Stephen B. Woolley

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidones may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.

The association between self-reported anxiety symptoms and suicidality

This cross-sectional study assessed the association between self-reported anxiety symptoms and self-reported suicidality among a mixed diagnostic sample of psychiatric outpatients. Data were obtained from chart review of 2,778 outpatients who completed a routine diagnostic clinical interview and a standardized self-report of psychiatric symptoms on admission. Bivariate analyses indicated that those with ≥ moderate anxiety symptoms were over three times as likely to report ≥ moderate difficulty with suicidality. Self-reported anxiety symptoms were associated with a 2-fold increased likelihood of reporting suicidality after controlling for confounding (demographics, depressive symptoms, and diagnoses). These data are consistent with a growing literature demonstrating an association between anxiety symptoms and suicidality, and suggest that this association is not accounted for by coexisting mood symptoms or diagnoses. A single item, self-report may be a useful screening tool for symptoms that are pertinent to assessment of suicide risk.

Last-Observation-Carried-Forward Imputation Method in Clinical Efficacy Trials: Review of 352 Antidepressant Studies

Study Objective. To determine the prevalence, over 40 years, of using the last‐observation‐carried‐forward (LOCF) imputation method in clinical trials, the association between use of LOCF and how the trials were conducted, and the extent of information about attrition and LOCF use in published reports.

Headache complaints and the risk of suicidal thoughts or behaviors.

The association between severe headaches and suicidal thoughts or behaviors is generally attributed to underlying depression, but it is plausible that severe headaches can lead to suicidal thoughts/behaviors, independent of the effects of psychiatric conditions. This association has been observed in only 1 previous study. Our multivariate analysis examined the longitudinal association between severe headaches and development of suicidal thoughts/behaviors over a period of 1 to 2 years among 6832 community-dwelling adults interviewed during the Epidemiologic Catchment Area Study. Severe headaches were significantly associated with developing suicidal thoughts/behaviors after adjusting for psychiatric diagnoses and demographics [adjusted odds ratio (ORa) = 1.48; 95% confidence interval (CI) = 1.04, 2.11], or additionally adjusting for interaction between anxiety and depression (ORa = 1.52; 95% CI = 1.07, 2.16). These results suggest that individuals with severe headaches should be screened for suicidal thoughts/behaviors, irrespective of the presence of a psychiatric condition.

Complex Psychotropic Polypharmacy in Bipolar Disorder Across Varying Mood Polarities: a Prospective Cohort Study of 2712 Inpatients

BACKGROUND It is common for patients with bipolar disorder (BP) to receive multiple psychotropics, but few studies have assessed demographic and clinical features associated with risk for receiving complex psychotropic polypharmacy. METHODS This longitudinal cohort study examined 2712 inpatients with a DSM-IV clinical diagnosis of BP to assess associations between complex polypharmacy (defined as ≥4 psychotropics) and demographic and clinical features; associations with risk of rehospitalization were also examined. Logistic regressions were performed with the sample as a whole and with each of four DSM-IV BP subtypes individually. RESULTS Complex polypharmacy was present in 21.0%. BP-I depressed patients were more likely to receive complex regimens than BP-I manic, BP-I mixed or BP-II patients. In the sample as a whole, variables significantly associated with complex polypharmacy included female, white, psychotic features and a co-diagnosis of borderline personality, post-traumatic stress or another anxiety disorder. The only examined medication not significantly associated with complex polypharmacy was lithium, although only in BP-I depressed and BP-I mixed. Complex polypharmacy was associated with rehospitalization in BP-I mania within 15 and 30days post index hospitalization. LIMITATIONS All data were from one clinical facility; results may not generalize to other settings and patient populations. CONCLUSIONS BP-I depression may pose a greater treatment challenge than the other BP subtypes. Lithium may confer an overall advantage compared to other medications in BP-I depressed and BP-I mixed. Further research is needed to guide pharmacotherapy decisions in BP patients.

Validation of candidate genes associated with cardiovascular risk factors in psychiatric patients

The purpose of this study was to identify genetic variants predictive of cardiovascular risk factors in a psychiatric population treated with second generation antipsychotics (SGA). 924 patients undergoing treatment for severe mental illness at four US hospitals were genotyped at 1.2 million single nucleotide polymorphisms. Patients were assessed for fasting serum lipid (low density lipoprotein cholesterol [LDLc], high density lipoprotein cholesterol [HDLc], and triglycerides) and obesity phenotypes (body mass index, BMI). Thirteen candidate genes from previous studies of the same phenotypes in non-psychiatric populations were tested for association. We confirmed 8 of the 13 candidate genes at the 95% confidence level. An increased genetic effect size was observed for triglycerides in the psychiatric population compared to that in the cardiovascular population.