Restlessness and an Increased Urge to Move (Drive for Activity) in Anorexia Nervosa May Strengthen Personal Motivation to Maintain Caloric Restriction and May Augment Body Awareness and Proprioception: A Lesson From Leptin Administration in Anorexia Nervosa.

Anorexia nervosa (AN), a disorder of voluntary food restriction leading to severe weight loss in female adolescents, remains an enigma. In particular, the appropriation of the starved thin body into the self-concept in AN is a process insufficiently researched and still poorly understood. Healthy humans undergoing starvation experience a slowing of movements and avoid voluntary exercise. By contrast, AN tends to be not infrequently associated with voluntary, sometimes excessive and/or compulsive exercise. Such deliberate exercise, not reported in starvation, seems to be facilitated by an increased urge for movement and physical restlessness, particular to AN. The increased urge to move would reflect spontaneous daily activity, the energy expended for everything that is not sleeping, eating, or voluntary exercise. Our hypothesis is that the starvation-induced increased urge to move and restlessness may promote the development of AN. Reversal of the fasting state, by either high caloric food or by leptin administration, would be expected to reduce restlessness and the increased urge to move along with improvement in other symptoms in AN. This review explores the idea that such restless activation in AN, in itself and through accelerating body weight loss, might foster the integration of the starving body into the self-concept by (1) enhancing the person's sense of self-control and sense of achievement and (2) through invigorating proprioception and through intensifying the perception of the changing body shape. (3) Tentative evidence from studies piloting leptin administration in chronic AN patients which support this hypothesis is reviewed. The findings show that short term administration of high doses of leptin indeed mitigated depressive feelings, inner tension, intrusive thoughts of food, and the increased urge to be physically active, easing the way to recovery, yet had little influence on the patients' personal commitment to remain at a low weight. Full recovery then requires resolution of the individuals' personal unresolved psychological conflicts through psychotherapy and frequently needs specialized treatment approaches to address psychiatric co-morbidities. AN might be conceptualized as a hereditary form of starvation resistance, facilitated by the effects of starvation on fitness allowing for an exceptionally intense personal commitment to perpetuate food restriction.

Might Starvation-Induced Adaptations in Muscle Mass, Muscle Morphology and Muscle Function Contribute to the Increased Urge for Movement and to Spontaneous Physical Activity in Anorexia Nervosa?

Severely undernourished and underweight anorexia nervosa (AN) patients typically remain active and mobile. Might such persistent physical activity in AN be supported by specific adaptations in muscle tissue during long term undernutrition? To identify potential differences, studies examining the effects of undernutrition on skeletal muscle mass, muscle morphology and muscle function in healthy humans and in AN patients were reviewed. Adjustments in muscle morphology and function in AN did not differ in substance from those in healthy humans, undernourished people, or undergoing semi-starvation. Loss of muscle mass, changes in muscle contractility and atrophy of muscle fibers (predominantly type II fibers) characterized both groups. Muscle innervation was unaffected. Work capacity in men in semi-starvation experiments and in females with AN declined by about 70% and 50%, respectively. Perceptions of fatigue and effort distinguished the groups: signs of general weakness, tiring quickly and avoidance of physical activity that were recorded in semi-starvation were not reported for AN patients. The absence of distinctive starvation-related adjustments in skeletal muscle in AN suggests that new methods, such as muscle gene expression profiles in response to deficient nutrient intake, and better knowledge of the central regulatory circuitries contributing to motor urgency will be required to shed light on the persistent mobility in AN patients.

Increased urge for movement, physical and mental restlessness, fundamental symptoms of restricting anorexia nervosa?

OBJECTIVE: Continued mobility in the presence of severe weight loss is a well known, yet insufficiently researched characteristic of anorexia nervosa (AN). This study was designed to assess the prevalence of the drive for activity, here operationalized as an increased urge for movement, physical restlessness, and mental restlessness. METHOD: Participants were 83 female consecutively admitted adolescent patients qualifying for a diagnosis of AN (ICD-10), restricting subtype. Information collected included responses to a questionnaire inquiring retrospectively about physical and psychological reactions after significant weight loss (on average 12.5 kg) and to measures of psychiatric and eating disorder pathology and exercise behaviors at hospital admission. RESULTS: Over 80% of AN patients reported experiencing, at least partly, either, an increased urge for movement, physical or mental restlessness after significant weight loss. Altogether 95.1% reported, at least partly, one or a combination of two or all three symptoms. The sensations coexisted with equally high levels of fatigue and loss of energy, typically observed in starvation. The increased urge for movement and physical restlessness were foremost associated with reported actual physical activity and with weight loss. By contrast, mental restlessness was strongly linked to the degree of eating disorder pathology and to the severity of psychiatric symptoms. DISCUSSION: This is the first investigation of the presence of an increased urge for movement, physical restlessness, and mental restlessness after significant weight loss in patients with acute AN. The symptoms, given their high frequency and specificity, are likely pathogenic for AN and, if replicated, deserve to be considered for inclusion as diagnostic criteria for AN.

