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Biomedical subjects

Philip B Mitchell

Publications and source records attributed to Philip B Mitchell.

At least 19 recordsLinked to original sources
PubMed2008

Escitalopram in major depressive disorder: a multicenter, randomized, double-blind, fixed-dose, parallel trial in a Chinese population.

Escitalopram, the S-enantiomer of citalopram and the most selective of the selective serotonin reuptake inhibitor (SSRI) has been shown to be efficacious in the treatment of major depression in white populations. Our aim in this study was to investigate the efficacy and tolerability of escitalopram in Chinese patients with moderate to severe major depression. Patients who met DSM-IV criteria for a major depressive episode were enrolled in this multicenter, randomized, double-blind, fixed-dose comparison trial. Patients were given escitalopram 10 mg/day or fluoxetine 20 mg/day for 8 weeks. All patients were assessed with the 17-item Hamilton Depression Rating Scale (HAM-D-17) and the Montgomery-Asberg Depression Rating Scale (MADRS). Tolerability was assessed on the basis of adverse effects (measured with a locally developed checklist), regular biochemical tests, and electrocardiograph (ECG) assessments. Two hundred forty patients were enrolled and randomized to escitalopram (123 patients) or fluoxetine (117 patients). The HAM-D-17 total scores of both groups decreased significantly from baseline, but there was no significant difference at week 8 between the two groups (15.8 for escitalopram and 14.7 for fluoxetine; P >.05). There were no significant differences in response rates at all visits after treatment based on either HAM-D-17 or MADRS. A post hoc analysis indicated that escitalopram was superior to fluoxetine on two items of the HAM-D-17: "depressed mood" (P =.023) and "work and interest" (P =.024). The adverse events reported in the escitalopram and fluoxetine groups were comparable, and most were mild to moderate. Both drugs showed good compliance profiles. Escitalopram 10 mg/day is at least as efficacious as fluoxetine 20 mg/day and well tolerated in Chinese patients with major depression, with possible superiority in some core symptoms such as "depressed mood" and "work and interest."

Adolescent↗
PubMed2006

A sham-controlled trial of the efficacy and safety of twice-daily rTMS in major depression.

BACKGROUND: Studies of repetitive transcranial magnetic stimulation (rTMS) in depression have mostly involved once-daily treatment, with positive but modest clinical results. This study tested the efficacy and safety of twice-daily rTMS over 2 weeks. METHOD: Thirty-eight depressed subjects enrolled in a double-blind, sham-controlled trial of twice-daily rTMS (left prefrontal cortex, 10 Hz, 110% intensity, 1500 stimuli per session) over 2 weeks. Mood and neuropsychological functioning were assessed weekly by blind raters, using the Montgomery-Asberg Depression Rating Scale (MADRS) as the primary outcome measure, plus the Hamilton Rating Scale for Depression (HRSD) and self-report measures. After the blind period, 22 subjects continued with once-daily rTMS to receive a total of 6 weeks of active rTMS. RESULTS: Subjects were moderately treatment resistant. Active treatment resulted in significantly greater improvement than sham over the 2-week blind period on one outcome measure only (MADRS p<0.05). Subjects showed further improvement over the 6 weeks of active rTMS. Neuropsychological test scores did not change significantly. CONCLUSIONS: rTMS given twice daily was effective and safe, with no adverse neuropsychological effects.

Adult↗
PubMed2006

Serotonin transporter gene status predicts caudate nucleus but not amygdala or hippocampal volumes in older persons with major depression.

