Predictors of Readmission in Young Adults with First-Episode Psychosis: A Multicentric Retrospective Study with a 12-Month Follow-Up.

BACKGROUND: A significant number of young individuals are readmitted one or more times shortly after their first episode of psychosis. Readmission may represent a marker of psychopathological vulnerability. Our primary aim was to evaluate the impact of clinical and socio-demographic variables on readmission at 12-month follow-up. Secondly, our goal was to determine whether the use of Long-Acting Injection (LAI) antipsychotics provides notable benefits compared to oral medications in preventing subsequent readmissions. SUBJECTS AND METHODS: 80 patients hospitalised for the first time with a diagnosis of psychotic disorder (ICD-10 criteria) were retrospectively assessed through clinical records. The mean age was 21.7 years. Patients were predominantly male (n = 62, 77.5%), and 55 subjects had at least 8 years of education. 50% of the sample was "NEET" (not in education, employment, or training). RESULTS: 35 patients (43.8%) were discharged with a LAI antipsychotic, while 45 (56.2%) recieved oral antipsychotic therapy. Substance use (p = 0.04) and oral antipsychotics at discharge (p = 0.003) were significantly associated with readmission at 1 year. We did not find any significant predictors of being discharged with LAI therapy. CONCLUSION: Our findings underlined the importance of identifying patients at risk of readmission in order to prevent future rehospitalization and promote appropriate prevention strategies. LAIs should be considered as a first-choice treatment for patients hospitalised for FEP since they proved to be effective in preventing relapse.

Facts and myths about use of esketamine for treatment-resistant depression: a narrative clinical review.

Introduction and aims: Treatment-resistant depression (TRD) occurs when at least two different antidepressants, taken at the right dosage, for adequate period of time and with continuity, fail to give positive clinical effects. Esketamine, the S-enantiomer of ketamine, was recently approved for TRD treatment from U.S. Food and Drug Administration and European Medicine Agency. Despite proved clinical efficacy, many misconceptions by clinicians and patients accompany this medication. We aimed to review the most common "false myths" regarding TRD and esketemine, counterarguing with evidence-based facts. Methods: The keywords "esketamine", "treatment resistance depression", "depression", "myth", "mythology", "pharmacological treatment", and "misunderstanding" were entered in the main databases and combined through Boolean operators. Results: Misconceptions regarding the TRD prevalence, clinical features and predictors have been found. With respect of esketamine, criteria to start treatment, dissociative symptoms, potential addiction and aspects of administration and monitoring, were found to be affected by false beliefs by clinicians and patients. Discussion and conclusion: TRD represents a challenging condition, requiring precise diagnosis in order to achieve patient's full recovery. Esketamine has been proved as an effective medication to treat TRD, although it requires precautions. Evidence can inform clinical practice, in order to offer this innovative treatment to all patients with TRD.

Cariprazine Augmentation in Treatment-Resistant Bipolar Depression: Data from a Retrospective Observational Study.

BACKGROUND: Treatment-resistant bipolar depression is one of the leading problems in psychiatry with serious consequences on patients functioning, quality of life and resource utilization. Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms. OBJECTIVE: The objective of the present study is to assess the acute effectiveness and tolerability of cariprazine in the management of treatment resistant bipolar depression. METHODS: This is a four weeks retrospective multicentric observational study on patients with treatment resistant bipolar depression receiving cariprazine in augmentation to the current treatment. Cariprazine dosage changed during the follow-up period according to clinical judgment. Since data followed a non-normal distribution, non-parametric tests were used to pursue the analysis. The effectiveness of cariprazine was assessed through the mean change in Hamilton Depression rating scale (HAM-D) scores from baseline to endpoint. For missing values, a "Last Observation Carried Forward" approach was applied. RESULTS: Fifty-one patients were enrolled. Four patients (7.8%) discontinued cariprazine mainly due to adverse events. Mean cariprazine dose was 1.7 mg/day. The mean HAM-D score decreased significantly from baseline (T0) to week 4 (T4) at each evaluation point. Fourty-five one percent of the patients benefited of cariprazine add-on strategy: 23.5% achieved a clinical response and 21.6% were remitters. Among the completers, 70.6% experienced at least one adverse event. All side effects were mild to moderate. CONCLUSION: Cariprazine seems to be an effective and well tolerated option in the management of patients with treatment resistant bipolar depression.

