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P B Mitchell

Publications and source records attributed to P B Mitchell.

At least 19 recordsLinked to original sources
PubMed2006

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

Adult↗
PubMed2005

A typical mood stabilizers: a "typical role for atypical antipsychotics.

OBJECTIVE: To assess the potential role of atypical antipsychotics as mood stabilizers. METHOD: A MedLine, PsychLIT, PubMed, and EMBASE literature search of papers published up to December 2004 was conducted using the names of atypical antipsychotics and a number of key terms relevant to bipolar disorder. Additional articles were retrieved by scrutinizing the bibliographies of review papers and literature known to the authors. Data pertinent to the objective was reviewed according to the various phases of bipolar disorder. RESULTS: The data is most substantive for the use of atypical antipsychotics in mania, to the extent that an argument for a class effect of significant efficacy can be made. This does not extend to bipolar depression, however, good data is now emerging for some agents and will need to be considered for each individual agent as it accumulates. As regards mixed states and rapid cycling the evidence is thus far sparse and too few maintenance studies have been conducted to make any firm assertions. However, with respect to long-term therapy the atypical antipsychotics do have clinically significant side-effects of which clinicians need to be aware. CONCLUSION: Based on the evidence thus far it is perhaps premature to describe the atypical antipsychotics as mood stabilizers. Individual agents may eventually be able to claim this label, however, much further research is needed especially with respect to maintenance and relapse prevention.

Affect↗
PubMed2005

Treatment-resistant depression: resistant to definition?

OBJECTIVE: To better define treatment-resistant depression (TRD) so as to assist clinical management and refine treatment guidelines. METHOD: In this study, we examine a broad range of clinical variables in depressed patients (n=196) referred to a tertiary referral Mood Disorders Unit (MDU). Information was collected from patients, referrers and assessors over a period of 32 months and included evaluations of treatments, treatment resistance and related variables. Data were analysed across trichotomized 'high', 'low' and 'no' treatment resistance groupings of patients. RESULTS: A significantly greater proportion of patients with melancholia were amongst the high TRD group, and this was consistent across different strategies for evaluating melancholia. CONCLUSION: Melancholia perhaps provides a prototypic TRD subset that perhaps reflects some innate aspects of melancholic depression or factors such as the impact of ageing. Research into TRD is needed to both replicate this finding and perhaps explicate it further.

Adolescent↗
PubMed2004

Twelve-month prevalence and disability of DSM-IV bipolar disorder in an Australian general population survey.

BACKGROUND: There have been few large-scale epidemiological studies which have examined the prevalence of bipolar disorder. The authors report 12-month prevalence data for DSM-IV bipolar disorder from the Australian National Survey of Mental Health and Well-Being. METHOD: The broad methodology of the Australian National Survey has been described previously. Ten thousand, six hundred and forty-one people participated. The 12-month prevalence of euphoric bipolar disorder (I and II)--similar to the euphoric-grandiose syndrome of Kessler and co-workers--was determined. Those so identified were compared with subjects with major depressive disorder and the rest of the sample, on rates of co-morbidity with anxiety and substance use disorders as well as demographic features and measures of disability and service utilization. Polychotomous logistic regression was used to study the relationship between the three samples and these dependent variables. RESULTS: There was a 12-month prevalence of 0-5 % for bipolar disorder. Compared with subjects with major depressive disorder, those with bipolar disorder were distinguished by a more equal gender ratio; a greater likelihood of being widowed, separated or divorced; higher rates of drug abuse or dependence; greater disability as measured by days out of role; increased rates of treatment with medicines; and higher lifetime rates of suicide attempts. CONCLUSIONS: This large national survey highlights the marked functional impairment caused by bipolar disorder, even when compared with major depressive disorder.

Adolescent↗
PubMed2004

Scale matters: the need for a Bipolar Depression Rating Scale (BDRS).

