Eva Peñas-Lledó

The Genetics of Eating Disorders

Over the past decade, considerable advances have been made in understanding genetic influences on eating pathology. Eating disorders aggregate in families, and twin studies reveal that additive genetic factors account for approximately 40% to 60% of liability to anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Molecular genetics studies have been undertaken to identify alterations in deoxyribonucleic acid sequence and/or gene expression that may be involved in the pathogenesis of disordered eating behaviors, symptoms, and related disorders and to uncover potential genetic variants that may contribute to variability of treatment response. This article provides an in-depth review of the scientific literature on the genetics of AN, BN, and BED including extant studies, emerging hypotheses, future directions, and clinical implications.

Lifetime obesity in patients with eating disorders: increasing prevalence, clinical and personality correlates

Objectives : The aims of our study were to examine the lifetime prevalence of obesity rate in eating disorders (ED) subtypes and to examine whether there have been temporal changes among the last 10 years and to explore clinical differences between ED with and without lifetime obesity. Methods : Participants were 1383 ED female patients (DSM-IV criteria) consecutively admitted, between 2001 and 2010, to Bellvitge University Hospital. They were assessed by means of the Eating Disorders Inventory-2, the Symptom Checklist-90—Revised, the Bulimic Investigatory Test Edinburgh and the Temperament and Character Inventory—Revised. Results : The prevalence of lifetime obesity in ED cases was 28.8% (ranging from 5% in anorexia nervosa to 87% in binge-eating disorders). Over the last 10 years, there has been a threefold increase in lifetime obesity in ED patients (p < .001). People with an ED and obesity had higher levels of childhood and family obesity (p < .001), a later age of onset and longer ED duration; and had higher levels of eating, general and personality symptomatology. Conclusions : Over the last 10 years, the prevalence of obesity associated with disorders characterized by the presence of binge episodes, namely bulimic disorders, is increasing, and this is linked with greater clinical severity and a poorer prognosis. Copyright

Lifetime obesity in patients with eating disorders

Objectives : The aims of our study were to examine the lifetime prevalence of obesity rate in eating disorders (ED) subtypes and to examine whether there have been temporal changes among the last 10 years and to explore clinical differences between ED with and without lifetime obesity. Methods : Participants were 1383 ED female patients (DSM-IV criteria) consecutively admitted, between 2001 and 2010, to Bellvitge University Hospital. They were assessed by means of the Eating Disorders Inventory-2, the Symptom Checklist-90—Revised, the Bulimic Investigatory Test Edinburgh and the Temperament and Character Inventory—Revised. Results : The prevalence of lifetime obesity in ED cases was 28.8% (ranging from 5% in anorexia nervosa to 87% in binge-eating disorders). Over the last 10 years, there has been a threefold increase in lifetime obesity in ED patients (p < .001). People with an ED and obesity had higher levels of childhood and family obesity (p < .001), a later age of onset and longer ED duration; and had higher levels of eating, general and personality symptomatology. Conclusions : Over the last 10 years, the prevalence of obesity associated with disorders characterized by the presence of binge episodes, namely bulimic disorders, is increasing, and this is linked with greater clinical severity and a poorer prognosis. Copyright

Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations

Introduction: The frequency of CYP2D6 alleles, related to either a lack of or increased enzymatic activity, which may lead to poor metabolism (PM) or ultrarapid metabolism (UM), can vary across ethnic groups and hence across geographic regions. Areas covered: Worldwide original research papers on CYP2D6 allelic frequencies, metabolic phenotype frequencies measured with a probe drug, and/or genotype frequencies that studied > 50 healthy volunteers, were included in analyses to describe the distributions of alleles, phenotypes predicted from genotypes (predicted poor metabolizers [gPMs], predicted ultrarapid metabolizers [gUMs]) and metabolic phenotypes (mPMs, mUMs) across ethnic groups and geographic regions. The analysis included 44,572 individuals studied in 172 original research papers. Expert opinion: As of today, Africa and Asia are under-represented in this area relative to the total number of their inhabitants, so that further studies in these regions are warranted. The CYP2D6*4 allele frequency was higher in Caucasians, CYP2D6*10 in East Asians, CYP2D6*41 and duplication/multiplication of active alleles in Middle Easterns, CYP2D6*17 in Black Africans and CYP2D6*29 in African Americans, than in other ethnic groups. Overall, gPMs and mPMs are more frequent among Caucasians, and gUMs among Middle Easterns and Ethiopians. However, mUMs could not be evaluated because only two studies were found presenting this information. Further studies including mUMs are thus warranted. There is a correspondence between gPMs and mPMs, but the few studies of mUMs meant that their relationship with gUMs could not be demonstrated. Finally, evolutionary aspects of the CYP2D6 allele distribution appear to support the Great Human Expansion model.

Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers

OBJECTIVES Our group has previously show that interindividual variability in CYP2D6 hydroxylation capacity was related to personality differences in cognitive social anxiety. Thus, we aimed to analyze whether this relationship between personality and CYP2D6 phenotype and genotype was found in a similar population of healthy volunteers from a different latitude and culture by using the same methodology. METHODS A total of 253 university students and staff from Havana Psychiatric Hospital and Calixto García Medical School in Cuba completed the Karolinska Scales of Personality (KSP), and were evaluated on debrisoquine hydroxylation capacity and CYP2D6 genotypes. KSP scores were compared between four groups, divided according to their CYP2D6 metabolic capacity: one of poor and three of extensive metabolizers. Furthermore, KSP scores were compared between another four different groups divided according to their number of CYP2D6 active genes: zero, one, two, and more than two. RESULTS In Cubans, the differences in cognitive social anxiety-related personality traits across the four CYP2D6 hydroxylation capacity groups were strikingly similar to those found in Spaniards. These differences also came out to be significant for psychic anxiety (p = 0.02) and socialization (p = 0.02). The same pattern of results obtained for the subscales of psychic anxiety, socialization, psychasthenia and inhibition of aggression with regard to phenotype in both the Cuban and Spanish studies were seen with regard to CYP2D6 genotypes. CONCLUSIONS Corroborating these results further strengthens evidence of the relationship between CYP2D6 metabolic capacity and personality. In this population of healthy Cuban volunteers, the CYP2D6 hydroxylation capacity was related to the degree of anxiety and socialization. These results support the postulated reduction of serotonin in CYP2D6 poor metabolizers, which may be associated with a cluster of behavioral traits (e.g., anxiety, impulsivity). Thus, research is warranted to determine CYP2D6 functional implications for interindividual differences in vulnerability to neuropsychiatric diseases and drug response.

Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity.

Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied genetic polymorphism of the CYP2D6 drug-metabolizing enzyme. Debrisoquine hydroxylation phenotype has been the most used test in humans to evaluate CYP2D6 activity. Two debrisoquine hydroxylation phenotypes have been described: poor and extensive metabolizers. A group with a very low debrisoquine metabolic ratio within the extensive metabolizers, named ultrarapid metabolizers, has also been distinguished. This CYP2D6 variability can be for a large part alternatively determined by genotyping, which appears to be of clinical importance given CYP2D6 involvement in the metabolism of a large number of commonly prescribed drugs. CYP2D6 pharmacogenetics may then become a useful tool to predict drug-related side effects, interactions or therapeutic failures. However, a number of reasons appear to have made research into this field lag behind. The present review focuses on the relevance of genetics and environmental factors for determining debrisoquine hydroxylation phenotype, as well as the relevance of CYP2D6 genetic polymorphism in psychiatric patients treated with antipsychotic drugs.

Schizophrenia and tobacco smoking in a Spanish psychiatric hospital

This study in a Spanish hospital replicated two US studies suggesting that schizophrenia is associated with smoking when compared with other severe mental illnesses. Neither antipsychotics nor institutionalism could explain this relationship. Seventy of the 100 schizophrenic and 53 of the 100 non-schizophrenic inpatients were current smokers. After correcting for confounding factors, schizophrenia increased the risk of smoking by 2- to 3-fold. Heavy smoking was not associated with schizophrenia.

CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans

CYP2D6 genotype and debrisoquine metabolic ratio (MR) were analyzed in 133 Nicaraguan Mestizos (NMs) and 260 Cubans divided into Cuban Mestizos (CMs) and White Cubans (WCs). The frequencies of poor metabolizers (MR⩾12.6) were 6% in NMs, 3.9% in CMs and 5.3% in WCs. The frequencies of ultrarapid metabolizers (MR⩽0.1) were 0% in NMs, 2.3% in CMs and 5.3% in WCs. Mean (±s.d.) MR among extensive metabolizers (MR<12.6) was higher in NMs (1.5±1.6; n=118) than in CMs (1.0±1.3; n=124; P<0.001) and WCs (0.7±1.0; n=124; P<0.001). MR correlated with the ‘activity score’ of CYP2D6 genotypes (P<0.05; r=−0.55). Mean MR was higher among NMs than WCs and CMs for groups classified as 1 (P<0.05) or 2 (P<0.01) ‘activity score’. In addition, mean (±s.d.) MR was higher among subjects carrying CYP2D6*17 than in CYP2D6 wt/wt (P<0.001). The CYP2D6*10 allele was higher in NMs (3.1%) than in CMs (0.8%; P<0.05) and WCs (0.4%; P<0.05). CYP2D6*17 allele was higher in CMs (10.2%) than WC (2.7%; P<0.005) and NMs (0%). Thus, the variability in CYP2D6 phenotypes found may be related to differences in allele frequency among groups (that is, CYP2D6*10 and *17 highest in NMs and CMs, respectively). However, the influence of environmental factors or alleles different than those studied here cannot be ruled out.

Schizophrenia stigma among medical and nursing undergraduates

Negative attitudes toward schizophrenia are associated with difficulty of integration of those suffering from this mental illness into the community. The program “Open the doors” (World Psychiatric Association, http//www.openthedoors.com) has detected in Spain that stigma was experienced by those who have contact with the illness (patients, family and professionals), while the general population showed little rejection. Other studies have found in the UK that the general population commonly perceived people with schizophrenia as dangerous [1], while in Canada [2], it was those of the general population with a greater knowledge of schizophrenia who tended to have lessdistancing attitudes. To our knowledge, there are no data about schizophrenia stigma in health care undergraduates. Therefore, the present study was aimed at exploring the knowledge and perceptions toward schizophrenia in this population with a potential influence on schizophrenia stigma. A total of 274 students of medicine and 70 students of nursing (18–24 years old) from the University of Extremadura (Spain) were surveyed during 2000 about their general knowledge of schizophrenia. They reported to have high awareness of the mental illness, its onset, associated risk factors, manifestations and treatment, with no significant differences between the both groups, medical and nursing undergraduates. However, they thought that people with schizophrenia never recover (50%), considered that they were or could be dangerous or violent (78%), and rejected or were ambivalent about whether to accept them in a social situation (40%). In addition, they did not feel they had enough information about schizophrenia (95%) and they did not know someone with this disorder (75%). The present findings suggest that medical and nursing undergraduates have ambivalent or discriminatory attitudes toward the recovery, level of violence or dangerousness, and social management of people with schizophrenia. Paradoxically, these results contrast with the fact that the students seem to be knowledgeable about the nature of schizophrenia, even so they do not perceive themselves to have enough information. This could be explained by the evidence that knowledge of the symptoms associated with the acute phase of schizophrenia creates more stigma than the label of schizophrenia alone; on the contrary, knowledge about the aftercare settings may reduce it [3]. A second explanation for the present findings might lie in the absence of social contact with people suffering the disorder. In this sense, it has been reported that those people with previous contact with individuals with a mental illness were more likely to perceive them as less dangerous than people without previous contact [4].

High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders

High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders