Philip Mitchell - Profile on Academia.edu (original) (raw)

Papers by Philip Mitchell

World Journal of Biological Psychiatry, Dec 8, 2020

Background: Major depressive disorder is a common, recurrent, disabling and costly disorder that ... more Background: Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant firstline antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility. Aim: This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression? Method: Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD-World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing. Outcomes: The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes ARTICLE HISTORY

Biological Psychiatry, Feb 1, 2000

Background: Carefully designed controlled studies are essential in further evaluating the therape... more Background: Carefully designed controlled studies are essential in further evaluating the therapeutic efficacy of transcranial magnetic stimulation (TMS) in psychiatric disorders. A major methodological concern is the design of the "sham" control for TMS. An ideal sham would produce negligible cortical stimulation in conjunction with a scalp sensation akin to real treatment. Strategies employed so far include alterations in the position of the stimulating coil, but there has been little systematic study of their validity. In this study, we investigated the effects of different coil positions on cortical activation and scalp sensation. Methods: In nine normal subjects, single TMS pulses were administered at a range of intensities with a "figure eight" coil held in various positions over the left primary motor cortex. Responses were measured as motor-evoked potentials in the right first dorsal interosseus muscle. Scalp sensation to TMS with the coil in various positions over the prefrontal area was also assessed. Results: None of the coil positions studied met the criteria for an ideal sham. Arrangements associated with a higher likelihood of scalp sensation were also more likely to stimulate the cortex. Conclusions: The choice of a sham for TMS involves a trade-off between effective blinding and truly inactive "stimulation." Further research is needed to develop the best sham condition for a range of applications. Biol

Stimulus Intensity in Transcranial Magnetic Stimulation (TMS) Studies

Journal of Ect, Dec 1, 2001

... Mitchell, Philip BMD, FRANZCP, FRACPsych.; Sachdev, Perminder S. Ph.D., MD, FRANZCP. Article ... more ... Mitchell, Philip BMD, FRANZCP, FRACPsych.; Sachdev, Perminder S. Ph.D., MD, FRANZCP. Article Outline. Collapse Box Author Information. School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney and Department of Psychiatry, Prince of Wales ...

Nuclear Medicine Communications, Apr 1, 1999

Australasian Psychiatry, Dec 20, 2018

T he 'clinical academic' is a professional who works concurrently in research and clinical practi... more T he 'clinical academic' is a professional who works concurrently in research and clinical practice, providing leadership across both domains, delivering innovative and evidence-based healthcare. Clinical academic psychiatrists remain a small but essential group amongst the larger body of consultant psychiatrists in Australia. 1-4 Recognising that the making of a clinical academic psychiatrist requires equal emphasis on scholarship and research as on the developing clinical expertise, the Royal Australian and New Zealand College of Psychiatrists (RANZCP) has reintroduced a mandatory research project undertaken during fellowship training. We examine pathways available for training as clinical academic psychiatrists in Australia offering the perspectives of two junior clinical academics (AM and AB) who were in receipt of funding through an initiative spearheaded by the Head of the School of Psychiatry (PBM) at the University of New South Wales (UNSW) to encourage clinical psychiatrists on to a pathway of research. Why are clinical academics important to psychiatry? The 'decade of the brain' (https://www.loc.gov/loc/ brain/proclaim.html) has seen advances in psychiatric investigation and research methodology. Scientific

Cover Image, Volume 186B, Number 8, December 2021

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Efficacy and Safety of Repeated Subcutaneous Ketamine Injections for Treatment Resistant Depression - The KADS Study: A Randomised, Double-Blind, Comparator-Controlled Trial

Social Science Research Network, 2022

Translational Psychiatry

Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors ... more Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS;n = 41) compared against the bottom two quintiles (Low-BD-PRS;n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-...

Translational Psychiatry

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs wide... more Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+...

JAMA Psychiatry, 2021

IMPORTANCE Large-scale neuroimaging studies have revealed group differences in cortical thickness... more IMPORTANCE Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows:

SummaryHuman brain structure changes throughout our lives. Altered brain growth or rates of decli... more SummaryHuman brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genesGPR139, DACH1andAPOEare associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain deve...

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, ... more BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronologi...