OBJECTIVE: To briefly review the clinical and biological distinctions between unipolar and bipolar depression critiquing in particular currently available depression rating scales and discuss the need for a new observer-rated scale tailored to bipolar depression. METHOD: Relevant literature pertaining to the symptomatic differences between bipolar disorder and unipolar disorder as well as their measurement using existing assessment scales was identified by computerized searches and reviews of scientific journals known to the authors. RESULTS: Bipolar depression is distinct from unipolar depression in terms of phenomenology and clinical characteristics. These distinguishing features can be used to identify bipolarity in patients that present with recurrent depressive episodes. This is important because current self-report and observer-rated scales are optimized for unipolar depression, and hence limited in their ability to accurately assess bipolar depression. CONCLUSION: The development of a specific bipolar depression rating scale will improve the assessment of bipolar depression in both research and clinical settings and assist the development of better treatments and interventions.

Bipolar Disorder↗
PubMed2003

Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression.

BACKGROUND: The efficacy and safety of bilateral prefrontal repetitive transcranial magnetic stimulation (rTMS) for treating resistant major depression were examined in a double-blind, placebo-controlled study. METHOD: Nineteen medication-resistant depressed subjects were randomly assigned to 3 weeks of active or sham rTMS. Effects on mood and neuropsychological function were assessed. RESULTS: Both groups improved significantly in mood over the 3 weeks, but there was no significant difference between active and sham treatments. There were no significant neuropsychological effects. CONCLUSIONS: Bilateral rTMS was not superior to sham in treating resistant depression in this pilot study, but caused no neuropsychological impairment.

Adult↗
PubMed2003

Slow binocular rivalry in bipolar disorder.

BACKGROUND: The rate of binocular rivalry has been reported to be slower in subjects with bipolar disorder than in controls when tested with drifting, vertical and horizontal gratings of high spatial frequency. METHOD: Here we assess the rate of binocular rivalry with stationary, vertical and horizontal gratings of low spatial frequency in 30 subjects with bipolar disorder, 30 age- and sex-matched controls, 18 subjects with schizophrenia and 18 subjects with major depression. Along with rivalry rate, the predominance of each of the rivaling images was assessed, as was the distribution of normalized rivalry intervals. RESULTS: The bipolar group demonstrated significantly slower rivalry than the control, schizophrenia and major depression groups. The schizophrenia and major depression groups did not differ significantly from the control group. Predominance values did not differ according to diagnosis and the distribution of normalized rivalry intervals was well described by a gamma function in all groups. CONCLUSIONS: The results provide further evidence that binocular rivalry is slow in bipolar disorder and demonstrate that rivalry predominance and the distribution of normalized rivalry intervals are not abnormal in bipolar disorder. It is also shown by comparison with previous work, that high strength stimuli more effectively distinguish bipolar from control subjects than low strength stimuli. The data on schizophrenia and major depression suggest the need for large-scale specificity trials. Further study is also required to assess genetic and pathophysiological factors as well as the potential effects of state, medication, and clinical and biological subtypes.

Adult↗
PubMed2003

High (15 Hz) and low (1 Hz) frequency transcranial magnetic stimulation have different acute effects on regional cerebral blood flow in depressed patients.

BACKGROUND: High and low frequency repetititve transcranial magnetic stimulation (rTMS) are both effective in treating depression but have contrary effects on motor cortical activity. This study aimed to understand further the mechanisms of action of high and low frequency rTMS by examining their acute effects on regional cerebral blood flow (rCBF) in depressed patients. METHOD: Eighteen depressed subjects underwent brain single photon emission computerized tomography (SPECT) scanning using split-dose 99mTc-HMPAO, and were examined during sham and active rTMS to the left prefrontal cortex, at 15 Hz or 1 Hz (N=9 each). Relative rCBF changes were examined by statistical parametric mapping and by regions of interest analysis. RESULTS: High (15 Hz) frequency rTMS resulted in relative rCBF increases in the inferior frontal cortices, right dorsomedial frontal cortex, posterior cingulate and parahippocampus. Decreases occurred in the right orbital cortex and subcallosal gyrus, and left uncus. Low (1 Hz) frequency rTMS led to increased relative rCBF in the right anterior cingulate, bilateral parietal cortices and insula and left cerebellum. High frequency rTMS led to an overall increase, whereas low frequency rTMS produced a slight decrease, in the mean relative rCBF in the left dorsolateral prefrontal cortex. CONCLUSIONS: High (15 Hz) and low (1 Hz) frequency rTMS led to different frontal and remote relative rCBF changes, which suggests different neurophysiological and possibly neuropsychiatric consequences of a change in frequency of rTMS.

