Mitchell P

Gender differences in response to differing antidepressant drug classes: two negative studies.

BACKGROUND A recent US study presented data suggesting that depressed women are more likely to respond to selective serotonin reuptake inhibitor (SSRI) than tricyclic (TCA) antidepressant drug therapies. We have undertaken replication studies in two independent databases. METHOD We have examined for gender differences in SSRI and TCA antidepressant response in both retrospective and prospective naturalistic uncontrolled studies, and in subsets of melancholic and non-melancholic depressed subjects. As the US study had indicated that women under the age of 40 years were particularly likely to show a differential response to SSRIs, we examined for age, gender and interactional effects. In addition, we examined for differential SSRI and TCA responsiveness in a subset of patients who had received drugs from both classes. RESULTS We failed to find evidence of women having a preferential response to SSRI medication or, conversely, of men having a superior response to TCA medication. Older age, however, was associated with a superior TCA response and younger age with a superior SSRI response. CONCLUSION As few studies have examined for differential gender and age effects in response to narrow action and broad action antidepressant drugs across major depressive subtypes, gender differential effects remain to be established.

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26

We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n = 385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P = 0.0043; rs2168351, P = 0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls = 0.41 vs 0.31; χ2 = 6.46, P = 0.011, OR = 1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n = 256) (χ2 = 8.41, P = 0.004, OR = 1.82). Using GWAS data from the NIMH bipolar disorder (n = 2055) and NIMH schizophrenia (n = 2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (χ2 = 5.91, P = 0.015, OR = 1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ2 = 2.3, P = 0.129, OR = 1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87) = 6.031, P = 0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults.

Hippocampal and amygdala volumes in an older bipolar disorder sample.

BACKGROUND Brain volumetric magnetic resonance imaging (MRI) studies of adult bipolar disorder samples, compared with healthy controls, have reported conflicting results in hippocampal and amygdala volumes. Among these, few have studied older bipolar samples, which would allow for examination of the effects of greater duration in mood episodes on brain volumes. The aim of this study was to compare hippocampal and amygdala volumes in older bipolar patients with controls. METHODS High-resolution MRI scans were used to determine hippocampal and amygdala volumes that were manually traced using established protocols in 18 euthymic patients with DSM-IV bipolar I disorder (mean age 57 years) and 21 healthy controls (mean age 61 years). Analysis of covariance (ANCOVA) was used to explore group differences while controlling for intracranial volume (ICV), age, sex, and years of education. RESULTS While gray matter, white matter, and cerebrospinal fluid volumes did not differ between the groups, bipolar disorder patients had smaller ICV (t = 2.54, p = 0.015). After correcting for ICV, the bipolar group had smaller hippocampal (left hippocampus F = 13.944, p = 0.001; right hippocampus F = 10.976, p = 0.002; total hippocampus F = 13.566; p = 0.001) and right amygdala (F = 13.317, p = 0.001) volumes. Total hippocampal volume was negatively associated with the duration of depressive (r = -0.636; p = 0.035) and manic (r = -0.659; p = 0.027) episodes, but not lithium use. Amygdala volumes were not associated with the duration of mood episodes. CONCLUSIONS Older bipolar disorder patients had smaller hippocampal and amygdala volumes. That smaller hippocampal volume was associated with the duration of mood episodes may suggest a neuroprogressive course related to the severity of the disorder.

Progressing a spectrum model for defining non-melancholic depression

Objective:  To further develop a ‘spectrum model’ for non‐melancholic disorders that encompasses underlying personality styles and clinical patterning.

Sub-Grouping Non-Melancholic Major Depression Using Both Clinical and Aetiological Features

Objective: In previous papers we have considered the extent to which two contrasting analytic approaches, examining reported clinical symptom variables alone and aetiological variables alone, assist definition of subgroups of non-melancholic major depression. Here, we address the same objective but combine both sets of variables, and contrast the combined solution with each of the contributing ones. Method: We study a sample of 185 subjects with a putative non-melancholic major depressive disorder, with analyses involving 13 aetiological and 38 symptom variables. Results: A four-class subgrouping was derived by use of a cluster analytic technique, with ‘neurotic depression’, non-anxious ‘depressed’, ‘situational’ and ‘residual’ groups. The largest group comprised ‘neurotic depression’ subjects, with characteristics compatible with a spectrum disorder encompassing both clinical features as well as an underlying temperament and personality style marked by anxiety. Conclusions: Comparative advantages and properties of the three differing analytic approaches to defining ‘meaningful’ non-melancholic major depressive subgroupings are considered. As a ‘neurotic depressive’ class has been consistently identified across those three approaches, but with quite varying numbers of subjects circumscribed, it is clearly a ‘fuzzy’ entity which may benefit from a dimensional approach to its measurement. As many of the non-melancholic groupings appear secondary to a substantive predisposing factor such as anxiety or disordered personality functioning, the clinical importance and treatment utility in identifying and circumscribing such classes are clearly supported.