European Neuropsychopharmacology, 2019

affect LTL in an extended sample including 313 BD patients and 316 controls, and 2) we explore th... more affect LTL in an extended sample including 313 BD patients and 316 controls, and 2) we explore the impact of agerelated disorders on telomere and inflammation dynamics in SMDs in a new cohort comprising 40 patients with BD, 40 with schizophrenia (SCZ), 40 with major depressive disorder (MDD) and 40 controls, stratified according to presence of comorbid-age related disorders. Methods: LTL was measured using SYBR Green quantitative PCR and quantitative fluorescence in situ hybridization. Correlation between LTL and quantitative variables was determined using the partial correlation and linear regression tests controlled for age. Differences in LTL and in levels of inflammatory markers between cases and controls were tested using general linear models, taking into the account the effect of cardiometabolic comorbidities, medication, single nucleotide polymorphisms suggested to affect telomere length and other important clinical characteristics (e.g. smoking, alcohol intake and physical activity). Results: In the sample of 313 BD patients and 316 controls, partial correlation test corrected for age confirmed the positive correlation between LTL and Li treatment duration in patients with long-term treatment (n = 173, beta = 0.17, p = 0.03). BD patients had longer LTL compared to controls (beta =-0.16, p < 0.0001). Moreover, BD patients treated with Li for at least one year (n = 234) had longer LTL compared to Li-naive patients (n = 62; p = 1.5 × 10-8). These findings were further supported by preliminary results from a subsample of the cross-diagnostic cohort showing longer LTL in patients with BD treated with Li compared to both MDD and SCZ patients (p = 0.008 and p < 0.0001, respectively). Conversely, we did not observe an effect of other psychotropic drugs on LTL. Patients with SCZ showed shorter LTL and higher plasma levels of C-reactive protein compared to controls (p = 0.002 and 0.005, respectively). Discussion: Our data further support previous findings showing that long-term Li treatment has a protective effect against telomere shortening in BD, while patients with SCZ seem to be more susceptible to accelerated telomere shortening. Measurement of LTL in the whole cohort and in a replication cohort of 350 individuals divided in four groups as in the investigation cohort and collected in Greece, as well as measurement of other plasma pro-inflammatory cytokines (TNF-α and IL-6) are currently ongoing. Results from this combined approach will allow us to shed light on the interplay of inflammation and TS in BD, SCZ and MDD, as well as to explore whether these three different psychiatric disorders may overlap in terms of altered telomere and inflammation dynamics, an aspect that has yet to be understood.

European Neuropsychopharmacology, 2019

PRS threshold. At 3 of 5 PRS thresholds, higher PRS for risk taking was associated with greater w... more PRS threshold. At 3 of 5 PRS thresholds, higher PRS for risk taking was associated with greater white matter tract MD (reflecting poorer integrity), and at 2 of 5 thresholds, with smaller middle frontal gyrus volume. Discussion: We provide evidence that genetic propensity towards risk taking behaviour is associated with structural brain differences. The middle frontal gyrus has been linked to inhibitory control, and poorer white matter integrity to risk taking behaviour and impulsivity: the current findings suggest these associations are linked to by genetic propensity for risk taking.

Acta Psychiatrica Scandinavica, 2016

Are there subtypes of bipolar depression? Objective: To investigate for subtypes of bipolar depre... more Are there subtypes of bipolar depression? Objective: To investigate for subtypes of bipolar depression using latent class analysis (LCA). Method: Participants were recruited through a bipolar disorder (BD) clinic. LCA was undertaken using: (i) symptoms reported on the SCID-IV for the most severe lifetime depressive episode; (ii) lifetime illness features such as age at first depressive and hypo/manic episodes; and (iii) family history of BD and unipolar depression. To explore the validity of any demonstrated 'classes', clinical, demographic and treatment correlates were investigated. Results: A total of 243 BD subjects (170 with BD-I and 73 with BD-II) were included. For the combined sample, we found two robust LCA solutions, with two and three classes respectively. There were no consistent solutions when the BD-I and BD-II samples were considered separately. Subjects in class 2 of the three-class solution (characterised by anxiety, insomnia, reduced appetite/weight loss, irritability, psychomotor retardation, suicidal ideation, guilt, worthlessness and evening worsening) were significantly more likely to be in receipt of government financial support, suggesting a particularly malign pattern of symptoms. Conclusion: Our study suggests the existence of two or three distinct classes of bipolar depression and a strong association with functional outcome.

Non Invasive Brain Stimulation Therapy Restores Neuroplasticity in Depression

Brain Stimulation, 2015

s / Brain Stimulation 8 (2015) 343e359 349 learning paradigms, C57Bl6/J mice receive daily iTBS i... more s / Brain Stimulation 8 (2015) 343e359 349 learning paradigms, C57Bl6/J mice receive daily iTBS immediately prior to undergoing a skilled pellet-reaching task for 10 days. In a separate group; Thy1-GFPM mice undergo cranial window insertion overlying the right motor cortex to enable visualisation of excitatory cortical neurons in the upper layers of the motor cortex. Images of synaptic structures are collected at regular intervals before and after iTBS and analysed for alterations in connectivity resulting from stimulation. Preliminary analysis suggests daily iTBS significantly increases accuracy but not speed of pellet reaching, relative to sham stimulation (handling control). Preliminary analysis of the imaging data suggests a single session of iTBS does not alter dendritic spine density. These results will help characterise the biological mechanisms underlying rTMS, which will undoubtedly pave the way forward in the therapeutic applications of non-invasive brain stimulation in health and disease.

