13.3 +/- 0.8, AAD) or placebo (21.4 +/- 1.2, HAM-D: 13.2 +/- 0.6, AAD). During placebo treatment, mean HAM-D scores declined by 22% (p less than .02) and AAD scores by 9% (p greater than .2). During d-fenfluramine treatment, HAM-D scores fell by 71% (p less than .001) and AAD scores by 73% (p less than .001). Thirteen (72%) of the patients demonstrated complete reversal of their abnormal test scores while taking d-fenfluramine. The group as a whole lost weight (mean = 1.2 kg) while receiving d-fenfluramine (p less than .033) but not when taking placebo. A second study, conducted in 1987-1988 with nine subjects who had previously responded to d-fenfluramine, showed that the drug remains effective for the full 3-month annual period of symptoms. These results indicate that d-fenfluramine may be useful in treating SAD and suggest that serotonin is involved in both SAD's affective and appetitive symptoms.

Circadian rhythms of activity in healthy young and elderly humans.

Patterns of activity of healthy adult humans were monitored in a controlled environment for several days using a wrist-mounted ambulatory activity meter. Subjects were 15 young males, 14 young females, 17 elderly males and 23 elderly females. Substantial differences in the absolute levels and patterns of daily rest and activity across age groups were observed. The elderly subjects were somewhat more active than the young subjects overall, especially in the early morning. Consistent with their increased levels of daytime activity the elderly subjects reported less sleepiness, especially in the morning, than the young volunteers. The age groups also differed significantly on all circadian parameters. The mean acrophase (peak of a sinusoid fitted to the activity rhythms) of the elderly group occurred at 1326 hr, significantly earlier than in the young group (1513 hr). The amplitude and the mesor (mean level) of the rhythms were both greater in the elderly group. It is uncertain whether these differences reflect changes in behavior that occur as a consequence of the aging process, previously-established differences in the life styles of the different populations studied, or some other factor. These findings suggest that levels and rhythms of daily activity in healthy elderly people are often well preserved and may not deteriorate as readily as had been assumed.