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Even with guideline-conform treatment in specialized outpatient clinics and intensive treatment programs, some patients suffering from severe and enduring anorexia nervosa do not achieve a satisfying level of mental health and quality of life. As this patient group is associated with a high mortality, a palliative stage of anorexia nervosa is postulated. In these cases, treatment decisions should factor in not only a prolongation of life but also quality of life, especially when compulsory treatment is considered. In doubtful cases, a palliative care physician and the clinical ethics committee should be consulted.

There is evidence from case studies suggesting that adapted dialectical behavior therapy (DBT) for borderline personality disorder (BPD) and eating disorders (ED) might improve disorder related complaints. Twenty-four women with BPD (9 with comorbid anorexia nervosa [AN] and 15 with bulimia nervosa [BN]), who already had failed to respond to previous eating-disorder related inpatient treatments were consecutively admitted to an adapted inpatient DBT program. Assessment points were at pre-treatment, post-treatment, and 15-month follow-up. At follow-up, the remission rate was 54% for BN, and 33% for AN. Yet 44% of women with AN crossed over to BN and one woman additionally met the criteria of AN. For women with AN, the mean weight was not significantly increased at post-treatment, but had improved at follow-up. For women with BN, the frequency of binge-eating episodes was reduced at post-treatment as well as at follow-up. Self-rated eating-related complaints and general psychopathology, as well as ratings on global psychosocial functioning, were significantly improved at post-treatment and at follow-up. Although these findings support the assumption that the adapted DBT inpatient program is a potentially efficacious treatment for those who failed to respond to previous eating-disorder related inpatient treatments, remission rates and maintained eating-related psychopathology also suggest that this treatment needs further improvement., (2010 Elsevier Ltd. All rights reserved.)

Low bone mineral density (BMD) is a frequent, often persistent complication in patients with major depressive disorder (MDD) and anorexia nervosa (AN) that increases the risk of pathologic fractures. The pathogenetic process underlying osteopenia in MDD and AN is still unclear, although several factors, including a dysbalance of cytokines, are associated with loss of bone mass. Alterations in the serum levels of cytokines have been observed in patients with MDD, AN, and other psychiatric disorders. Therefore, we examined serum levels of cytokines, markers of bone turnover, and BMD in 13 patients with MDD and a lifetime history of AN. Bone turnover markers (osteocalcin and C-terminal degradation products of type I collagen) and tumor necrosis factor alpha (TNF-alpha) in patients were significantly increased compared with those of the control group. Osteoprotegerin (OPG) in patients was significantly decreased. Eight of 13 patients (62%) displayed osteopenia at the lumbar spine. TNF-alpha correlated significantly with C-terminal degradation products of type I collagen, an osteoclastic marker, but significantly negatively with OPG. Our data suggest that TNF-alpha and OPG may play a role in the pathogenetic process underlying osteopenia in these patients.

Anorexia nervosa (AN) is a complex disorder of unclear etiology. We argue that the current DSM-IV criteria do not adequately describe the cardinal symptoms of this "eating disorder". Our reasoning is based on the lack of empirical evidence supporting the terminology of some of the criteria, which underlie the core of our current conceptualisation of AN. We propose alternative criteria which allow a better integration of biologically derived hypotheses addressing the nosology and the symptomatology of AN.

Low leptin levels are an endocrinological hallmark of acute anorexia nervosa (AN); a subthreshold leptin secretion in adipocytes as a consequence of a reduced energy intake is presumed to be the major trigger of the adaptation of an organism to semistarvation. The aim of the current study is to define symptoms of AN that are potentially linked to low leptin levels. For this purpose, quantitative somatic and psychopathological variables were obtained in 61 inpatients with acute AN (study group 1) upon referral for inpatient treatment, and they were concomitantly blood sampled to allow determination of serum leptin levels. Correlations between these variables and logarithmic transformed (lg10) leptin levels were descriptively assessed. Apart from the well-known correlations between leptin levels and anthropometric measurements, the strongest correlation was observed between lg10 serum leptin levels and expert ratings of motor restlessness (r = -0.476; nominal P = 0.003) upon use of visual analog scales. We thus generated the hypothesis that physical activity levels in AN patients are related to serum leptin levels. This hypothesis was tested in an independent study group of 27 adolescent inpatients (study group 2) who were also assessed upon referral. Physical activity levels, which, in this study group, were assessed with the activity module of the expert rating form of the Structured Inventory for Anorexic and Bulimic Syndromes, were significantly correlated with lg10 leptin levels (r = -0.51; one-sided P = 0.006). A regression model based on the independent variables body mass index and lg10 leptin levels explained 37% of the variance of physical activity (R(2) = 0.37; P = 0.003); only the lg10 leptin levels contributed significantly to the variance (P = 0.003). Our results suggest that, similar to semistarvation-induced hyperactivity in rats, hypoleptinemia in patients with AN may be one important factor underlying the excessive physical activity.

