Metabolic polygenic risk scores effect on antipsychotic-induced metabolic dysregulation: A longitudinal study in a first episode psychosis cohort.

OBJECTIVE: Metabolic syndrome is a health-threatening condition suffered by approximately one third of schizophrenia patients and largely attributed to antipsychotic medication. Previous evidence reports a common genetic background of psychotic and metabolic disorders. In this study, we aimed to assess the role of polygenic risk scores (PRSs) on the progression of the metabolic profile in a first-episode psychosis (FEP) cohort. METHOD: Of the 231 FEP individuals included in the study, 192-220 participants were included in basal analysis and 118-179 in longitudinal 6-month models. Eleven psychopathologic and metabolic PRSs were constructed. Basal and longitudinal PRSs association with metabolic measurements was assessed by statistical analyses. RESULTS: No major association of psychopathological PRSs with the metabolic progression was found. However, high risk individuals for depression and cholesterol-related PRSs reported a higher increase of cholesterol levels during the follow-up (FDR ≤ 0.023 for all analyses). Their effect was comparable to other well-established pharmacological and environmental risk factors (explaining at least 1.2% of total variance). CONCLUSION: Our findings provide new evidence of the effects of metabolic genetic risk on the development of metabolic dysregulation. The future establishment of genetic profiling tools in clinical procedures could enable practitioners to better personalize antipsychotic treatment selection and dosage.

Strengths and weaknesses of pharmacogenetic studies of antipsychotic drugs: the potential value of the PEPs study.

The successful application of pharmacogenetics in routine clinical practice is still a long way from becoming a reality. In order to favor the transfer of pharmacogenetic results to clinical practice, especially in psychiatry, these studies must be optimized. This article reviews the strengths and weaknesses that characterize pharmacogenetic studies in psychiatry and condition their implementation in clinical practice. We also include recommendations for improving the design of pharmacogenetic studies, which may convert their limitations into strengths and facilitate the implementation of their results into clinical practice. Finally, we discuss the potential value of naturalistic, prospective, multicenter and coordinated projects such as the 'Phenotype-genotype and environmental interaction. Application of a predictive model in first psychotic episodes' (known as the PEPs study, from the Spanish abbreviation) in pharmacogenetic studies.

Psychobiology of borderline personality traits related to subtypes of eating disorders: a study of platelet MAO activity.

Increased and decreased levers of platelet monoamine oxidase (MAO) activity have been reported in patients with eating disorders, indicating abnormalities of the serotonin turnover. However, whether these findings are related to eating disorders or are rather reflecting the pathophysiology of borderline personality traits in these patients is still unknown. Platelet MAO activity and comorbid personality disorders were investigated in 72 patients with different subtypes of eating disorders (ED) and in a group of 28 healthy controls. ED patients comprised the following subtypes: 25 anorexia nervosa (AN) restrictive, 14 AN binge eating-purging (AN b-p), 3 anorexia nervosa not otherwise specified (AN NOS) and 30 bulimia nervosa (BN). Personality disorders and traits were assessed with the Structured Interview for Personality Disorders (SCID-II), the Zanarini Rating Scale for Borderline Personality Disorder, and the Barrat Impulsiveness Scale. Platelet MAO activity was significantly lower in ED patients with comorbid borderline personality disorder (BPD) than in ED without Borderline personality disorder (BDP). Platelet MAO activity was significantly and inversely correlated with the number and severity of BPD clinical features. In the subsample of patients with binge eating-purging symptoms (AN b-p, AN NOS and BN), platelet MAO activity was significantly lower in binge-purge patients with comorbid BPD than in binge-purge patients without BPD. The whole group of eating disorders had a significantly reduced lever of platelet MAO activity compared with the control group. The results suggest that low platelet MAO activity might characterize eating disorders with comorbid borderline personality traits, reflecting greater serotonin dysfunction in these patients. The role of decreased platelet MAO as an endophenotype with specific clinical manifestations should be explored in future studies.