Not the Function of Eating, but Spontaneous Activity and Energy Expenditure, Reflected in "Restlessness" and a "Drive for Activity" Appear to Be Dysregulated in Anorexia Nervosa: Treatment Implications.

Anorexia nervosa (AN) is uncommon as a syndrome, despite widespread dieting or voluntary food restriction, especially among female adolescents. This suggests that restriction of caloric intake might not be the only component driving weight loss in AN. Historical observations and experimental evidence from energy expenditure studies and recordings from movement sensors reviewed in this paper reveal that AN is associated with motor activity levels and with an energy output not significantly different from that in normal-weight healthy age-matched controls. By contrast, other conditions of prolonged caloric under-nutrition are typically associated with loss of energy, slowing of movements and a decrease in self-initiated activity and well-being. Several hypotheses can be inferred from the findings: (a) that long term severe caloric restriction fails in downregulating movements and energy expenditure in AN. (b) Clinically and subjectively observable as mental and physical restlessness and continued motor activity, this restless energy, differing in intensity, seems to serve as the permissive factor for and possibly to drive exercise and hyperactivity in AN. (c) Such restless energy and increased arousal, generated sometime in the course of the weight loss process, appear to enhance the person's self-perception and wellbeing, to heighten proprioception, to intensify body awareness and to improve self-esteem. (d) Restlessness and continued motor activity may constitute a phenotype of AN. The therapeutic value of the concept of an abnormality in the energy regulatory system, likely the result of a host of genetic and epigenetic changes in AN, lies primarily in its heuristic and explanatory power and its potential for disease prevention. Restless energy as a permissive and important component for the development and in the maintenance of AN, does not fundamentally alter treatment, since prolonged food deprivation is the principal causal factor for the development of AN. Re-nutrition within a structured treatment plan, to include individual and family therapy and, if indicated, heat application, remains the most effective symptomatic treatment for AN. Corroboration of the concept of restless activation will require the patient's cooperation and input to identify and capture more precisely the experiences, sensations, and changes that allow the emaciated patient to remain mobile and active.

Use of selective serotonin reuptake inhibitor antidepressants in pregnancy does carry risks, but the risks are small.

The paper by Robinson posits that risks from prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants are not different from the risks encountered in the general population and that untoward effects of SSRIs are difficult to distinguish from those of the mood disorder. Indeed, maternal depression and anxiety can have negative consequences for fetal and postnatal development. Fortunately, experimental evidence suggests that mood and anxiety disorder symptoms often respond to psychosocial interventions. If pharmacotherapy becomes necessary, it is, however, important to know that even if SSRI drugs have been shown to be safe overall, research has shown that fetal development can be adversely affected by in utero exposure to SSRIs in a subgroup of neonates. Examples would be the transient neonatal adaptation syndrome, an increased risk of persistent pulmonary hypertension of the newborn, and small, albeit measurable, changes in motor and social adaptability in infancy and childhood.

Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development.

OBJECTIVES: This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants might affect neonatal outcome and psychomotor development in infancy. METHODS: Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies. At an average age of 14 months, children underwent a pediatric examination and an evaluation with the Bayley Scales of Infant Development (BSID-II). RESULTS: Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score (<2) on this scale were 3.8 and 6.0 at 1 and 5 min, respectively. Newborns with longer exposure were more often admitted to the Neonatal Intensive Care Unit (p < .03). Mental Development Index scores of the infants were not associated with the length of gestational exposure to SSRIs. A longer duration of exposure increased the risk for lower Psychomotor Developmental Index and Behavioral Rating Scale scores in infancy (p = 0.012 and p = 0.007, respectively) on the BSID-II. CONCLUSIONS: The findings provide evidence that the length of prenatal SSRI antidepressant use can affect neonatal adjustment and can have an effect on psychomotor test scores in infancy. Importantly, the children's mental development and motor function by neurological examination were within the normal range. Timing of exposure to SSRIs during susceptible periods of fetal development and variations in the severity of maternal depression may have contributed to the associations.

Relevance of animal models to human eating disorders and obesity.

BACKGROUND AND RATIONALE: This review addresses the role animal models play in contributing to our knowledge about the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) and obesity. OBJECTIVES: Explore the usefulness of animal models in complex biobehavioral familial conditions, such as AN, BN, and obesity, that involve interactions among genetic, physiologic, psychological, and cultural factors. RESULTS AND CONCLUSIONS: The most promising animal model to mimic AN is the activity-based anorexia rodent model leading to pathological weight loss. The paradigm incorporates reward elements of the drive for activity in the presence of an appetite and allows the use of genetically modified animals. For BN, the sham-feeding preparation in rodents equipped with a gastric fistula appears to be best suited to reproduce the postprandial emesis and the defects in satiety. Animal models that incorporate genes linked to behavior and mood may clarify biobehavioral processes underlying AN and BN. By contrast, a relative abundance of animal models has contributed to our understanding of human obesity. Both environmental and genetic determinants of obesity have been modeled in rodents. Here, we consider single gene mutant obesity models, along with models of obesigenic environmental conditions. The contributions of animal models to obesity research are illustrated by their utility for identifying genes linked to human obesity, for elucidating the pathways that regulate body weight and for the identification of potential therapeutic targets. The utility of these models may be further improved by exploring the impact of experimental manipulations on the behavioral determinants of energy balance.

