Altered response to meta-chlorophenylpiperazine in anorexia nervosa: support for a persistent alteration of serotonin activity after short-term weight restoration.

OBJECTIVE: Patients with anorexia nervosa (AN) have disturbances of appetite and behaviors, such as dysphoria, inhibition, and obsessions, that could be related to altered serotonin activity. To investigate such relationships, we administered meta-chlorophenylpiperazine (m-CPP), a relatively serotonin-specific drug. METHODS: To avoid the confounding effects of malnutrition or weight loss, we studied 12 patients with restricting-type AN between 5 and 17 days after a return to a normal weight and while on a stable dietary intake. We compared them to 12 healthy control women (CW). m-CPP was administered double blind and placebo controlled. RESULTS: Although weight restored, AN women had lower body weight and increased ratings for depression and obsessionality compared with CW. After m-CPP, AN women had an elevation in mood and a reduction in body image distortion when compared with placebo. After m-CPP, groups had similar cortisol, adrenocorticotropin (ACTH), and growth hormone responses whereas AN women had an uncertain reduction in prolactin response. DISCUSSION: These data support other studies that suggest that altered serotonin activity persists after weight restoration in AN patients. The finding that m-CPP temporarily improved mood and reduced body image distortions supports the hypothesis that altered serotonin activity may contribute to the pathophysiology of AN.

Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-purging-type anorexia nervosa.

BACKGROUND: Anorexia nervosa is an often chronic disorder with high morbidity and mortality. Many people relapse after weight restoration. This study was designed to determine whether a selective serotonin reuptake inhibitor would improve outcome and reduce relapse after weight restoration by contributing to maintenance of a healthy normal weight and a reduction of symptoms. METHODS: We administered a double-blind placebo-controlled trial of fluoxetine to 35 patients with restricting-type anorexia nervosa. Anorexics were randomly assigned to fluoxetine (n = 16) or a placebo (n = 19) after inpatient weight gain and then were observed as outpatients for 1 year. RESULTS: Ten of 16 (63%) subjects remained on fluoxetine for a year, whereas only three of 19 (16%) remained on the placebo for a year (p =.006). Those subjects remaining on fluoxetine for a year had reduced relapse as determined by a significant increase in weight and reduction in symptoms. CONCLUSIONS: This study offers preliminary evidence that fluoxetine may be useful in improving outcome and preventing relapse of patients with anorexia nervosa after weight restoration.

Effects of acute tryptophan depletion on mood in bulimia nervosa.

BACKGROUND: The present study investigated the role of serotonin in the pathophysiology of bulimia nervosa (BN) by studying the affective and appetitive responses of women ill with BN to an acute tryptophan depletion (ATD) paradigm. METHODS: Twenty-two women with BN and 16 healthy control women (CW) were studied on 2 separate days during the follicular stage of the menstrual cycle. Participants drank a control mix of essential amino acids (100 g + 4.6 g tryptophan) on one day and a tryptophan deficient (100 g - 4.6 g tryptophan) mixture (ATD) on the other in a double-blind fashion. Mood/appetite ratings and blood samples were taken at baseline and at intervals up to 420 minutes. Participants were then presented with an array of foods and were allowed to binge and vomit if they desired. RESULTS: CW and BN women had a similar and significant reduction in plasma tryptophan levels and the tryptophan: LNAA ratio after ATD. After ATD, the BN women had a significantly greater increase in peak (minus baseline) depression, mood lability, sadness and desire to binge compared to the CW. BN subjects and CW had similar peak changes in mood after the control amino acid mixture. BN subjects and CW consumed similar amounts of food after the two amino acid treatments. CONCLUSIONS: Women with BN seem more vulnerable to the mood lowering effects of ATD, suggesting they have altered modulation of central 5-HT neuronal systems.

Obsessive-compulsive disorder symptoms before and after recovery from bulimia nervosa.

OBJECTIVE: Obsessive-compulsive disorder (OCD) symptoms are common in people who are ill with bulimia nervosa. However, little is known about whether OCD symptoms persist after long-term recovery from bulimia. METHOD: Thirty-one female patients with bulimia nervosa, 29 women who had been recovered from bulimia for more than 1 year, and 19 healthy female comparison subjects completed the Yale-Brown Obsessive Compulsive Scale, which measures OCD-like symptoms. Items related to symptoms of core eating disorders were omitted from the Yale-Brown scale. RESULTS: The Yale-Brown scale scores of the women with bulimia (mean = 13.1, SD = 10.6) and those who had recovered from bulimia (mean = 7.9, SD = 7.0) were significantly higher than the scores of the normal comparison subjects (mean = 1.9, SD = 2.6). Women with bulimia and those who had recovered from bulimia had similar Yale-Brown scale scores and endorsed similar Yale-Brown scale target symptoms, such as obsessions related to symmetry and exactness. CONCLUSIONS: OCD symptoms persist after recovery from bulimia. Moreover, the types of OCD symptoms experienced by bulimia patients do not vary dramatically with improvement in bulimic symptoms. Persistent OCD symptoms after recovery from bulimia raise the possibility that these behaviors are trait-related and contribute to the pathogenesis of bulimia.

