The effects of type 1 diabetes on cerebral white matter.

AIM/HYPOTHESIS: Studies investigating the structure, neurophysiology and functional outcomes of white matter among type 1 diabetes patients have given conflicting results. Our aim was to investigate the relationship between type 1 diabetes and white matter hyperintensities. METHOD: We assessed white matter integrity (using magnetic resonance imaging), depressive symptoms and neuropsychological function in 114 type 1 diabetes patients and 58 age-matched non-diabetic controls. RESULTS: Only Fazekas grade 1 and 2 white matter hyperintensities were found among 114 long-duration, relatively young diabetes patients; the severity of lesions did not differ substantially from 58 healthy controls. White matter hyperintensities were not associated with depressive history or with clinical characteristics of diabetes, including retinopathy, severe hypoglycaemia or glycaemia control. CONCLUSIONS/INTERPRETATION: Our data do not support an association between diabetes characteristics and white matter hyperintensities among relatively young type 1 diabetes participants.

Co-morbidity and disorder-related distress and impairment in purging disorder.

BACKGROUND: Recent studies suggest that purging disorder (PD) may be a common eating disorder that is associated with clinically significant levels of distress and high levels of psychiatric co-morbidity. However, no study has established evidence of disorder-related impairment or whether distress is specifically related to PD rather than to co-morbid disorders. METHOD: Three groups of normal-weight women [non-eating disorder controls (n=38), with PD (n=24), and with bulimia nervosa (BN)-purging subtype (n=57)] completed structured clinical interviews and self-report assessments. RESULTS: Both PD and BN were associated with significant co-morbidity and elevations on indicators of distress and impairment compared to controls. Compared to BN, PD was associated with lower rates of current and lifetime mood disorders but higher rates of current anxiety disorders. Elevated distress and impairment were maintained in PD and BN after controlling for Axis I and Axis II disorders. CONCLUSIONS: PD is associated with elevated distress and impairment and should be considered for inclusion as a provisional disorder in nosological schemes such as the Diagnostic and Statistical Manual to facilitate much-needed research on this clinically significant syndrome.

Laboratory screening for electrolyte abnormalities and anemia in bulimia nervosa: a controlled study.

OBJECTIVE: Abnormal eating patterns and recurrent purging behaviors can result in significant medical complications. The purpose of this study was to assess the frequency of abnormalities in clinical laboratory tests in patients with bulimia nervosa who reported being otherwise in good health. METHODS: Subjects included nonhospitalized women (N = 74) who met criteria for bulimia nervosa outlined in the 3rd Rev. ed. of the Diagnostic and Statistical Manual of Mental Disorders. They also reported use of self-induced vomiting and/or laxatives as compensatory behaviors (purging subtype). The control group (N = 110) included female volunteers with no history of a psychiatric disorder. All subjects reported being in good medical health, were medication free, and were in a normal weight range. Blood samples were analyzed in the hospital clinical laboratory. RESULTS: Compared with controls, patients showed more frequent occurrence of low values for serum potassium (6.8% vs. 0.9%; p <.05) and chloride (8.1% vs. 0.9%; p <.02). Electrolyte abnormalities occurred most often in patients with frequent bulimic episodes. Study groups did not differ significantly in frequency of abnormal hemoglobin concentrations. DISCUSSION: These results help to clarify the expected frequency of electrolyte abnormalities in individuals with bulimia nervosa who report otherwise good medical health. The substantial frequency of hypokalemia and hypochloremia underscores the importance of an appropriate medical assessment for individuals with this disorder.

Serotonin function following remission from bulimia nervosa.

Abnormal serotonergic regulation in bulimia nervosa is thought to contribute to recurrent binge eating, depressed mood, and impulsivity. To follow-up on previous studies showing decreased neuroendocrine responses in symptomatic patients, this study assessed serotonin-mediated prolactin responses in individuals who had remitted from bulimia nervosa. Subjects included 21 women with a history of bulimia nervosa and 21 healthy female controls, as well as an additional comparison group of 19 women with current bulimia nervosa. Placebo-controlled neuroendocrine response studies utilized a single oral dose (60 mg) of the indirect serotonin agonist d,l-fenfluramine. For the bulimia nervosa remitted group, the fenfluramine-stimulated elevation in serum prolactin concentration was not significantly different from the response in healthy controls, but was significantly larger than the response in patients with current bulimia nervosa (p < .01). These findings suggest that diminished serotonergic neuroendocrine responsiveness in bulimia nervosa reflects a state-related abnormality. The results are discussed in relationship to recent reports indicating that some alterations in central nervous system serotonin regulation may persist in symptomatically recovered individuals.