BACKGROUND: Although the short allele of the serotonin transporter promoter polymorphism (5-HTT) has been linked to increased risk of major depression in early adult life, its relationships with late-life depression and to changes in subcortical nuclei remain unclear. METHODS: 5-HTT genotypes (SS, SL, LL) were determined for 45 older persons with major depression (mean age=52.0, sd=12.8) and 16 healthy controls (mean age=55.8, sd=10.3). MRI-derived volumes of the amygdala, hippocampus, caudate and putamen were determined by reliable tracing techniques. RESULTS: In those with depression, the short allele of 5-HTT was associated with smaller caudate nucleus volumes. Although hippocampal and amygdala volumes were smaller in those with depression as compared with control subjects, 5-HTT gene status did not predict this reduction in size. LIMITATIONS: The findings are limited by the number of clinical and control participants. CONCLUSIONS: Reduced caudate nucleus volume in older patients with major depression was associated with the short allele of the 5-HTT gene. This regional brain change may be a consequence of early developmental expression as well as later vascular or degenerative effects of this genotype.

Aged↗
PubMed2006

The management of bipolar disorder in general practice.

General practitioners have a key role in managing patients with bipolar disorder, a condition which affects at least one in 200 Australians each year and is the sixth leading cause of disability in the population. Although diagnosis and treatment of the illness is complex, effective treatment can lead to good outcomes for many patients. GPs can contribute significantly to early recognition of bipolar disorder, avoiding the long delays in accurate diagnosis that have been reported. As in other complex recurrent or persistent illnesses, GPs are well placed to coordinate multidisciplinary "shared care" with specialists and other health care professionals. GPs also provide continuing general medical care for patients with bipolar disorder, and are in a unique position to understand patients' life circumstances and to monitor their progress over time. The last decade has seen many advances in medication for bipolar disorder, including the introduction of new therapies and the refinement of treatment protocols using older medications. There has also been increasing recognition of the contribution of psychological therapies to symptom relief, relapse prevention, optimal function, and quality of life.

Antidepressive Agents↗
PubMed2006

Transcranial magnetic stimulation for depression.

OBJECTIVE: To review the accumulated literature on the efficacy, safety and predictors of response for repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. METHODS: A descriptive review of the more than 25 published sham-controlled rTMS studies in depression was undertaken, focusing on reported meta-analyses as well as individual trial reports. Potential determinants of efficacy were examined, including the form of shams employed, stimulation parameters and clinical features. RESULTS: There is now clear evidence for the statistical superiority of left-prefrontal high frequency rTMS compared with sham therapy. However, the clinical benefits are marginal in the majority of reports. There is also still considerable uncertainty concerning the optimal stimulation parameters. Those clinical features which appear to be associated with greater response include younger age, lack of refractoriness to antidepressants and no psychotic features. CONCLUSIONS: Current studies confirm statistical efficacy, but insubstantive clinical benefit. Large multicentre studies currently underway should clarify if rTMS should be approved by regulatory agencies for widespread clinical availability. Furthermore, there is a need to clarify the preferred parameters for administering this treatment.

Major Depressive Disorder↗
PubMed2006

Life events, first depression onset and the serotonin transporter gene.

BACKGROUND: A relationship between the serotonin transporter gene, adverse events and onset of major depression has been reported. AIMS: To replicate a gene x environment interaction in a cohort with longitudinal data for life events, experience of depression, parental bonding and neuroticism. METHOD: At the 25-year follow-up, genomic DNA was obtained from 127 cohort members (mean age 48 years) to determine the genotype of the serotonin transporter gene-linked promoter region (5-HTTLPR). Associations were investigated between the 5-HTTLPR genotype, positive and adverse life events and the gene x environment interaction, and also between the 5-HTTLPR genotype and risk factors for depression. RESULTS: No relationship was found between 5-HTTLPR genotype and either risk factors for depression or positive life events. Adverse life events had a significantly greater impact on the onset of depression for individuals with the s/s genotype. CONCLUSIONS: The 5-HTTLPR genotype is a significant predictor of onset of major depression following multiple adverse events. This is one of the more robust findings concerning specific biological risk factors for depression.

Adult↗
PubMed2006

Emerging drugs for bipolar disorder.