Cariprazine augmentation in patients with treatment resistant unipolar depression who failed to respond to previous atypical antipsychotic add-on. A case-series.

Among individuals receiving an adequate pharmacological treatment for Major Depressive Disorder (MDD), only 30% reach a full symptom recovery; the remaining 70% will experience either a pharmacological response without remission or no response at all thus configuring treatment resistant depression (TRD). After an inadequate response to an antidepressant, possible next step options include optimizing the dose of the current antidepressant, switching to a different antidepressant, combining antidepressants, or augmenting with a non-antidepressant medication. Augmentation strategies with the most evidence-based support include atypical antipsychotics (AAs). Few data are available in literature about switching to another antipsychotic when a first augmentation trial has failed. We present a case-series of patients with unipolar treatment resistant depression who were treated with a combination of antidepressant and low dose of cariprazine after failing to respond to a first augmentation with another AA. We report data about ten patients affected by unipolar depression, visited at the outpatients unit of Mental Health Department of ASL CN2 of Bra and NA1 of Napoli (Italy). All patients failed to respond to conventional antidepressant therapy. A low dose of AA (aripiprazole, risperidone or brexpiprazole) was added for one month to the ongoing antidepressant treatment without clinical improvement. A second augmentation trial was then made with cariprazine. Seven out of ten patients were responders at the end of period, of them 1 patient reached responder status by week 2. HAM-D mean scores decreased from 23.9 ± 3.9 (baseline) to 14.8 ± 5.3 (4 weeks). Cariprazine was well tolerated, no severe side effect was observed during the trial. Our sample of treatment resistant unipolar patients showed good response to augmentation with cariprazine. Failure to a first AA-augmentation trial does not preclude response to a second one. This preliminary result requires confirmation through more rigorous studies conducted over greater samples.

A Systematic Review on the Effectiveness of Antipsychotic Drugs on the Quality of Life of Patients with Schizophrenia.

Pharmacological antipsychotic drug interventions represent the cornerstone of the management of patients with schizophrenia and other psychotic spectrum disorders. The choice of the "best" treatment should be made on the basis of several clinical domains. However, despite available treatments, the quality of life reported by patients with schizophrenia taking antipsychotics is still very poor, and this outcome is rarely taken into account in trials assessing the efficacy and effectiveness of antipsychotic treatments. Therefore, we performed a systematic review in order to assess the impact of antipsychotic treatment on patients' quality of life. In particular, we aimed to identify any differences in the improvement in quality of life according to the (a) type of formulation of antipsychotic drugs (i.e., oral vs. depot vs. long-acting injectable); (b) type of the drug (first vs. second vs. third generation); and (c) patients' clinical characteristics. One hundred and eleven papers were included in the review. The main findings were as follows: (1) quality of life is usually considered a secondary outcome in trials on the efficacy and effectiveness of drugs; (2) second-generation antipsychotics have a more positive effect on quality of life; and (3) long-acting injectable antipsychotics are associated with a more stable improvement in quality of life and with a good safety and tolerability profile. Our systematic review confirms that quality of life represents a central element for selecting the appropriate treatment for people with schizophrenia. In particular, the availability of new treatments with a better tolerability profile, a proven effectiveness on patients' cognitive and social functioning, and with a more stable blood concentration might represent the appropriate strategy for improving the quality of life of people with schizophrenia.

Predicting outcome with Intranasal Esketamine treatment: A machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING).

Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients' probability of response to ESK-NS is needed. This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD.

Investigating the Effectiveness and Tolerability of Intranasal Esketamine Among Older Adults With Treatment-Resistant Depression (TRD): A Post-hoc Analysis from the REAL-ESK Study Group.

INTRODUCTION: Treatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear. OBJECTIVES: To evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD. METHODS: This is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2). RESULTS: The sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: pholm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: pholm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment. CONCLUSIONS: Our findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension.

Metacognition in schizophrenia: A practical overview of psychometric metacognition assessment tools for researchers and clinicians.