Alterations in serotonin activity and psychiatric symptoms after recovery from bulimia nervosa.

BACKGROUND: Women with bulimia nervosa (BN) have disturbances of mood and behavior and alterations of monoamine activity when they are bingeing and purging. It is not known whether these alterations are secondary to pathological eating behavior or traits that could contribute to the pathogenesis of BN. METHODS: To avoid the confounding effects of pathological eating behavior, we studied 30 women after long-term recovery (>1 year with no bingeing or purging, normal weight, and regular menstrual cycles) from BN. Subjects were compared with 31 healthy volunteer women. We assessed psychiatric diagnoses and symptoms to determine whether there was any persistent disturbance of behavior after recovery. We measured cerebrospinal fluid (CSF) levels of the major metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) as well as hormonal and behavioral response to m-chlorophenylpiperazine (m-CPP), a serotonin-specific agent. RESULTS: Women who were recovered from BN had mild to moderate negative moods and obsessions with perfectionism and exactness and exaggerated core eating disorder symptoms compared with healthy volunteer women. Recovered BN women had increased levels of CSF 5-HIAA compared with control women (117 +/- 33 vs 73 +/- 15 pmol/mL; P< or =.001) but normal CSF HVA and MHPG concentrations. Recovered BN women had an anxious and disorganized behavioral response to m-CPP but a normal hormonal response. CONCLUSIONS: Persistent serotonergic and behavioral abnormalities after recovery raise the possibility that these psychobiological alterations might be trait-related and contribute to the pathogenesis of BN.

Relationship of depression, anxiety, and obsessionality to state of illness in anorexia nervosa.

OBJECTIVE: Depression, anxiety, and obsessionality frequently are present in underweight, malnourished patients with anorexia nervosa. It is less certain if these symptoms persist after recovery. Thus, we assessed these symptoms in anorexic women at three states of illness (underweight, short-term weight restored, and long-term weight restored) in comparison to a group of healthy women. METHOD: We used standardized self- and trained rater instruments to assess depression (Hamilton Depression Rating Scale and Beck Depression Inventory), anxiety (Spielberger State-Trait Anxiety Inventory and Hamilton Anxiety Rating Scale), and obsessions and compulsions (Yale-Brown Obsessive Compulsive Scale). RESULTS: A similar pattern was found for all symptoms. That is; scores for depression, anxiety, and obsessionality were most elevated in the underweight state. These symptoms improved with weight restoration. However, milder but significantly elevated symptoms persisted in long-term weight-restored anorexic women compared to healthy control women. DISCUSSION: These data suggest that malnutrition intensifies the severity of depression, anxiety, and obsessionality in anorexia nervosa. However, the fact that mild to moderate symptoms persisted after long-term weight restoration raises the possibility that such behaviors are related to the pathogenesis of this illness.

Comparison of obsessions and compulsions in patients with anorexia nervosa and obsessive compulsive disorder.

Patients with anorexia nervosa (n = 18) and patients with obsessive-compulsive disorder (OCD) (n = 16) had similar scores on the Yale-Brown Obsessive Compulsive Scale (19 + or - 9 vs. 22 + or - 6). This suggests that these disorders have similar magnitude of impairment from obsessions and compulsions; however, OCD patients endorsed a wide variety of obsessions and compulsions, whereas anorexics tended to endorse symptoms that were related to symmetry and order.

Short-term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male subjects.

Fasting male subjects received each of four treatments on different days: a large oral dose of monosodium L-glutamate (MSG; 12.7 g), the MSG vehicle, an iv injection of TRH, or a high protein meal. Blood samples were drawn via an indwelling venous line before and at 20-min intervals after each treatment for 4 h. Plasma glutamate levels rose 11-fold within 1 h of MSG ingestion, but did not change appreciably with any of the other treatments. Plasma PRL levels rose 10-fold after TRH infusion and 2-fold after the protein meal, but did not rise significantly after MSG ingestion. No effects resulted from any of the treatments on plasma LH, FSH, testosterone, GH, or cortisol concentrations. Plasma levels of TSH, T4, and T3 showed minimal changes after any of the treatments except TRH; TRH elevated plasma TSH and T3 levels. Self-rating instruments of mood and side-effects revealed no treatment-related effects on mood or physical state for up to 48 h after each treatment. Together, these results suggest that acute pharmacological elevations of plasma glutamate levels in adult men produce minimal, if any, effects on hypothalamic or pituitary function.