Bipolar disorder is a relatively common condition characterised by recurrent episodes of mania and depression, and associated with high levels of morbidity and mortality. Although there have been substantial advances in the pharmacotherapeutics of this condition over the last 10-15 years, the benefits have been predominantly in terms of tolerability and safety, with no new treatments being demonstrated to be more effective than lithium--the prototype mood stabiliser. This article reviews current and emerging medications for bipolar disorder. Most of the emerging treatments in pharmaceutical industry developmental programmes are new or modified anticonvulsants or atypical antipsychotics. A number of possible future directions and challenges for the field are discussed. The treatment of bipolar disorder is unlikely to advance substantially until the causative pathogenetic molecular processes are elucidated.

Bipolar Disorder↗
PubMed2006

A randomized controlled trial of cognitive therapy for bipolar disorder: focus on long-term change.

BACKGROUND: This study reports the outcome of a randomized controlled trial of cognitive therapy (CT) for bipolar disorder. The treatment protocol differed from other published forms of CT for bipolar disorder through the addition of emotive techniques. METHOD: Fifty-two patients with DSM-IV bipolar I or II disorder were randomly allocated to a 6-month trial of either CT or treatment as usual, with both treatment groups also receiving mood stabilizers. Outcome measures included relapse rates, dysfunctional attitudes, psychosocial functioning, hopelessness, self-control, and medication adherence. Patients were assessed during treatment by independent raters blind to the patients' group status. RESULTS: At posttreatment, patients allocated to CT had experienced less severe depression scores (Beck Depression Inventory and Montgomery-Asberg Depression Rating Scale) and less dysfunctional attitudes. After controlling for the presence of major depressive episode at baseline, there was a statistical trend toward a greater time to depressive relapse (p=.06) for the CT group. At 12-month follow-up, the CT group showed a trend toward lower Young Mania Rating Scale scores and improved behavioral self-control. The Clinical Global Impressions-Improvement scale, comparing the 18 months prior to treatment to the severity of illness status at follow-up, showed a substantial difference between groups in favor of CT. CONCLUSION: Our findings corroborate previous bipolar disorder research in demonstrating the value of CT, particularly immediately post-treatment, and indicate some continuation (albeit diminishing) of benefits in the succeeding 12 months. These findings suggest that psychological booster sessions may be crucial for maintaining the beneficial effects of cognitive therapy.

Adult↗
PubMed2005

A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy.

BACKGROUND: There is a growing interest in extending the use of repetitive transcranial magnetic stimulation (rTMS) beyond research centres to the widespread clinical treatment of depression. Thus it is timely to critically review the evidence for the efficacy of rTMS as an antidepressant treatment. Factors relevant to the efficacy of rTMS are discussed along with the implications of these for the further optimization of rTMS. METHOD: Clinical trials of the efficacy of rTMS in depressed subjects are summarized and reviewed, focusing mainly on sham-controlled studies and meta-analyses published to date. RESULTS: There is a fairly consistent statistical evidence for the superiority of rTMS over a sham control, though the degree of clinical improvement is not large. However, this data is derived mainly from two-week comparisons of rTMS versus sham, and evidence suggests greater efficacy with longer treatment courses. Studies so far have also varied greatly in approaches to rTMS stimulation (with respect to stimulation site, stimulus parameters etc) with little empirical evidence to inform on the relative merits of these approaches. LIMITATIONS: Only studies published in English were reviewed. Many of the studies in the literature had small sample sizes and different methodologies, making comparisons between studies difficult. CONCLUSIONS: Current published studies and meta-analyses have evaluated the efficacy of rTMS as given in treatment paradigms that are almost certainly suboptimal (e.g of two weeks' duration). While the data nevertheless supports positive outcomes for rTMS, there is much scope for the further refinement and development of rTMS as an antidepressant treatment. Ongoing research is critical for optimizing the efficacy of rTMS.

Depressive Disorder↗
PubMed2005

Altered gene expression in mice treated with the mood stabilizer sodium valproate.