The 'drive for activity' and "restlessness" in anorexia nervosa: potential pathways.

This paper discusses the hypothesis that a 'drive for activity" in the presence of physiological and endocrine changes consistent with starvation is a characteristic symptom of acute anorexia nervosa (AN). This 'drive for movement', along with alertness and lack of fatigue, so unlike the motor slowing and loss of energy observed in simple starvation has been recognized in AN throughout history, but has received little attention in the past fifty years. Clinical reports and experimental evidence suggest that 'restlessness' and a 'drive for activity' vary in intensity, they appears to be starvation-dependent and to wane with food intake. Central nervous system (CNS) systems known to be involved in mediating activity and arousal levels that are altered by the negative energy expenditure in AN are reviewed. Among these, the corticotropin-releasing hormone (CRH) system, the melanocyte stimulating hormone/agouti-related protein (MSH/AGRP) system and the norepinephrine/epinephrine (NE/EPI) and dopamine (DA) system may contribute to the 'drive for activity' and alertness in AN. AN appears to represent a disorder of gene/environment interaction. Future research will reveal whether in individuals predisposed to AN, the 'drive for activity' reflects the reactivation of mechanisms important in food scarcity, controlled by one or more evolutionary conserved genes including those regulating foraging behavior. Recognition of the 'drive for activity' as a diagnostic symptom of AN and its assessment prior to re-nutrition would permit clarification of its role in the etiology of AN.

Nutrients, neurodevelopment, and mood.

Human neurodevelopment is the result of genetic and environmental interactions. This paper examines the role of prenatal nutrition relative to psychiatric disorders and explores the relationship among nutrients, mood changes, and mood disorders. Epidemiologic studies have found that adults who were born with a normal, yet low birth weight have an increased susceptibility to diseases such as coronary heart disease, diabetes, and stroke in adulthood. Prenatal caloric malnutrition, low birth weight, and prematurity also increase the risk for neurodevelopmental disorders, schizophrenia, affective disorders, and schizoid and antisocial personality disorders. Placebo-controlled studies in medicated patients suggest that add-on treatment with omega-3 fatty acids, particularly eicosapentaenoic acid, may ameliorate symptoms of major depressive disorder. Additional studies are necessary to confirm any benefits for bipolar disorders.

Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy.

OBJECTIVE: To compare the structural growth and developmental outcome of children born to mothers diagnosed with major depressive disorder during pregnancy who were exposed or not exposed to selective serotonin reuptake inhibitors (SSRIs) in utero. STUDY DESIGN: Children whose mothers were diagnosed with major depressive disorder in pregnancy and elected not to take medication (n = 13) were compared with children of depressed mothers treated with SSRIs (n = 31) on birth outcomes and postnatal neurodevelopmental functioning between ages 6 and 40 months. Children underwent blinded standardized pediatric and dysmorphology examinations and evaluations of their mental and psychomotor development with the use of the Bayley Scales of Infant Development (BSID II). RESULTS: The Bayley mental developmental indexes were similar in both groups. Children exposed to SSRIs during pregnancy had lower APGAR scores and scored lower on the Bayley psychomotor development indexes and the motor quality factor of the Bayley Behavioral Rating Scale than unexposed children. CONCLUSIONS: The findings that SSRIs during fetal development might have subtle effects on motor development and motor control are consistent with the pharmacologic properties of the drugs.

How useful are pharmacological treatments in eating disorders?

The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are multifactorial syndromes of unknown origin which occur typically in female adolescents or young women. Nowadays, AN and BN are most often triggered by dietary restriction. Both are treatable conditions. As in other psychiatric disorders, a lower comorbidity, a shorter duration of illness, less familial psychopathology, and, in AN, a higher minimal weight have been shown to be associated with a better outcome. So far, no abnormalities specific to AN or BN that would shed light on their etiology have been identified. Controlled and uncontrolled studies testing antipsychotic, antidepressant, weight-promoting, and prokinetic drugs have demonstrated that the core symptoms of AN are refractory to currently available psychotropic medication. For relapse prevention, however, antidepressant medication may be useful. Renutrition, psychotherapy, and family therapy remain the cornerstones of treatment for AN. Placebo-controlled studies with antidepressant drugs have been far more promising for treating BN in the short term. Recent studies have found that lasting symptomatic improvement and remission require the addition of psychological treatments in the form of cognitive and interpersonal psychotherapy. The steady stream of newly identified peptides and other molecules involved in appetite and body weight control may ultimately provide cues to better targeted treatments of eating disorders.