Sub-typing depression, II. Clinical distinction of psychotic depression and non-psychotic melancholia

Psychological Medicine, 1995

SYNOPSISWe have attempted to clarify clinical differentiating features of psychotic depression. F... more SYNOPSISWe have attempted to clarify clinical differentiating features of psychotic depression. Forty-six depressed subjects meeting DSM-III-R criteria for major depression with psychotic features were compared with (i) DSM-defined melancholic, (ii) Newcastle-defined endogenous, and (iii) a residual DSM-defined major depressive episode group. Additionally, a ‘bottom up’ latent class analysis (LCA) suggested a larger sample of 82 ‘psychotic depressive’ subjects, and multivariate analyses contrasted these subjects with both LCA-identified melancholic and all residual depressed subjects. Analyses suggested that, in addition to two features with absolute specificity (delusions and hallucinations), both the DSM-defined and LCA-defined ‘psychotic depressive’ subjects were significantly more likely to demonstrate marked psychomotor disturbance, to report two morbid cognitions (feeling sinful and guilty; feeling deserving of punishment), as well as be more likely to report constipation, ter...

Sub-typing depression, I. Is psychomotor disturbance necessary and sufficient to the definition of melancholia?

Psychological Medicine, 1995

SYNOPSISMelancholia is most commonly distinguished from non-melancholic depression by the presenc... more SYNOPSISMelancholia is most commonly distinguished from non-melancholic depression by the presence of psychomotor disturbance (PMD) and a set of ‘endogeneity’ symptoms. We examine the capacity of an operationalized clinician-rated measure of PMD (the CORE system) to predict diagnostic assignment to ‘melancholic/endogenous’ classes by the DSM-III-R and Newcastle systems. Examining a pre-established CORE cut-off score (≥ 8) against independent diagnostic assignment, PMD was present in 51% of those assigned as melancholic by DSM-III-R, and 85% of those assigned as endogenous by the Newcastle system, quantifying the extent to which it is ‘necessary’ to the two definitions of ‘melancholia’. Additionally, multivariate analyses established that the addition of a refined set of historically suggested endogeneity symptoms added only slightly to overall discrimination of melancholic and non-melancholic depressives. While only few endogeneity symptoms independent of psychomotor disturbance wer...

Sub-typing depression, III. Development of a clinical algorithm for melancholia and comparison with other diagnostic measures

Psychological Medicine, 1995

SYNOPSISWe describe the development of a clinical algorithm to differentiate melancholic from non... more SYNOPSISWe describe the development of a clinical algorithm to differentiate melancholic from non-melancholic depression, using refined sets of ‘endogeneity’ symptoms together with clinician-rated CORE scores assessing psychomotor disturbance. Assignment by the empirically developed algorithm is contrasted with assignment by DSM-III-R and with several other melancholia subtyping indices. Both the numbers of ‘melancholies’ assigned by the several systems and their capacity to distinguish ‘melancholics’ on clinical, demographic and a biological index test (the DST) varied across the systems with the algorithm being as ‘successful’ as several systems that include inter-episode and treatment response variables. Analyses provide information on the criteria set developed for DSM-IV definition of ‘melancholia’.

The Lancet, 2012

Background Measuring disease and injury burden in populations requires a composite metric that ca... more Background Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specifi c epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. Methods We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable defi nitions and methods. YLLs were calculated from age-sex-country-time-specifi c estimates of mortality by cause, with death by standardised lost

World Journal of Biological Psychiatry, Dec 8, 2020

Biological Psychiatry, Feb 1, 2000

Stimulus Intensity in Transcranial Magnetic Stimulation (TMS) Studies

Journal of Ect, Dec 1, 2001

Nuclear Medicine Communications, Apr 1, 1999

Australasian Psychiatry, Dec 20, 2018

Cover Image, Volume 186B, Number 8, December 2021

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Efficacy and Safety of Repeated Subcutaneous Ketamine Injections for Treatment Resistant Depression - The KADS Study: A Randomised, Double-Blind, Comparator-Controlled Trial

Social Science Research Network, 2022

Translational Psychiatry

JAMA Psychiatry, 2021

European Neuropsychopharmacology, 2019

Acta Psychiatrica Scandinavica, 2016

Non Invasive Brain Stimulation Therapy Restores Neuroplasticity in Depression

Brain Stimulation, 2015

Sub-typing depression, II. Clinical distinction of psychotic depression and non-psychotic melancholia

Psychological Medicine, 1995

Sub-typing depression, I. Is psychomotor disturbance necessary and sufficient to the definition of melancholia?

Psychological Medicine, 1995

Sub-typing depression, III. Development of a clinical algorithm for melancholia and comparison with other diagnostic measures

Psychological Medicine, 1995

The Lancet, 2012