Persistent perfectionism, symmetry, and exactness after long-term recovery from anorexia nervosa.

OBJECTIVE: It is well recognized that patients with anorexia nervosa have perfectionistic and obsessive behaviors. This study investigated whether such behaviors persist after recovery. METHOD: Twenty subjects who had recovered from anorexia nervosa were recruited for the study. They had been at normal weight and their menses had been regular for more than a year. These subjects were compared with 16 healthy women with the use of the Eating Disorder Inventory, the Frost Multidimensional Perfectionism Scale, and the Yale-Brown Obsessive Compulsive Scale. RESULTS: The recovered anorexic patients had significantly higher scores than the comparison women on the measures of perfectionism on the Eating Disorder Inventory and on overall perfectionism on the Frost scale. Moreover, the recovered patients had higher scores on the Yale-Brown scale, with target symptoms suggesting that many had specific concerns with symmetry and exactness. CONCLUSIONS: Certain characteristics of anorexia nervosa, such as a need for order and precision, persist after good outcome and recovery, raising the question of whether these behaviors are traits that contribute to the pathogenesis of this illness.

Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa.

OBJECTIVE: Data suggest that serotonin activity is reduced in women at normal weight who have bulimia nervosa. The authors tested whether acute perturbations in serotonin activity could alter short-term eating behavior and mood. METHOD: They examined the effect of acute tryptophan depletion in 10 women with and 10 women without bulimia nervosa. RESULTS: Women with bulimia nervosa exhibited an increase in caloric intake and mood irritability after acute tryptophan depletion. CONCLUSIONS: These results indicate that women with bulimia nervosa have an exaggerated or pathological response to transient alterations in serotonin activity.

Low discharge weight and outcome in anorexia nervosa.

OBJECTIVE: Because recent limitations in health care coverage have resulted in shorter lengths of inpatient stay, many patients with anorexia nervosa are discharged while still underweight. The authors' goal was to determine whether anorectic patients who were underweight when they were discharged had a worse outcome and a higher rate of rehospitalization than those who had achieved normal weight at discharge. METHOD: They assessed weight and height, eating disorder symptoms, and severity of depressive and anxiety symptoms in 22 women with anorexia nervosa at hospital admission and at follow-up a mean of 29 months after discharge. RESULTS: Anorectic patients who were discharged while severely underweight reported significantly higher rates of rehospitalization and endorsed more symptoms than those who had achieved normal weight before discharge. CONCLUSIONS: These data suggest that brief hospitalization for severely underweight women with anorexia may not be cost effective because the majority are rehospitalized.

Differences in weight gain between restrictor and bulimic anorectics.

After admission for weight restoration, restrictor anorectics (n = 17) gained significantly less weight than bulimic anorectics (n = 17) in a 30-day period. However, these groups had similar caloric intake. Severity of illness was found to be a predictor of rate of weight gain for restrictor anorectics, but not for bulimic anorectics.

Temperament in eating disorders.

This study examined dimensional personality and temperamental characteristics in women with eating disorders. Clinical symptoms, personality, and temperament were examined in 30 women with anorexia nervosa (AN), 32 women with bulimia nervosa with no history of anorexia nervosa (BN), and 20 women with comorbid anorexia and bulimia nervosa (AB). Temperament differed markedly across the groups on the Tridimensional Personality Questionnaire (TPQ) with AN women showing greater reward dependence, BN women scoring higher on novelty seeking subscales, and AB women showing high harm avoidance. The TPQ subscales also displayed higher classification accuracy than other personality and symptom measures. Temperamental features are distinct across eating disorder subtypes. Temperament could reflect differential vulnerabilities for the development of specific eating disorder symptom clusters.

Premorbid onset of psychopathology in long-term recovered anorexia nervosa.