Enhanced cortisol suppression in eating disorders with impulsive personality features.

Evidence of both blunted and enhanced cortisol suppression with the dexamethasone test (DST) is available in eating disorders (ED), suggesting that different subtypes of ED might be characterized by distinct neurobiological stress response dysfunctions. Other evidence indicates that ED patients with impulsive clinical features might have enhanced cortisol suppression similar to patients with impulsive personality disorders. A group of 52 patients with restrictive anorexia, binge eating-purging anorexia and bulimia nervosa were studied with a very low dose (0.25 mg) dexamethasone test and measures of phenomenology, personality and impulsivity. Patients with bulimic symptoms had significantly higher rates of cortisol suppression than controls and than restrictive anorectic patients. Percent cortisol suppression showed a strong and significant correlation with the patient's score on the Barratt Impulsiveness Scale. A hypersensitive cortisol response to dexamethasone, which might reflect hypothalamic-pituitary-adrenal axis dysfunctions might be specifically associated with impulsive subtypes of eating disorders.

Diagnostic Interview for Genetic Studies (DIGS): inter-rater and test-retest reliability and validity in a Spanish population.

OBJECTIVE: To test the reliability and validity of the DIGS in Spanish population. METHODS: Inter-rater and test-retest reliability of the Spanish version of DIGS was tested in 95 inpatients and outpatients. The resultant diagnoses were compared with diagnoses obtained by the LEAD (Longitudinal Expert All Data) procedure as "gold standard". The kappa statistic was used to measure concordance between blind inter-raters and between the diagnoses obtained by LEAD procedure and through the DIGS. RESULTS: Overall kappa coefficient for inter-rater reliability was 0.956. The kappa value for individual diagnosis varied from major depression=0.877 to schizophrenia=1. Test-retest reliability was 0.926. Kappa for all individual target diagnoses ranged from 0.776 (major depression) to 1. Kappa between LEAD procedure and DIGS ranged from 0.704 (major depression) to 0.825 (bipolar I disorder). CONCLUSION: Most of the DSM-IV major psychiatric disorders can be assessed with acceptable to excellent reliability with the Spanish version of the DIGS interview. The Spanish version of DIGS showed an acceptable to excellent concurrent validity. Giving the good reliability and validity of Spanish version of DIGS it should be considered to identify psychiatric phenotypes for genetics studies.

Partial response and nonresponse to antidepressant therapy: current approaches and treatment options.

BACKGROUND: Response to antidepressant drug therapy is less than optimal for a considerable proportion of depressed patients; at present, however, few data exist to guide their rational therapeutic management. This review describes general principles for the management of such patients. This review is the result of an expert roundtable meeting convened to review published clinical data and clinical experience and provide clinicians with evidence-based principles on the management of patients who fail to respond optimally to initial antidepressant therapy. ROUNDTABLE FINDINGS: Failure to respond may be defined as a < 25% decrease on an accepted symptom rating scale such as the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D) in a patient who has received an adequate dosage for 4 weeks. In these patients, a neuropharmacologic rationale exists to switch to an agent with a different mode of action or a dual action. Partial response may be defined as 6 to 8 weeks at an adequate dosage and 25% to 50% decrease in MADRS or HAM-D score. In these patients, dose escalation should be considered, followed by augmentation and switching strategies. For augmentation, knowledge of neuropharmacology may allow prediction of which second agent will potentiate or complement the action of the first agent; it may also permit the prediction of potential safety concerns. CONCLUSIONS OF THE PANEL: On the basis of a review of the medical literature and clinical experience regarding patients with partial response or nonresponse to antidepressant drug therapy, it appears that simultaneous targeting of both the noradrenergic and serotonergic systems is one of the most effective augmentation strategies. Switching to an agent of a different class is probably optimal for those patients who fail to respond to first-line therapy.