Metacognition refers to the cognitive ability to control, monitor and modulate cognitive processes thus guiding and orienting behavior: a continuum of mental activities that ranges from more discrete ones, such as the awareness of the accuracy of others' judgment, to more integrated activities, such as the knowledge of cognitive processes. Metacognition impairment in schizophrenia, which is considered a core feature of the illness, has become a growing research field focusing on a wide range of processes including reasoning, autobiographical memory, memory biases, cognitive beliefs and clinical insight. There is a well-established relationship between metacognition and schizophrenia symptoms severity, as well as between impaired metacognitive functioning and specific symptomatic sub-domains, such as positive symptoms, negative symptoms, or disorganization. The development of specific cognitive-derived psychotherapies for metacognitive deficits in schizophrenia has been ongoing in the last years. Although sharing a metacognitive feature, these treatments focus on different aspects: false or unhelpful beliefs for metacognitive therapy; cognitive biases for metacognitive training; schematic dysfunctional beliefs for cognitive behavioral therapy (CBT) for psychoses; metacognitive knowledge and sense of identity for MERIT; interpersonal ideas or events triggering delusional thinking for MIT-P. This article reviews the instruments designed to assess metacognitive domains and functions in individuals with schizophrenia, providing mental health professionals with an overview of the heterogeneous current scenario ranging from self-administered scales to semi-structured interviews, which are supported by a variety of theoretical frameworks. Future directions may address the need for more specific and refined tools, also able to follow-up psychotherapeutic-induced improvements.

Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study).

Background: Treatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings. Objectives: Evaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services. Methods: REAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups. Results: A significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities. Limitations: The open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale. Conclusions: Our findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings.

The effect of paliperidone palmitate long-acting injectable (PP-LAI) on "non-core" symptoms of schizophrenia: a retrospective, collaborative, multicenter study in the "real world" everyday clinical practice.

BACKGROUND: Schizophrenia is frequently complicated by the occurrence of depressive symptoms, anhedonia, obsessions and compulsions, suicidal ideation, and substance abuse, that causes exacerbations and remissions and, in several cases, sustained morbidity and disability. AIM: The present study aimed to evaluate the effect of paliperidone palmitate once-monthly long-acting injection (PP-LAI) mainly on "non-core" symptoms in persons with recent diagnosis schizophrenia, during a follow-up period of almost 12 months (T1) in the context of the "real world" everyday clinical practice. RESULTS: Concerning core symptoms of schizophrenia, PP-LAI was effective in reducing all symptoms at T1 as measured by Positive and Negative Syndrome Scale (PANSS), including depressive symptoms, and increased the functioning. Moreover, concerning the non-core symptoms of schizophrenia, PP-LAI treatment was effective in reducing scores of anhedonia, suicidal ideation and obsessive-compulsive symptoms at T1. However, the levels of alexithymia remained relatively stable, even if reduced. DISCUSSION: The present retrospective, multicenter, non-sponsored, collaborative study showed that early PP-LAI treatment was effective in improving almost all the core dimensions and "non-core" symptoms of schizophrenia, and this may have positive repercussions on both functioning and quality of life. CONCLUSIONS: PP-LAI treatment should be offered earlier as possible and was effective on "non-core" symptoms of schizophrenia at follow-up, but had a little effect on alexithymia. However, study' limitations must be considered and future researches are needed to confirm these interesting findings.

Flattened cortisol awakening response in chronic patients with schizophrenia onset after cannabis exposure.

Cannabis may play a causal role in the onset of some schizophrenia cases; however, the biological vulnerability that predisposes some individuals to develop schizophrenia after exposure to cannabis is not known. According to the diathesis-stress pathogenetic model, it is likely that the endogenous stress response system, including the hypothalamus-pituitary-adrenal (HPA) axis, could be involved. Therefore, we investigated the saliva cortisol awakening response (CAR) of 16 patients with schizophrenia onset after the exposure to cannabis (Can+) as compared to 12 patients with schizophrenia onset without cannabis exposure (Can-) and to 15 healthy controls. The CAR was assessed by collecting saliva samples at awakening and after 15, 30 and 60 min. As compared to healthy controls, Can+ schizophrenia patients exhibited significantly enhanced baseline saliva cortisol levels and a flattened CAR. No significant abnormality in both baseline cortisol levels and CAR was detected in Can- schizophrenia patients. These findings demonstrate a dysregulation of the HPA axis in chronic schizophrenic patients whose illness started after cannabis exposure but not in those with an illness onset without cannabis exposure. Further studies need to clarify whether this HPA dysregulation is a part of the biological background underlying the increased risk to schizophrenia after exposure to cannabis.

Circadian rhythms and treatment implications in depression.