Decreased serum leptin in bulimia nervosa.

The eating disorder bulimia nervosa has been associated with impaired satiety, decreased resting metabolic rate, and abnormal neuroendocrine regulation. Preclinical studies suggest that such alterations could be associated with impaired leptin function. Thus, the goal of this study was to assess whether leptin function is decreased in bulimia nervosa. Serum leptin levels measured in women with bulimia nervosa (n = 18) and in women who had maintained stable recovery from bulimia nervosa (n = 15) were compared with values in healthy female controls (n = 20). Subjects were studied during the follicular phase of their menstrual cycle after an overnight fast and bed rest. Baseline serum samples were analyzed for leptin concentration by RIA. Subject groups were matched for age and body weight. Analysis of covariance, adjusting for percent body fat, demonstrated abnormally low serum leptin levels in the bulimia nervosa group (P: = 0.02), with a trend toward an inverse correlation between frequency of binge episodes and serum leptin concentration (P: < 0.1). Additionally, the remitted patient group demonstrated abnormally low leptin values (P: = 0.01). These results are consistent with the hypothesis that decreased leptin function may be associated with alterations in eating patterns, metabolic rate, and neuroendocrine regulation in bulimia nervosa.

Salivary gland enlargement and elevated serum amylase in bulimia nervosa.

BACKGROUND: Clinical reports have described salivary gland enlargement in bulimia nervosa, particularly in patients with elevated serum amylase concentration. The goal of the current study was to provide a controlled comparison of salivary gland size in patients with bulimia nervosa and healthy volunteers. METHODS: Subjects included 17 women with bulimia nervosa and 21 healthy female control subjects. Dimensions of the parotid and submandibular salivary glands were estimated by ultrasonography. Blood samples for amylase measurement were obtained after overnight fast. RESULTS: Parotid gland size was enlarged 36% in patients with bulimia nervosa in comparison to control subjects (p < .01). For the patient group, salivary gland size was significantly correlated with frequency of bulimic symptoms and with serum amylase concentration. CONCLUSIONS: These results provide new quantitative data demonstrating increased salivary gland size in bulimia nervosa. Further studies are needed to evaluate factors responsible for salivary gland enlargement and hyperamylasemia in this disorder.

Effects of suppressing thoughts about body weight: a comparison of dieters and nondieters.

OBJECTIVE: Experimental suppression of a neutral target thought often results in a subsequent "rebound" in the frequency of the thought. In this study, we tested the hypothesis that suppression of weight-related thoughts contributes to body weight preoccupations characteristic of dieters. METHOD: Subjects included 19 female dieters and 21 female nondieters. Following a randomized design, subjects were asked either to suppress (experimental condition) or express (control condition) the thought of weighing themselves. RESULTS: Nondieters demonstrated a significant rebound in frequency of the target thought following suppression (p < .05). Dieters expressed weight-related thoughts more frequently than nondieters, but did not show a rebound following target thought suppression. DISCUSSION: Thought suppression may foster development of weight-related preoccupations whereas the role suppression plays in the maintenance of dieters' weight-related preoccupations remains unclear.

Decreased serotonin function in bulimia nervosa.

BACKGROUND: Evidence that serotonin-active antidepressant medications decrease binge eating in patients with bulimia nervosa has fueled interest in the hypothesis that abnormal serotonergic neurotransmitter function contributes to symptoms of the disorder. To evaluate this hypothesis, we employed pharmacological challenge testing to compare serotonin function in patients with bulimia nervosa and healthy controls. METHODS: Neuroendocrine response patterns were compared for 15 nonhospitalized, medication-free, normal-weight women with bulimia nervosa and 14 age-matched healthy female controls. Behavioral assessment included ratings of eating disorder symptoms, depression, and anxiety. Serotonergic response patterns were assessed by measuring the increase in serum prolactin concentration during 5 hours following single-dose, oral administration of 60 mg of d,l-fenfluramine hydrochloride (Pondimin). RESULTS: For patients with bulimia nervosa, the fenfluramine-stimulated increase in serum prolactin concentration was significantly less than for controls. Within the patient group, the frequency of binge eating episodes during the 4 weeks prior to the study exhibited a significant inverse correlation with serotonin-stimulated prolactin secretion. CONCLUSION: Our study provides new evidence that impaired central nervous system serotonergic responsiveness may contribute to the onset or maintenance of abnormal eating patterns in patients with bulimia nervosa.

Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain.

Studies in rodents have shown that leptin acts in the central nervous system to modulate food intake and energy metabolism. To evaluate the possible role of leptin in the weight loss of anorexia nervosa, this study compared cerebrospinal fluid (CSF) and plasma leptin concentrations in anorexic patients and controls. Subjects included 11 female patients with anorexia nervosa studied at low weight and after treatment, and 15 healthy female controls. Concentrations of leptin in blood and CSF were measured by RIA. Patients with anorexia nervosa, compared to controls, had decreased concentrations of leptin in CSF (98 +/- 26 vs. 160 +/- 58 pg/mL; P < 0.0005) and plasma (1.75 +/- 0.46 vs. 7.01 +/- 3.92 ng/mL; P < 0.005). The CSF to plasma leptin ratio, however, was higher for patients (0.060 +/- 0.023) than for controls (0.025 +/- 0.007; P < 0.0001). At posttreatment testing, although patients had not yet reached normal body weight, CSF and plasma leptin concentrations had increased to normal levels. These results demonstrate the dynamic changes in plasma and CSF leptin during positive energy balance in anorexia nervosa. The results further suggest that normalization of CSF leptin levels before full weight restoration during treatment of anorexic patients could contribute to resistance to weight gain and/or incomplete weight recovery.

Research update on serotonin function in bulimia nervosa and anorexia nervosa.

The extent to which dysregulation of serotonin function in the central nervous system may contribute to core symptoms in patients with bulimia nervosa and anorexia nervosa is currently an area of intensive psychobiological investigation. Preclinical and clinical studies have demonstrated the involvement of the neurotransmitter serotonin in the regulation of food intake, suggesting that impaired serotonin-mediated satiety signals could contribute to patterns of recurrent binge eating. Other symptom patterns in patients with eating disorders, including mood dysregulation, impulsivity, and obsessionality, as well as therapeutic response to serotonergic agents, suggest involvement of serotonergic pathways. With a primary focus on serotonin function, this article reviews clinical studies of neuroendocrine and behavioral response to pharmacological challenges, levels of neurotransmitter metabolite in cerebrospinal fluid, and platelet studies. Controlled clinical trials involving pharmacological treatment with serotonergic medications are summarized. Considerations for future research are discussed.

Medications in the treatment of eating disorders.

Effective planning for medication treatment in patients with bulimia nervosa and anorexia nervosa is based on a comprehensive clinical assessment, including a careful review of comorbid psychiatric disorders and response to treatments for previous episodes of the disorder. Although most patients with bulimia nervosa are offered a trial of psychotherapy, significant results of controlled trials have contributed to an increased role for medications in the treatment of patients with this disorder. Pharmacologic treatment of anorexia nervosa has similarities to that of treatment-resistant depression, with the clinician turning to open trials and clinical reports for clues to rational management. As described in this article, considerations of potential side effects and medical complications are likely to play an important role in guiding the choice of medication used for treatment of patients with eating disorders.

Studies of serotonin function in anorexia nervosa.

Neuroendocrine, temperature, test-meal, and psychometric responses are reviewed following challenges with the post-synaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), the 5-HT precursor L-tryptophan (L-TRP), and placebo in 12 patients with anorexia nervosa (AN) and 16 healthy controls. A subset of the AN patients (n = 8) were rechallenged 3-4 weeks after attaining a predetermined goal weight. AN patients had blunted prolactin (PRL) responses to both m-CPP and L-TRP at low-weight and at goal-weight in comparison to controls, although there was a tendency toward normalization with weight gain. There were trends for blunted growth hormone (GH) responses following both L-TRP and m-CPP in the low-weight but not the goal-weight AN patients. Cortisol (CORT) responses following m-CPP and L-TRP were not significantly different among any of the groups. Temperature and test-meal measures were largely unaffected by serotonergic agents in the patients, although m-CPP decreased meal size in the controls. Psychometric responses were variable and are briefly described. Taken together, these findings indicate that responsiveness in post-synaptic hypothalamic-pituitary serotonergic pathways is altered in AN patients. Although there were some trends toward normalization of responsiveness following goal-weight attainment, many differences tended to persist in the patients despite an average increase of 13 kilograms. These may represent changes in serotonergic function at levels in the CNS "above" the hypothalamus.