It is recognized that patients with anorexia nervosa commonly have other psychiatric illnesses. No study, to our knowledge, has determined whether these other psychiatric disorders occur prior to the age of onset of anorexia nervosa. We obtained a retrospective history from 24 subjects who were long term (more than 1 year) recovered from anorexia nervosa. We found that 58% reported that they had the onset of one or more childhood anxiety disorder diagnoses at the age of 10 +/- 5 years old. This was 5 years before the mean age of onset of anorexia nervosa. The onset of depression was about 1 year before the onset of anorexia nervosa in about one half the subjects. Alcohol and substance abuse/dependency tended to occur after the onset of anorexia nervosa and only occurred in anorexic subjects who binged and/or purged. The early and common onset of childhood anxiety disorders in a substantial percentage of anorexics raises the possibility that childhood anxiety disorders herald the first behavioral expression of a biologic vulnerability in some subjects who develop anorexia nervosa.

Laxative withdrawal and anxiety in bulimia nervosa.

Symptoms of anxiety can be prominent during treatment of bulimia nervosa. Our experience is that bulimics who abuse laxatives have the most prominent symptoms of anxiety. We conducted ratings of anxiety in 23 bulimics who purge with laxatives and 17 who purge by vomiting. We found that the laxative-abusing group had higher levels of state but not trait anxiety and that they were more likely to be treated with medication for anxiety during hospitalization. These data suggest an association between laxatives and anxiety in bulimia nervosa.

Serotonin and bulimia nervosa.

Serotonin (5HT) is one of several neuromodulators of feeding. Experimentally reducing 5HT activity in animals increases food intake, while increasing 5HT activity has the opposite effect. Studies suggest that women with bulimia nervosa show signs of reduced 5HT activity, which may be related to binge eating. Data supporting the theory that reduced central nervous system 5HT activity may play a role in the pathophysiology of bulimia nervosa is reviewed. Disturbances of 5HT activity and the relationship to other psychopathology in bulimia nervosa, such as depression, substance abuse, and impulsivity, are also reviewed.

Defense style in women with eating disorders.

A relatively new instrument, the Defense Style Questionnaire (DSQ), represents an efficient method by which to quantify an individual's psychological defense style. We administered the DSQ to 66 women hospitalized for anorexia nervosa, bulimia nervosa, or concurrent anorexia and bulimia nervosa. Contrary to our expectations, there were no consistent patterns of identifiable defense styles specific to these groups in qualitative, univariate, and multivariate analyses. The failure of the DSQ to demonstrate specificity across eating disorder subgroups suggests it is not informative in regard to the pathogenesis of these specific syndromes. In contrast, in a previous study, we found temperamental measures to be informative.

Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects.

Ad libitum feeding over 24 hours was assessed in underweight restrictor anorectic (RAN) women (n = 8) and matched healthy control subjects (n = 9) in a relatively naturalistic laboratory setting. RAN consumed 828 +/- 210 kcal/day (20 +/- 6 kcal/kg/day); controls ingested 2274 +/- 564 kcal/day (41 +/- 13 kcal/kg/day). Expressed as macronutrient consumption, RAN, compared to healthy controls, ate less fat (13% vs 31%), more carbohydrate (73% vs 57%), and similar amounts of protein (14% vs 12%). RAN initiated fewer eating episodes than controls (4 vs 7). This study quantitatively confirms the growing body of evidence suggesting that RAN avoid fat-containing foods. Such persistent fat avoidance may significantly contribute to the difficulty RAN experience in gaining and maintaining body weight.

Acute tryptophan depletion in bulimia: effects on large neutral amino acids.

Acute tryptophan depletion, which may reduce brain serotonin synthesis in humans, was evaluated in bulimic and normal subjects assessing its effects on the plasma ratio of tryptophan to the sum of the other large, neutral amino acids (TRP/sigma LNAA). Thirteen bulimic and 9 control women ingested an amino acid mixture containing either 2.3 g (control mixture) or 0 g of tryptophan (active mixture), in combination with 100 g of the other amino acids. Six healthy male volunteers were also studied, using a similar mixture containing 4.6 g of tryptophan. Bulimic and control women both experienced sizable reductions in the plasma TRP/sigma LNAA ratio, compared to baseline values, for both the active mixture (10% of baseline) or the control mixture (45% of baseline). For bulimic women, the active mixture produced a significant increase in fatigue and a trend toward increased anxiety and indecisiveness. The control mixture did not maintain baseline TRP/sigma LNAA ratios so we identified a control amino acid mixture that does not cause a drop in the plasma TRP/sigma LNAA ratio when ingested (4.6 g tryptophan in combination with 100 g of other amino acids). An oral, tryptophan-deficient amino acid mixture produced acute, substantial reductions in the plasma TRP/sigma LNAA ratio in all subjects, suggesting that the treatment should reduce brain tryptophan uptake and serotonin synthesis. A control mixture containing tryptophan was also identified that maintains the plasma TRP/sigma LNAA ratio at pretreatment values.