In humans almost all physiological and behavioural functions occur on a rhythmic basis. Therefore the possibility that delays, advances or desynchronizations of circadian rhythms may play a role in the pathophysiology of psychiatric disorders is an interesting field of research. In particular mood disorders such as seasonal affective disorder and major depression have been linked to circadian rhythms alterations. Furthermore, the antidepressant efficacy of both pharmacological and non-pharmacological strategies affecting endogenous circadian rhythms, such as new antidepressant medications, light-therapy and sleep deprivation, is consistent with the idea that circadian alterations may represent a core component of depression, at least in a subgroup of depressed patients. This paper briefly describes the molecular and genetic mechanisms regulating the endogenous clock system, and reviews the literature supporting the relationships between depression, antidepressant treatments and changes in circadian rhythms.

Management of schizophrenia with obesity, metabolic, and endocrinological disorders.

People with schizophrenia have an increased prevalence of overweight/obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome, which increases the risk for cardiovascular diseases and mortality. Part of this increased risk is attributable to the use of antipsychotic medications, especially second-generation antipsychotics. Antipsychotic drugs differ in their potential to induce weight gain, with clozapine and olanzapine exhibiting the highest weight gain liability; evidence for differing effects of antipsychotics on glucose and lipid metabolism is less convincing. Individuals with schizophrenia may develop hyperprolactinemia, with or without clinical symptoms, after starting antipsychotic medications. This effect is particularly frequent with first-generation antipsychotics and with the second-generation antipsychotic risperidone and paliperidone. Psychiatrists should be aware of metabolic and endocrine side effects of antipsychotics and should make every effort to prevent or minimize them to improve the patients' compliance and quality of life.

Plasma obestatin, ghrelin, and ghrelin/obestatin ratio are increased in underweight patients with anorexia nervosa but not in symptomatic patients with bulimia nervosa.

INTRODUCTION: Peptides of the gut-brain axis have a pivotal role in the regulation of energy homeostasis. Obestatin, a sibling of ghrelin derived from preproghrelin, is thought to oppose ghrelin effects on food intake. Because changes in ghrelin levels have been associated with anorexia nervosa (AN) and bulimia nervosa (BN), the investigation of obestatin production may further contribute to understanding the role of peripheral peptides in patients with eating disorders. METHODS: In the present study, we measured circulating blood levels of obestatin and ghrelin and assessed their relationships with anthropometric and clinical measures in 20 AN patients, 21 BN patients, and 20 appropriate healthy controls. RESULTS: Compared with healthy women, patients with BN showed no significant differences in plasma obestatin and ghrelin concentrations and in the ghrelin/obestatin ratio, whereas underweight AN patients displayed significantly increased circulating levels of both obestatin (P<0.009) and ghrelin (P<0.002) and an increased ghrelin/obestatin ratio (P<0.04). Moreover, in AN women, positive correlations emerged between the ghrelin/obestatin ratio and current body weight and body mass index. CONCLUSIONS: Underweight AN patients are characterized by increased concentrations of ghrelin and obestatin and a higher ghrelin to obestatin ratio. No changes in circulating ghrelin or obestatin as well as in ghrelin to obestatin ratio seem to occur in acutely ill patients with BN. Although those changes likely reflect the physiological state of symptomatic AN individuals, they may also contribute to the pathophysiology of the disorder.

Deranged secretion of ghrelin and obestatin in the cephalic phase of vagal stimulation in women with anorexia nervosa.

BACKGROUND: Vagal activation in the cephalic phase response to food ingestion promotes ghrelin secretion. Because underweight individuals with anorexia nervosa (AN) are characterized by increased vagal tone, we hypothesized an enhanced ghrelin production in the cephalic phase of vagal stimulation. Therefore, we investigated the responses of ghrelin and its recently discovered sibling peptide obestatin to modified sham feeding (MSF) in both AN and healthy women. METHODS: Eight AN women and eight age-matched healthy female subjects underwent MSF, with initially seeing and smelling a meal and then chewing the food without swallowing it. Blood samples were drawn before and after MSF for hormone assays. RESULTS: Circulating ghrelin increased, whereas obestatin decreased after MSF. Compared with healthy women, AN individuals exhibited enhanced ghrelin and obestatin baseline plasma levels and amplified MSF-induced ghrelin increase and obestatin drop. Ghrelin secretion positively correlated with subjects' eating behavior as assessed by the Three-Factor Eating Questionnaire. CONCLUSIONS: Opposite changes in circulating ghrelin and obestatin occur in the cephalic phase of vagal stimulation, and these changes are amplified in symptomatic AN patients. Given the opposite effects of ghrelin and obestatin on food intake, these findings may have pathophysiologic implications for the dysregulated eating behavior of AN individuals.