Valproate is now the most widely prescribed mood-stabilizing drug and is being used increasingly in the treatment of bipolar disorder. However, the mechanism of action for valproate remains unclear. Microarray analysis was used to identify genes and cellular pathways that are affected in the mouse brain after treatment with valproate at human therapeutic concentrations. This study has identified 11 genes that are differentially expressed by >or=2-fold when compared to control untreated mice. Altered expression of four of these genes was also validated by quantitative PCR analysis. Valproate was found to significantly decrease the expression of zinc finger protein of the cerebellum 1 (ZIC1) and increase the expression of Scm-related gene containing four mbt domains (SFMBT2), structural maintenance of chromosome 4-like 1 (SCM4L1), and prostate apoptosis response-4 (PAR-4). Many of the genes identified are involved in the development and function of the brain. These results indicate that valproate regulates a large number of different functional pathways in the brain. Understanding the molecular and cellular mechanisms by which valproate achieves its therapeutic action represents a valuable step in clarifying the pathophysiology of bipolar disorder.

Animals↗
PubMed2005

Association analysis of transcripts from the bipolar susceptibility locus on chromosome 4q35, exclusion of a pathogenic role for eight positional candidate genes.

Bipolar affective disorder is a major psychiatric illness with a population prevalence of up to 1.6%. The disorder is genetically complex. To date, no specific gene or DNA sequence variation that predisposes to the disorder has been described, however several susceptibility loci have been proposed through genetic linkage analysis. We previously identified one such susceptibility locus on chromosome 4q35, and refined the interval harboring this susceptibility gene to a size that is amenable to positional cloning. Several independent studies have now been described that support the presence of a susceptibility gene at this locus. In order to identify candidate genes for testing association with bipolar disorder, we previously established a comprehensive transcript map that encompasses the chromosome 4q35 susceptibility locus implicated in our linkage analysis. In this study, we have selected full-length genes from the transcript map and determined the genomic structure of each gene. We identified informative, intragenic single nucleotide polymorphisms (SNPs) by screening all exons and flanking intron sequences in affected individuals from seven bipolar pedigrees that we previously reported as showing evidence for linkage to chromosome 4q35. Analysis of these SNPs was then extended to our unrelated bipolar case-control cohort to test for association with the disorder. Our data suggests that all genes analyzed can be excluded from direct involvement in the disorder. We have therefore, excluded approximately half the genes within the chromosome 4q35 candidate interval from playing a direct pathogenic role in bipolar disorder.

Alleles↗
PubMed2005

Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study.

While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.

Adolescent↗
PubMed2005

Techniques for the identification of genes involved in psychiatric disorders.

OBJECTIVE: Most psychiatric disorders are complex genetic traits involving both genetic and environmental risk factors. This paper aims to review the gene identification strategies being applied by molecular geneticists in their efforts to elucidate the genetic and molecular basis of psychiatric disorders. Future strategies will also be canvassed. METHOD: The psychiatric genetic literature was reviewed to identify current strategies applied to gene identification, with examples provided where available. The future strategies and applications that will arise from genome projects, including the International Haplotype Mapping Project, are also discussed. RESULTS: Many advances in the techniques of gene discovery, and the increasing resources available, are rapidly being adopted by researchers and applied to the complex problem of identifying susceptibility genes for mental illnesses. Perhaps the single most important advance to date is the Human Genome Project and all that has stemmed from the vast quantity of information that this endeavour has provided. With these technological advances and the massive increase of publicly available genetic resources, several genes have recently been implicated in the susceptibility to psychiatric illnesses including schizophrenia and depression. After many years of fruitless endeavours, these recent reports indicate that the labours of researchers in psychiatric genetics are beginning to show exciting results. CONCLUSIONS: Identification of these susceptibility genes holds great promise, with the unravelling of the molecular and biochemical basis of some conditions now being a more realistic and tangible goal. The increasing number of genes being identified augers well for the future treatment of psychiatric disorders. The genes identified, and the pathways of genes and proteins that they implicate, will provide potential novel targets for new therapeutic drugs. Psychiatric genetics appears to be poised for significant advances in our knowledge and understanding of the molecular genetic basis of mental illness.