Comparison of the effects of amino acid mixture and placebo on plasma tryptophan to large neutral amino acid ratio.

To assess the possible role of altered central serotonin function in psychiatric disorders, investigators have utilized pharmacological challenge testing with an amino acid mixture to decrease blood tryptophan concentration and, indirectly, brain serotonin levels. The aim of this pilot study was to assess the effectiveness of a modified amino mixture, administered in capsule form, in decreasing plasma tryptophan levels. Studies were conducted in six healthy, medication-free female volunteers. Following double-blind, randomized, cross-over design, subjects received on separate days capsules containing a tryptophan-free amino acid mixture (31.5 grams) or lactose placebo. Over the six hours following amino acid administration, plasma tryptophan concentrations decreased to 21% of baseline values, while the tryptophan/large neutral amino acid ratio decreased to 6% of baseline. Subjects reported minimal symptoms of nausea or other side effects following amino acid administration. The results suggest that the modified amino acid mixture may be useful in assessing behavioral responses to acute tryptophan depletion challenge testing.

Elevated sweet taste pleasantness ratings in bulimia nervosa.

Recent studies suggest that some patients with bulimia nervosa may experience elevated pleasantness responses to sweet taste. This study explored possible associations between symptoms patterns and pleasantness ratings for sucrose solutions in bulimic patients. Subjects included 15 women meeting DSM III-R criteria for narrowly defined bulimia nervosa (no history of other eating disorder); five patients with current bulimia nervosa and a past history of anorexia nervosa; and 20 healthy age-matched female controls. Subjects ate a standardized breakfast prior to the morning study visit. Sucrose-water solutions (0% to 40% sucrose) were rated for sweetness intensity and pleasantness. Patients with narrowly defined bulimia nervosa showed significantly higher pleasantness ratings for 40% sucrose solutions than controls and patients with a history of anorexia nervosa. Pleasantness ratings were not significantly correlated with frequency of binge eating or purging behaviors. These results extend previous evidence for altered sweet taste pleasantness responses in bulimia nervosa, and for differences in eating-related behaviors between patients with narrowly defined bulimia nervosa vs. those with past anorexia nervosa.

Resting metabolic rate of anorexia nervosa patients during weight gain.

To determine whether changes in energy metabolism may contribute to the difficulty of weight gain observed in anorexic patients, resting metabolic rate (RMR) and neuroendocrine function were studied in 10 patients diagnosed with anorexia nervosa. RMR per kilogram lean body mass (+/- SEM) was not significantly different from that of healthy volunteers on admission (95.9 +/- 5.6 vs 103.6 +/- 3.3 kJ/kg, respectively), during early refeeding (108.6 +/- 6.9 kJ/kg), or at target weight (102.1 +/- 3.8 kJ/kg). At late refeeding RMR was significantly higher (132.1 +/- 4.9 kJ/kg, P < 0.0001). There were no significant correlations between plasma norepinephrine and thyroid hormones and RMR. The rise in RMR during refeeding is at least double that observed in other studies in which normal-weight subjects are experimentally overfed or experimentally underfed and then refed. These results suggest that the increase in RMR during refeeding is disproportionate to weight gain and this large magnitude of increase may be unique to anorexia nervosa.

Hypnotizability, dissociation, and bulimia nervosa.

This study examined the levels of hypnotizability and dissociation in an outpatient sample of 17 normal-weight bulimic women and 20 healthy controls. Bulimic patients were significantly more hypnotizable than controls (p < .003) and scored higher on a self-report scale of dissociative experiences (p < .02). The results of measures of hypnotizability and dissociation showed a significant positive correlation in the combined subject group. These results are consistent with previous reports on hospitalized patients and college students and suggest that psychological factors associated with hypnotizability might play a role in the etiology and treatment of bulimia nervosa.

Testmeal responses following m-chlorophenylpiperazine and L-tryptophan in bulimics and controls.

