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.

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.

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.

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.

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.

Nutrient imbalances in depressive disorders. Possible brain mechanisms.

We examined the utility of d-fenfluramine, a serotonin-releasing drug previously shown to diminish carbohydrate craving and weight gain in obese people, in treating patients with seasonal affective disorder (SAD), a variant of depression that occurs each fall and winter and is usually associated with hyperphagia and carbohydrate craving. Eighteen patients participated in a double-blind, placebo-controlled study in 1986-1987, each receiving, in random order, d-fenfluramine (15 mg p.o. twice daily) or a placebo for four weeks, separated by a two-week washout period. Symptoms of SAD were assessed before and after each treatment period using clinical interviews by a psychiatrist, and the Hamilton Depression Rating Scale (HDS) with a special SAD addendum (ADD). Subjects were also weighed. Patients' depression scores (mean +/- SEM) were identical before treatment with drug (20.9 +/- 1.3, HDS: 13.3 +/- 0.8 ADD) or placebo (21.4 +/- 1.2, HDS; 13.2 +/- 0.6 ADD). During placebo treatment, HDS scores declined by 22.6% (p less than 0.02) and ADD scores by 9% (p greater than 0.2). During d-fenfluramine treatment, HDS scores fell by 71% (p less than 0.0001) and ADD scores by 73% (p less than 0.0001). Thirteen of the subjects (72%) demonstrated complete reversal of their abnormal test scores on d-fenfluramine. In two others, test scores fell to normal levels with both the drug and its placebo; one subject responded only to placebo; and two failed to show therapeutic responses to either drug or placebo treatment. The group as a whole lost weight (1.2 kg) on d-fenfluramine (p less than 0.033) but not on placebo. A subsequent study on nine of the responders showed that improvements persisted for the full three-month duration of the SAD season. These results indicate that d-fenfluramine, a drug not previously identified as an antidepressant, may be useful in treating SAD. Moreover, since d-fenfluramine acts specifically to enhance serotonin-mediated neurotransmission, the data further suggest that serotonin is involved in both the affective and appetitive symptoms of SAD. Indeed, the carbohydrate craving of these patients may constitute a kind of substance abuse in which the nutrient is eaten precisely for its serotonin-mediated psychotropic effects.

Aging, nutrient choice, activity, and behavioral responses to nutrients.

We directly measured nutrient consumption, activity patterns, and behavior in young volunteers and healthy elderly volunteers (N = 86) living in an identical environment. Compared to the young subjects, the elderly adults consumed fewer calories and less carbohydrate and fat, but not less protein, after adjustment for differences in body weight. Males of both ages consumed more protein than females after adjustment for body weight. All subjects snacked predominantly on carbohydrate-rich foods. The elderly subjects, however, consumed significantly fewer snacks than the young. Patterns of mood and activity also differed between age groups: the elderly volunteers were more active and alert than the young, especially early in the day, as measured by activity monitors and self-report questionnaires. We also examined the behavioral effects of high-protein and high-carbohydrate meals on these subjects because of the effects such meals can have on brain serotonin levels. The subjects ingested isocaloric carbohydrate- or protein-rich breakfasts and dinners and then participated in a series of behavioral tasks. Significant interactions between the type of meal consumed (protein versus carbohydrate) and the time at which they were ingested (breakfast versus dinner were observed. A protein meal consumed at breakfast induced more fatigue and sleepiness than an isocaloric carbohydrate meal; this was reversed in the evening when a carbohydrate meal induced more fatigue. Elderly subjects were less sensitive to sleepiness induced by carbohydrate in the evening. Overall, the young and old adults exhibited significant differences in calorie and carbohydrate intakes and also mood and activity, even when they chose their foods from an identical selection of food items and followed the same basic daily routines while living in a controlled study environment.

Calorie and nutrient intakes of elderly and young subjects measured under identical conditions.

