ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression.

The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.

HPA axis genetic variation, cortisol and psychosis in major depression.

Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.

Third ventricle enlargement and developmental delay in first-episode psychosis: preliminary findings.

BACKGROUND: Third rather than lateral ventriculomegaly may be a more specific finding in psychosis. The relevance of ventricular abnormality remains unclear. AIMS: To investigate the developmental correlates of ventricular enlargement. METHOD: Information on childhood development and magnetic resonance images in 1.5-mm contiguous sections were collected on 21 patients experiencing a first episode of psychosis. RESULTS: Patients (n = 21) had significantly less whole brain volume and enlarged third and lateral ventricles compared to controls (n = 25). Third ventricle (r = 0.48, P < 0.03) and lateral ventricle (r = 0.65, P < 0.01) volumes correlated with developmental score. Patients with developmental delay had significantly larger third and lateral ventricles than those without. CONCLUSIONS: Enlargement of both third and lateral ventricles is found in first-episode psychosis and is related to developmental delay in childhood. Insult to periventricular areas is relevant to the neurobiology of the disease. These findings support the view that schizophrenia involves disturbance of neurodevelopmental processes in some patients.

Experience of caregiving: relatives of people experiencing a first episode of psychosis.

BACKGROUND: There has been relatively little research on caregivers of people experiencing their first episode of psychosis. AIMS: To investigate dimensions of caregiving and morbidity in caregivers of people with first-episode psychosis. METHOD: Caregivers of 40 people with first-episode psychosis were interviewed at home about their experience of caregiving, coping strategies and distress. RESULTS: Caregivers used emotional and practical strategies to cope with participants' negative symptoms and difficult behaviours and experienced more worry about these problems. They increased supervision when the participants displayed difficult behaviours. Twelve per cent of caregivers were suffering from psychiatric morbidity as defined by the General Health Questionnaire. Those living with the participant had more frequent visits to their general practitioner. CONCLUSIONS: At first-episode psychosis, caregivers are already having to cope with a wide range of problems and are developing coping strategies. Caregivers worried most about difficult behaviours and negative symptoms in participants.

Features of structural brain abnormality detected in first-episode psychosis.

OBJECTIVE: Structural magnetic resonance imaging (MRI) studies that focus on first-episode psychosis avoid some common confounds, such as chronicity of illness, treatment effects, and long-term substance abuse. However, such studies may select subjects with poor short-term treatment response or outcome. In this study, the authors focus on structural brain abnormalities in never or minimally treated patients who underwent MRI scanning early in their first episode of psychosis. METHOD: The authors examined 37 patients (13 medication naive, 24 previously treated) who were experiencing their first episode of psychosis; the mean duration of symptoms was short (31 weeks). These patients were comparable in age, gender, handedness, ethnicity, and parental socioeconomic status to a group of 25 healthy comparison subjects. A three-dimensional, inversion recovery prepared, fast spoiled gradient/recall in the steady state scan of the whole brain that used 1.5-mm contiguous sections was performed to acquire a T(1)-weighted data set. Human ratings of volumetric measurement of brain structures were performed with stereological techniques on three-dimensional reconstructed MRIs. RESULTS: The patient group had significant deficits in cortical gray matter, temporal lobe gray matter, and whole brain volume as well as significant enlargement of the lateral and third ventricles. Structural deviations were found in both treatment-naive and minimally treated subjects. No relationships were found between any brain matter volumes and positive or negative symptoms. CONCLUSIONS: Structural brain abnormalities were distributed throughout the cortex with particular decrement evident in gray matter. This feature is consistent with altered cell structure and disturbed neuronal connectivity, which accounts for the functional abnormality of psychosis.

Neuropsychological functioning in first-episode psychosis--evidence of specific deficits.

Neuropsychological impairment is ubiquitous in schizophrenia even at the first presentation of psychotic symptoms. We sought to elucidate the nature of the neuropsychological profile at the onset of the illness by examining the neuropsychological functioning of 40 patients experiencing their first episode of psychosis and 22 matched controls. All participants completed a battery of neuropsychological tasks designed to assess attention, verbal learning/memory, non-verbal memory, spatial ability, psychomotor speed, and executive function. First-episode patients showed significant impairment on tasks of executive function, including those requiring the ability to form and initiate a strategy, to inhibit prepotent responses, and to shift cognitive set, and also on tasks of verbal fluency. Memory impairments were seen on verbal learning and delayed non-verbal memory only. Impairment on tasks of psychomotor speed suggests that there may be a significant amount of cognitive slowing even at the first onset of psychosis. We suggest that our patients may be experiencing difficulty in specific aspects of executive functions, including the ability to form and execute a strategy, and these difficulties may be mediating the deficits observed on tasks of verbal learning.