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Oliver D Howes

Publications and source records attributed to Oliver D Howes.

10 recordsLinked to original sources
PubMed2022

Polygenic heterogeneity in antidepressant treatment and placebo response.

The genetic architecture of antidepressant response is poorly understood. Polygenic risk scores (PRS), exploration of placebo response and the use of sub-scales might provide insights. Here, we investigate the association between PRSs for relevant complex traits and response to vortioxetine treatment and placebo using clinical scales, including sub-scales and self-reported assessments. We collected a clinical test sample of Major Depressive Disorder (MDD) patients treated with vortioxetine (N = 907) or placebo (N = 455) from seven randomized, double-blind, clinical trials. In parallel, we obtained data from an observational web-based study of vortioxetine-treated patients (N = 642) with self-reported response. PRSs for antidepressant response, psychiatric disorders, and symptom traits were derived using summary statistics from well-powered genome-wide association studies (GWAS). Association tests were performed between the PRSs and treatment response in each of the two test samples and empirical p-values were evaluated. In the clinical test sample, no PRSs were significantly associated with response to vortioxetine treatment or placebo following Bonferroni correction. However, clinically assessed treatment response PRS was nominally associated with vortioxetine treatment and placebo response given by several secondary outcome scales (improvement on HAM-A, HAM-A Psychic Anxiety sub-scale, CPFQ & PDQ), (P ≤ 0.026). Further, higher subjective well-being PRS (P ≤ 0.033) and lower depression PRS (P = 0.01) were nominally associated with higher placebo response. In the self-reported test sample, higher schizophrenia PRS was significantly associated with poorer self-reported response (P = 0.0001). The identified PRSs explain a low proportion of the variance (1.2-5.3%) in placebo and treatment response. Although the results were limited, we believe that PRS associations bear unredeemed potential as a predictor for treatment response, as more well-powered and phenotypically similar GWAS bases become available.

Humans↗
PubMed2006

The relationship between prolactin levels and glucose homeostasis in antipsychotic-treated schizophrenic patients.

OBJECTIVES: To determine if prolactin levels are associated with glucose-insulin homeostasis in antipsychotic-treated patients with schizophrenia. METHOD: Prolactin levels and glucose homeostasis (quantified using oral glucose tolerance testing, insulin measurement, and homeostasis model assessment) were measured in 15 patients with elevated prolactin levels secondary to antipsychotic treatment of schizophrenia (mean age, 30.4 years; SD, 5.3 years). The effect of reducing prolactin levels by switching patients' antipsychotic treatment to clozapine was ascertained by performing the measures before and after the switch to clozapine. RESULTS: There was no significant correlation between prolactin and glucose-insulin measures at baseline. There was a large reduction in prolactin (593 mIU/L) after switching to clozapine, but this was not associated with changes in glucose-insulin measures. CONCLUSIONS: Prolactin is not a significant determinant of glucose-insulin homeostasis in patients taking antipsychotics for schizophrenia. There was no benefit from lowering prolactin levels using clozapine. This could be because prolactin does not have a major effect on glucose homeostasis or that the effects of prolactin reduction are countered by clozapine.

Adult↗
PubMed2005

Bone mineral density and its relationship to prolactin levels in patients taking antipsychotic treatment.

Antipsychotic treatment is frequently associated with elevated prolactin levels. Raised prolactin levels have been linked with osteoporosis. The objective of this study is to determine whether patients taking antipsychotics show reduced bone mineral density (BMD), and whether this is associated with prolactin levels. BMD (standardized as z scores) was compared using dual x-ray absorptiometry of the lumbar spine and hip in patients taking antipsychotics (n = 102, mean age: 46.0, SD: 13.1, 47% male, median treatment duration: 3.0 years) to matched reference controls. Levels of prolactin, markers of bone metabolism, and risk factors for osteoporosis were measured. Mean BMD was not significantly reduced, other than the total spine score for black males (mean z score: -0.88, P = 0.00001). BMD was correlated with body mass index but there was no correlation with prolactin. BMD was not correlated with prolactin levels and showed no clinically significant reduction. The low BMD in black males warrants further investigation.

Adult↗
PubMed2004

Pathways to schizophrenia: the impact of environmental factors.

Schizophrenia is an aetiologically complex disorder arising from the interaction of a range of factors acting at various stages of life. Schizophrenic individuals inherit genes that cause structural brain deviations which may be compounded by early environmental insults. As a result some pre-schizophrenic children exhibit subtle developmental delays, cognitive problems, or poor interpersonal relationships. They are susceptible to dysregulation of dopamine, the final pathway leading to the onset of a psychotic illness. Dopamine dysregulation may arise through a process of sensitization, which, in animals, can be caused by repeated administration of dopamine-releasing drugs. It is clear that the same process occurs in humans, and that some individuals are particularly sensitive to the effects of such drugs for either genetic reasons or through early environmental damage. Stress has also been shown to induce dopamine release in animal studies, and epidemiological studies have demonstrated that social stresses can precipitate schizophrenia. Thus, stresses, such as drug use and social adversity, in adolescence or early adult life may propel the neurodevelopmentally impaired individual over a threshold into frank psychosis.

Adult↗
PubMed2004

A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance.

OBJECTIVE: This prospective study examines the effect of clozapine on glucose control and insulin sensitivity. METHOD: Glucose homeostasis was measured in nine female and 11 male patients with schizophrenia (mean age=30.5 years, SD=7.4) before clozapine treatment and after a mean of 2.5 months (SD=0.95) of clozapine treatment. Oral glucose tolerance and insulin levels were measured. Insulin resistance level was measured by the homeostasis model assessment. RESULTS: Eleven (55%) of the patients developed abnormal glucose control; the mean age of these patients was 30.2 (SD=7.1), and five were women. Patients' insulin resistance at baseline (mean insulin resistance level=3.88, SD=2.93) was unaffected by clozapine. Mean fasting and 2-hour glucose levels significantly increased by 0.55 mmol/liter and 1.4 mmol/liter, respectively. There was no correlation between change in body mass index and change in fasting glucose levels. CONCLUSIONS: Clozapine impairs glucose control within 4 months of treatment, independent of changes in insulin sensitivity and body mass index.

Adult↗
PubMed2004

The effect of clozapine on factors controlling glucose homeostasis.

BACKGROUND: This prospective study examines the effect of clozapine on factors determining glucose homeostasis. METHOD: The sample consisted of all patients meeting DSM-IV criteria for schizophrenia who commenced clozapine treatment within the South London and Maudsley hospitals during 1 year (2000-2001). Growth hormone (GH), insulin-like growth factor-1 (IGF-1), and IGF binding protein-1 (IGFBP-1) were measured in 19 patients (10 female; mean age = 31.1 years [SD = 5.8]; 9 black British/African, 10 white British) before and after a mean of 2.5 (SD = 0.9) months of clozapine treatment. RESULTS: Baseline IGFBP-1 was low. IGFBP-1, GH, and IGF-1 were not significantly changed by clozapine treatment. CONCLUSIONS: Clozapine does not alter GH, IGF-1, or IGFBP-1 within 3 months of commencing treatment, indicating that alteration in glucose tolerance associated with clozapine treatment involves other mechanisms yet to be elucidated. Baseline abnormalities in IGFBP-1 indicate a preexisting susceptibility to glucoregulatory dysfunction.

Adult↗