In the long term anorexia nervosa has after toxicomania the second highest lethality of all psychiatric disorders. The genesis of this eating disorder may be found in a combination of biological, cultural, familial and intrapsychic factors. Long-term investigations have not only verified the seriousness of the prognosis of lethality but have also demonstrated that depressive illness, compulsive behaviour and addiction quite often supersede anorexia nervosa. It therefore seems justified to assume biological pathomechanisms as co-factors both in triggering the disease as well as in the chronification of this illness. Besides the discussion on a genetic disposition based on results of twin- and family research, psychobiological models of appetite and satiation behavior based on known neuropeptides and neurotransmitters are presented with regard to the development of anorexia nervosa.

Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa.

Insulin, glucose, and large neutral amino acids (LNAA) were studied in 10 patients with anorexia nervosa, 13 patients with bulimia nervosa, and 15 healthy controls. Blood samples were collected at hourly intervals during the day and at two-hour intervals during the night over a 24-hour period. Ad libitum caloric and relative carbohydrate intake was significantly reduced in the anorectic and bulimic patients. Elevated concentrations of beta-hydroxybutyric acid (BHBA) were seen in the bulimic group, and low triiodothyronine (T3) concentrations in the anorectic group. Mean plasma glucose and insulin concentrations were significantly lowered in both groups. The tryptophan (Trp) to LNAA ratio was reduced in anorectic, but not in bulimic patients. These findings suggest that Trp influx into the brain is reduced in anorectic patients, possibly impairing central serotonergic function.

Fifteen patients with bulimia (DSM-III) and 22 patients with anorexia nervosa (10 "restricters" and 12 "vomiters") were compared with 24 age- and sex-matched healthy controls. Serial blood samples were collected between 8:30 and 9:30 a.m. with patients in supine and standing positions. Elevated blood values of beta-hydroxybutyric acid and free fatty acids were observed in the majority of patients with bulimia and anorexia nervosa. These data indicate that many patients with bulimia showed the metabolic signs of starvation at the time of the study, a finding supported by the symptoms of endocrine adaptation to starvation, namely low triiodothyronine and a decreased noradrenaline response to an orthostatic test in many of these patients.

The relationship between depressive symptoms and starvation, reflected by body weight and biochemical parameters, was investigated in 64 patients fulfilling DSM-III criteria for anorexia nervosa or bulimia. Multiple regression analysis revealed significant effects of body weight and beta-hydroxybutyric acid, respectively, on such specific depressive symptoms as depressed or dysphoric mood when controlling for severity of psychopathology of the eating disorder.

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

The relationship between mood and noradrenergic activity, measured by orthostatic norepinephrine response (delta NE), was investigated in 24 patients with anorexia nervosa during inpatient treatment. Mood and delta NE correlated significantly at four out of five measurement points. Group comparisons identified significantly worse mood in patients with pathologically low delta NE values. Thus, biological consequences of altered eating behavior may also affect such psychological symptoms as depressed mood.

Twenty-two patients with anorexia nervosa were studied at 2-week intervals during treatment on psychiatric wards. In order to characterize the metabolic situation in starvation, levels of free fatty acids, beta-hydroxybutyric acid, and acetoacetate were measured. The endocrine adaptation to starvation was studied by measuring triiodothyronine, noradrenaline, and cortisol. Anorectic symptoms were assessed by the Anorexia Nervosa Inventory Scale (ANIS) and mood changes on the basis of a "Befindlichkeits" Scale (BF). Only half of the patients showed metabolic and endocrine signs of starvation on admission to the hospital, despite low body weight. This group had significantly more severe anorectic symptoms (ANIS) and gained weight at a lesser rate. Metabolic signs of starvation disappeared during the first 4 weeks of therapy in most of the patients. The endocrine indicators for starvation normalized much more slowly, with noradrenaline having the slowest pace. "Bulimics" and "restricters" could not be distinguished from one another by metabolic or endocrine observations. The "bulimics," however, showed more severe anorectic symptoms (ANIS) and a more depressed mood.

The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier, has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term ‘allocation’ refers to the allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary–adrenal (LHPA) system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a ‘glutamate command’ signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress, traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine system. Disorders in the ‘energy on demand’ process or the LHPA-system can influence the allocation of energy and in so doing alter the body mass of the organism. In summary, the presented model includes a newly discovered ‘principle of balance’ of how pairs of high and low-affinity receptors can originate setpoints in biological systems. In this ‘Selfish Brain Theory’, the neocortex and limbic system play a central role in the pathogenesis of diseases such as anorexia nervosa and obesity. [Copyright &y& Elsevier]