The calorie and nutrient intakes of elderly and young healthy males and females were monitored for four days at the MIT Clinical Research Center. Subjects were free to select foods for meals and snacks from among a variety of high protein and high carbohydrate foods; when necessary, fat was added to make the foods isocaloric. The elderly subjects consumed significantly fewer calories, carbohydrates, and fat than the young subjects, both absolutely and when adjusted for differences in body weight (p less than .001). Mealtime protein intake when adjusted for body weight was similar among males of both age groups and significantly greater than the intakes of both young and elderly females (p less than .001). However, young males consumed more protein from snacks than young females or older adults and thus exhibited the highest daily protein intakes. The two age groups differed significantly in their pattern of food intake from meals and snacks. Elderly adults consumed almost 85% of their total calories from meals, whereas the younger adults consumed about 72% (p less than .001) from meals. Both groups snacked mainly on carbohydrate-rich foods. The elderly subjects consumed significantly fewer snacks than the young; their daily average consumption was 2.2 and that of the young, 4.5 (p less than .001). The persistence of different patterns of food intake between young and elderly individuals when measured under identical clinical conditions suggests that age per se, in addition to age-associated lifestyle changes, may affect eating behavior.

Carbohydrate craving, mood changes, and obesity.

Carbohydrate craving can cause weight gain in affected people and is present in women with premenstrual syndrome (PMS) and persons with seasonal affective disorder (SAD). The neurotransmitter serotonin regulates carbohydrate intake; its precursor, tryptophan, enhances serotonin release. Animal studies have shown that serotonergic drugs decrease carbohydrate consumption. Three studies of the eating patterns of over 150 obese subjects have shown that carbohydrate craving occurred at specific times, that is, at 4 p.m. and 9 p.m. A serotonergic drug (D-fenfluramine) has been shown to decrease carbohydrate consumption by 40%. Further dietary and pharmacological studies of PMS and SAD are needed to determine serotonin's involvement with symptoms of depressed mood, increased fatigue, and carbohydrate craving.

The anorexia of aging: a problem not restricted to calorie intake.

Anorexia in the elderly may represent not only disorders of calorie intake but of macronutrient intake as well. Excessive consumption of carbohydrate at the expense of protein characterizes some mild depressive disorders and may result in an inadequate protein intake among elderly individuals suffering from such disorders.

Carbohydrate cravings: a disorder of food intake and mood.

Current findings on the relationship between excessive appetite for carbohydrate-rich foods and mood disorders may explain repetitive weight gain or the inability to lose weight among some obese individuals. Obese individuals who crave carbohydrates, exhibit positive changes in mood after carbohydrate intake; individuals suffering from Seasonal Affective Disorder experience a craving for carbohydrate-rich foods in association with their mood disturbances. Brain serotonin may be involved in these disorders of affect and appetite; thus therapies that mimic the effect of carbohydrate intake on the synthesis and release of this neurotransmitter may be useful in treating obesity arising from these causes.

Do carbohydrates affect food intake via neurotransmitter activity?

The consumption of a carbohydrate-rich, protein-poor meal or snack can increase the synthesis of the brain neurotransmitter serotonin; proteins block this effect. The mechanism of the rise in brain serotonin involves the secretion of insulin, and the decrease that the hormone produces in plasma levels of certain amino acids that compete with tryptophan, serotonin's precursor, for transport across the blood-brain barrier. The rise in serotonin can thus be produced by any carbohydrate that elicits insulin secretion, independent of its sweetness. Pharmacologic treatments that amplify serotonin-mediated neurotransmission can selectively decrease the consumption of carbohydrate (i.e., in relation to that of protein). A group of diseases seems to exist in which depressive symptoms are associated with "carbohydrate-craving", and the consumption of large quantities of carbohydrate-rich, protein-poor snacks. Patients describe positive subjective responses to the dietary carbohydrates which are unrelated to hunger. These responses may be mediated by the rise in brain serotonin.