A wealth of data support a role for serotonin (5-HT) function in the mediation of satiety responses, that are impaired in patients with bulimia nervosa. Testmeal results are presented in which 26 bulimic patients and 17 normal controls were given in randomized, double-blind-fashion, placebo, and the 5-HT agents m-chlorophenylpiperazine (m-CPP, 0.5 mg/kg p.o.) and L-tryptophan (L-TRP, 100 mg/kg i.v.). Three and one-half hours after drug administration, subjects were allowed to eat and lib from a standardized testmeal of 3,500 calories, after which postprandial vomiting was not allowed. M-CPP, but not L-TRP, significantly decreased meal size in the combined group, the controls, and to a lesser extent, the bulimics (P < or = .06). Maximum m-CPP concentrations were inversely correlated to the number of calories consumed in the total group. Following m-CPP, there were significant decreases in carbohydrate, protein, and fat intake in the total group of subjects. There were also trends for decreased carbohydrate and protein intake in the bulimics following m-CPP. There were trends for both m-CPP and L-TRP to reduce fat intake in the controls. Differences in the effects between m-CPP and L-TRP are likely due to differential involvement of 5-HT receptor subtypes at presynaptic and postsynaptic sites. These studies in humans confirm reports in animals that m-CPP decreases food intake, including carbohydrates, protein, and fat in a mixed testmeal.

Concentrations of adipsin in blood and rates of adipsin secretion by adipose tissue in humans with normal, elevated and diminished adipose tissue mass.

Adipsin, which is identical to complement factor D, is synthesized by fat cells, circulates in the bloodstream and is profoundly deficient in mice with genetic and hypothalamic obesity. With the recent cloning of human adipsin, a quantitative human immunoassay has been developed. In the present study, we measured adipsin blood concentrations in humans with increased and decreased adipose stores as well as adipsin secretion by adipose tissue obtained from lean and obese individuals. The results demonstrate that adipsin is released by human adipose tissue fragments as has previously been shown in mice, and that, in contrast to obese mice, blood adipsin concentrations were not reduced in the obese humans tested in this study. We also observed that blood adipsin concentrations can vary as a function of feeding or adiposity, in that they tend to be mildly elevated in obese individuals or mildly reduced in individuals with total lipo-atrophy, cachexia related to AIDS and anorexia nervosa. Thus, the circulating concentration of adipsin tends to correlate positively with degree of adiposity. Clearly, no deficiency in blood adipsin concentrations or adipsin secretion by adipose tissue was observed in the obese individuals studied.

Impulsivity ratings in bulimia nervosa: relationship to binge eating behaviors.

Although impulsive behavioral patterns are often described by patients with bulimia nervosa, there has been little formal evaluation of the relationship between impulsivity and eating-related symptomatology in this disorder. In this controlled outpatient study, ratings on the Barratt Impulsivity Scale were significantly elevated in 20 women with bulimia nervosa in comparison to 20 healthy female volunteers. Frequency of binge eating episodes was not significantly correlated with impulsivity ratings. Although these results indicate increased prevalence of impulsive behavioral style in patients with bulimia nervosa, impulsivity per se does not appear to be a predictor of symptom severity as reflected in frequency of bulimic episodes.

Alexithymia ratings in bulimia nervosa: clinical correlates.

Previous reports indicate that some patients with eating disorders have alexithymic characteristics, including affect deficit states and paucity of imagination. This study evaluated whether nonhospitalized patients with bulimia nervosa had elevated ratings of alexithymia in comparison to age-matched controls, and whether severity of bulimic symptoms was correlated with elevations in alexithymia ratings. Because alexithymia may be secondary to concurrent depression, this study was limited to patients with bulimia nervosa who were free of major depression. The authors compared alexithymia ratings for nonhospitalized normal weight women meeting DSM-III-R criteria for bulimia nervosa (N = 20) to healthy female volunteers (N = 20), utilizing the Toronto Alexithymia Scale (TAS) as the primary assessment instrument. Subjects also completed standardized rating scales for bulimic symptoms, depression, and anxiety. Alexithymia rating scale scores were significantly higher for patients with bulimia nervosa than for controls. In comparison to controls, patients had significant elevations on TAS factors reflecting affect deficit states, but normal scores for factors reflecting imagination and abstract thinking. Frequency of binge eating or purging behaviors was not correlated with alexithymia ratings. These data indicate that some patients with bulimia nervosa have alexithymic characteristics. Affect dysregulation was more prominent than limitation in fantasy or metaphorical thought. Additional studies are needed to assess whether presence of alexithymic characteristics may be predictive of response to treatment in patients with bulimia nervosa.