Adult↗
PubMed2002

A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13-pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P= 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.

Bipolar Disorder↗
PubMed2002

A transcript map encompassing a susceptibility locus for bipolar affective disorder on chromosome 4q35.

Bipolar affective disorder is one of the most common mental illnesses with a population prevalence of approximately 1%. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. However, the specific genetic variations and molecules involved in bipolar susceptibility and pathogenesis are yet to be identified. Genetic linkage analysis has identified a bipolar disorder susceptibility locus on chromosome 4q35, and the interval harbouring this susceptibility gene has been narrowed to a size that is amenable to positional cloning. We have used the resources of the Human Genome Project (HGP) and Celera Genomics to identify overlapping sequenced BAC clones and sequence contigs that represent the region implicated by linkage analysis. A combination of bioinformatic tools and laboratory techniques have been applied to annotate this DNA sequence data and establish a comprehensive transcript map that spans approximately 5.5 Mb. This map encompasses the chromosome 4q35 bipolar susceptibility locus, which localises to a "most probable" candidate interval of approximately 2.3 Mb, within a more conservative candidate interval of approximately 5 Mb. Localised within this map are 11 characterised genes and eight novel genes of unknown function, which together provide a collection of candidate transcripts that may be investigated for association with bipolar disorder. Overall, this region was shown to be very gene-poor, with a high incidence of pseudogenes, and redundant and novel repetitive elements. Our analysis of the interval has demonstrated a significant difference in the extent to which the current HGP and Celera sequence data sets represent this region.

Bipolar Disorder↗
PubMed2002

A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.

Bipolar Disorder↗
PubMed2001

Rediscovering chronic mania.

OBJECTIVE: This paper presents a case of chronic mania and reviews the diagnosis with respect to its definition and utility. METHOD: A case of chronic mania is described. RESULTS: Unremitting mania poses a diagnostic and management challenge. CONCLUSION: Persistent mania of this duration is rare, but a diagnosis of chronic mania should not be rejected on the basis of chronicity.

Adult↗
PubMed2001

A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.

Alleles↗
PubMed2001

Therapeutic drug monitoring of psychotropic medications.

Therapeutic drug monitoring (TDM) of a number of psychotropic medications has proven to be of value, enabling minimization of the limitations of considerable genetic variability in their metabolism and the high rates of poor compliance with many psychiatric disorders. Therapeutic ranges have been established for lithium, some of the tricyclic antidepressants, and clozapine. TDM has also been shown to be useful in avoiding toxicity (as many psychotropics have narrow therapeutic indices), particularly that due to interactions with other compounds.

Bipolar Disorder↗
PubMed2001

'Why getting fat, Doc?' Weight gain and psychotropic medications.

OBJECTIVES: Weight gain associated with the use of psychotropic medications is a common clinical problem that is of particular importance because of its effects on the general health of psychiatric patients and their compliance with treatment. This paper aims to explore this issue and discuss the mechanisms of weight gain and methods of prevention. METHOD: A literature review (Index Medicus/Medline) was carried out as well as a review of other relevant papers and data known to the authors. RESULTS: Significant weight gain may result in considerable morbidity. The majority of psychotropic medications are associated with weight gain, however, the mechanisms of weight gain are often complex and poorly understood. CONCLUSION: Clinically, weight gain can be anticipated and often managed with some success in the majority of psychiatric patients with simple but relatively effective measures. It is important for clinicians to be aware of this common clinical problem and educate patients from the outset, monitoring them regularly and intervening when necessary.

Humans↗