The cDNA 385C to A missense polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) is associated with overweight/obesity but not with binge eating disorder in overweight/obese women.

Endocannabinoids are involved in the modulation of eating behavior; hence, alterations of this system may play a role in obesity. Recently, a single nucleotide polymorphism (cDNA 385C to A) of the gene coding for fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, has been found to be associated with obesity. However, the possibility that the FAAH gene cDNA 385C to A single nucleotide polymorphism (SNP) is associated to binge eating disorder (BED), a condition that frequently occurs in obese individuals, has not been investigated. In order to address this issue, we assessed the distribution of the cDNA 385C to A SNP in 115 overweight/obese subjects with BED, 74 non-BED patients with obesity and 110 normal weight healthy controls. As compared to healthy controls, the whole group of overweight/obese BED and non-BED patients had a significantly higher frequency of the CA genotype and the A allele of the FAAH gene cDNA 385C to A SNP. Moreover, the SNP resulted significantly correlated to the presence of overweight/obesity (F(2, 296)=3.58, P=0.02), but not to the occurrence of BED (F(2, 296)=0.98; P=0.3). The present study confirms previously published significant over-representations of the FAAH 385 A allele in overweight/obese subjects and presents new data in BED patients that the 385 mutation is not significantly associated with BED-related obesity.

Association between A218C polymorphism of the tryptophan-hydroxylase-1 gene, harm avoidance and binge eating behavior in bulimia nervosa.

Genes involved in serotonin transmission are likely involved in the biological predisposition to bulimia nervosa. We investigated whether the A218C polymorphism of the tryptophan-hydroxylase-1 gene was associated to bulimia nervosa and/or to some phenotypic aspects of the disorder. One hundred eighty Caucasian women (91 patients with bulimia nervosa and 89 healthy controls) were enrolled into the study. They underwent a blood sample collection for A218C polymorphism of the tryptophan-hydroxylase-1 genotyping and a clinical evaluation assessing comorbidity for Axis I and II psychiatric disorders, harm avoidance personality dimension and bulimic symptoms. The distribution of both tryptophan-hydroxylase-1 A218C genotypes and alleles did not significantly differ between patients and controls. Bulimic women with the AA genotype exhibited a more severe binge eating behavior and higher harm avoidance scores than those with CC genotype. These findings support the idea that tryptophan-hydroxylase-1 A218C polymorphism does not play a part in the genetic susceptibility to bulimia nervosa, but it seems to be involved in predisposing bulimic patients to a more disturbed eating behavior and higher harm avoidance.

The 3111T/C polymorphism of the CLOCK gene confers a predisposition to a lifetime lower body weight in patients with anorexia nervosa and bulimia nervosa: a preliminary study.

Feeding is subjected to circadian regulation; therefore, changes in the components of the endogenous oscillator regulating circadian rhythms may be involved in disordered rhythmicity of eating behavior as it occurs in anorexia nervosa (AN) and bulimia nervosa (BN). We investigated whether the 3111T/C polymorphism of the CLOCK gene, which is part of the endogenous oscillator system, was associated to AN and/or BN. A total of 241 women, including 90 healthy controls, 60 patients with AN and 91 patients with BN, participated into the study. The frequencies of 3111T/C genotypes and alleles did not significantly differ among the groups. In both the AN and BN group, subjects carrying one copy of the C allele had a lifetime body weight significantly lower than those carrying the T/T genotype. These findings, although preliminary, suggest that the 3111T/C polymorphism of the CLOCK gene does not play a major role in the genetic vulnerability to AN and BN, but it seems to predispose eating disorders (EDs) patients to a more severe lifetime body weight loss.

Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia.

CONTEXT: Cannabinoid CB(1) receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake. OBJECTIVE: The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic beta-cells. DESIGN, SETTING, AND PATIENTS: Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F beta-cells, pancreas and fat from mice with diet-induced obesity, visceral and sc fat from patients with body mass index equal to or greater than 30 kg/m(2), and serum from normoglycemic and type 2 diabetes patients were studied. MAIN OUTCOME MEASURE: Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured. RESULTS: Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F beta-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F beta-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB(1) receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F beta-cells kept in high glucose. CONCLUSIONS: Peripheral endocannabinoid overactivity might explain why CB(1) blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.