Chromosome Mapping↗
PubMed2005

Identification, characterization, and association analysis of novel genes from the bipolar disorder susceptibility locus on chromosome 4q35.

The cause of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical, biochemical, or genetic defect. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. We previously identified a bipolar disorder susceptibility locus on chromosome 4q35 and refined the interval harboring this susceptibility gene to approximately 5 Mb, a size that is amenable to positional cloning. Several independent studies have reported the presence of a susceptibility gene at this locus. To identify candidate genes for testing for association with bipolar disorder, we previously established a transcript map that encompasses the candidate interval. We have continued to seek novel genes from this region in order to expand this transcript map. Here, we describe the further identification and characterization of eight novel genes from the chromosome 4q35 bipolar candidate interval. Expression analysis determined that six of these novel genes are expressed in the brain, and these genes were therefore analyzed for association with bipolar disorder. Single nucleotide polymorphisms were identified from the candidate genes and tested for association in our case-control cohort. Our data suggest that the six candidate genes analyzed can be excluded from involvement in the disorder.

Bipolar Disorder↗
PubMed2005

When euthymia is just not good enough: the neuropsychology of bipolar disorder.

Bipolar disorder (BD) is a debilitating psychiatric illness that is uniquely characterized by switching between psychopathologically contrasting phases of mania and depression, often with intervening periods of euthymia. However, these periods of apparent clinical recovery (euthymia) are marked by subtle social, occupational, and cognitive impairments, profiled by recent neuropsychological investigations. Determining the cognitive changes across these three phases may help differentiate the disruptions that are mood state-dependent from those associated with underlying pathology. This article therefore critically reviews the reported neuropsychological impairments in BD and the methodological limitations facing such research. Integration of the available evidence, principally from the field of neuropsychology, when synthesized, implicates the prefrontal cortex in the etiopathogenesis of BD and posits cortical-subcortical-limbic disruption in recovered euthymic patients that manifests as cognitive dysfunction.

Bipolar Disorder↗
PubMed2005

The epidemiology of bipolar disorder: sociodemographic, disability and service utilization data from the Australian National Study of Low Prevalence (Psychotic) Disorders.

OBJECTIVES: Data from the Australian National Study of Low Prevalence (Psychotic) Disorders were used to describe the clinical and sociodemographic profile of individuals with bipolar disorder, their levels of impairment and disability, and use of medication and treatment services. METHODS: A 1-month census of contacts with mental health services, private psychiatric and general practices, as well as contact points in marginalized settings, was conducted in a national catchment of 1.1 million adults. The census yielded 3,800 individuals who screened positive for psychosis, of whom a random sample of 980 were administered a comprehensive semi-structured interview schedule. Results are presented on 112 persons with an ICD-10 diagnosis of bipolar disorder. RESULTS: Overall, 69.6% of the 112 persons who met the ICD-10 criteria for bipolar disorder reported a recurrent episodic illness, 25.0% had a chronic course without clear remissions, and 5.4% had a single episode of mania. Assessed on a lifetime basis, suicidal ideation was common (78.6%) and levels of drug and alcohol abuse/dependence were high (32.1%). The majority (84.8%) had had at least one contact with inpatient, outpatient or emergency services in the previous year. Those with serious impairment had levels of service utilization similar to the rest of the sample, but were more likely to report a poorer quality of life and unmet service needs. While the percentage experiencing social and occupational dysfunction was substantial and similar for both sexes, women appeared to be better integrated socially than men. Comparisons with schizophrenia patients within the same survey sample highlighted less chronic impairment but equal or greater utilization of services by bipolar patients. CONCLUSIONS: Despite low levels of chronicity, the burden of social disablement associated with bipolar disorder is high. The data suggest a number of important gaps in the provision of services for this predominantly treated population.

Adult↗