O-10 - Safety monitoring guidelines for treatments for major depressive disorder

Introduction Antidepressants are amongst the most commonly prescribed classes of drugs and their use continues to grow. Adverse outcomes are part of the landscape in prescribing medications and therefore management of safety issues need to be an integral part of practice. Objectives We have developed consensus guidelines for safety monitoring with antidepressant treatments. Aims To present an overview of screening and safety considerations for pharmacotherapy of clinical depressive disorders and make recommendations for safety monitoring. Methods Data were sourced by a literature search using Medline and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content. Results A guidelines document was produced after approval by all 19 co-authors. The final document gives guidance on; the decision to treat, baseline screening prior to commencement of treatment, and ongoing monitoring during antidepressant treatment. The guidelines state or reference screening protocols that may detect medical causes of depression as well as screening and monitoring protocols to investigate specific adverse effects associated with antidepressant treatments that may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment. Conclusions The implementation of safety monitoring guidelines for treatment of clinical depression may significantly improve outcome, by improving a patients overall physical health status.

07-02 TMS treatment for depression: overview of efficacy and report on a sham-controlled trial of twice daily left prefrontal rTMS

330 generation, STROOP, Autobiographical Memory Interview) were assessed at baseline, after six ECT and at the end of the ECT course. Results: The study is in progress and preliminary results (mood, neuropsychological function, seizure indexes) will be presented. Conclusions: All four forms of ECT appear effective, but preliminary results suggest some forms may be advantageous in terms of a lower rate of cognitive side-effects. There is evidence for the clinical use of bifrontal ECT. Ultrabrief unilateral ECT may hold great promise for the future.

The Stress Sampler Study II: psychological functioning and coping within a diabetes sample.

308 tested if alterations in dysbindin mRNA were found in the hippocampus of patients with schizophrenia by using in situ hybridization. We found signifi cantly reduced dysbindin mRNA in the dentate gyrus, CA4 and CA3, but not CA1, subregions of the hippocampus of patients with schizophrenia as compared with normal controls. Additionally, we found that dysbindin mRNA levels strongly and positively correlated with synaptophysin and spinophilin mRNA levels, which are known to be reduced in patients with schizophrenia. Our results suggest that reductions in dysbindin protein previously found in the hippocampus of patients with schizophrenia may be because of decreased dysbindin mRNA. The signifi cant reduction of dysbindin mRNA found in the hippocampus confi rms and extends our initial fi ndings that dysbindin mRNA is signifi cantly reduced in the frontal cortex and tends to be decreased in the midbrain of patients with schizophrenia (Weickert et al. 2004). Taken together, our results suggest that dysbindin mRNA reduction is not anatomically restricted, but may be anatomically specifi c, in the brains of patients with schizophrenia. Furthermore, subfi eld-specifi c reductions in dysbindin mRNA may lead to subfi eld-specifi c synaptic pathology in the hippocampus of patients with schizophrenic.

Stress Sampler I: psychosocial adjustment and psychiatric and physical comorbidity in diabetes mellitus.

305 measured on the SF-36. In general, depression was not associated with a diagnosis of either asthma or COPD. Conclusions: The prevalence of depression was higher than in previous studies. Importantly, depression was more common in people with signifi cant health risk factors but not with chronic lung diseases. Regular exercise was associated with a reduction in rates of depression. The possible reasons for this will be examined.

Predictors of suicide in major depressive disorder: a follow-up of patients seen at a specialist mood disorders unit.

290 the DEX, Neuropsychiatric Inventory (NPI), SF-36 and Zarit Burden Scale. Patient insight was measured using the discrepancy between carer and patient total scores on the DEX questionnaire. Results: The DEX discrepancy score correlated signifi cantly with total burden score (r = .52, P = 0.009). Burden was not correlated with patient cognition, age, neuropsychiatric symptoms and patient or carer SF-36 scores. A stepwise multiple regression with total burden as the outcome variable was statistically signifi cant (R2 = .65, F = 8.72, P < 0.001), signifi cant predictors of outcome were DEX discrepancy, patient GDS, CDR sum of boxes and NPI score. Carer relationship and living status did not affect perceived burden. Conclusions: Reduced insight in patients with dementia may result in increased isolation and frustration for their carer (compared with carers of patients who have good insight). Therefore, measuring insight in patients with dementia may be useful in identifying carers at risk for high burden levels.