The British Journal of Psychiatry (13)
BJPsych Advances (2)
The Royal College of Psychiatrists (15)
Clinical indicators of treatment-resistant psychosis
Sophie E. Legge, Charlotte A. Dennison, Antonio F. Pardiñas, Elliott Rees, Amy J. Lynham, Lucinda Hopkins, Lesley Bates, George Kirov, Michael J. Owen, Michael C. O'Donovan, James T.R. Walters
Journal: The British Journal of Psychiatry , FirstView
Published online by Cambridge University Press: 03 June 2019, pp. 1-8
Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank
Kimberley M. Kendall, Matthew Bracher-Smith, Harry Fitzpatrick, Amy Lynham, Elliott Rees, Valentina Escott-Price, Michael J. Owen, Michael C. O'Donovan, James T.R. Walters, George Kirov
Journal: The British Journal of Psychiatry / Volume 214 / Issue 5 / May 2019
Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.
We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.
We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.
Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.
CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.
Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort
Valentina Escott-Price, Daniel J. Smith, Kimberley Kendall, Joey Ward, George Kirov, Michael J. Owen, James Walters, Michael C. O'Donovan
Journal: Psychological Medicine , First View
Published online by Cambridge University Press: 04 March 2018, pp. 1-6
There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this 'season of birth' effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.
Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.
Neither genetic measure was associated with season or month of birth within the UKBB sample.
As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.
Authors' reply
George Kirov, Maria Atkins
Journal: The British Journal of Psychiatry / Volume 209 / Issue 1 / July 2016
Published online by Cambridge University Press: 02 January 2018, pp. 84-85
Evaluation of cumulative cognitive deficits from electroconvulsive therapy
George G. Kirov, Laura Owen, Hazel Ballard, Adele Leighton, Kara Hannigan, Danielle Llewellyn, Valentina Escott-Price, Maria Atkins
Journal: The British Journal of Psychiatry / Volume 208 / Issue 3 / March 2016
Electroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but widely held concerns about memory problems may limit its use.
To find out whether repeated or maintenance courses of ECT cause cumulative cognitive deterioration.
Analysis of the results of 10 years of cognitive performance data collection from patients who have received ECT. The 199 patients had a total of 498 assessments, undertaken after a mean of 15.3 ECT sessions (range 0–186). A linear mixed-effect regression model was used, testing whether an increasing number of ECT sessions leads to deterioration in performance.
The total number of previous ECT sessions had no effect on cognitive performance. The major factors affecting performance were age, followed by the severity of depression at the time of testing and the number of days since the last ECT session.
Repeated courses of ECT do not lead to cumulative cognitive deficits. This message is reassuring for patients, carers and prescribers who are concerned about memory problems and confusion during ECT.
Lo que un psiquiatra necesita saber sobre variaciones en el número de copias [translation of "What a psychiatrist needs to know about copy number variants" by Rodolfo Zaratiegui]
George Kirov, Elliott Rees, James Walters
Journal: BJPsych Advances / Volume 21 / Issue 3 / May 2015
Published online by Cambridge University Press: 02 January 2018, E1
What a psychiatrist needs to know about copy number variants
Copy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders.
Elliott Rees, James T. R. Walters, Michael J. Owen, George Kirov
Published online by Cambridge University Press: 02 January 2018, p. 78
Analysis of copy number variations at 15 schizophrenia-associated loci
Elliott Rees, James T. R. Walters, Lyudmila Georgieva, Anthony R. Isles, Kimberly D. Chambert, Alexander L. Richards, Gerwyn Mahoney-Davies, Sophie E. Legge, Jennifer L. Moran, Steven A. McCarroll, Michael C. O'Donovan, Michael J. Owen, George Kirov
Journal: The British Journal of Psychiatry / Volume 204 / Issue 2 / February 2014
A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.
To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.
We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.
We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10−4).
We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.
Creativity and mental disorder
George Kirov, Geoffrey Miller
Journal: The British Journal of Psychiatry / Volume 200 / Issue 4 / April 2012
Published online by Cambridge University Press: 02 January 2018, p. 347
Quick recovery of orientation after magnetic seizure therapy for major depressive disorder
George Kirov, Klaus P. Ebmeier, Allan I. F. Scott, Maria Atkins, Najeeb Khalid, Lucy Carrick, Andrew Stanfield, Ronan E. O'Carroll, Mustafa M. Husain, Sarah H. Lisanby
Journal: The British Journal of Psychiatry / Volume 193 / Issue 2 / August 2008
Magnetic seizure therapy, in which seizures are elicited with a high-frequency magnetic field, is under development as a new treatment for major depressive disorder. Its use may be justified if it produces the antidepressant effects of electroconvulsive therapy (ECT), coupled with limited cognitive side-effects.
To evaluate the usefulness of a new 100 Hz magnetic seizure therapy device.
We induced seizures with 100 Hz magnetic transcranial stimulation in 11 patients with major depressive disorder during one session of a regular course of ECT. Recovery times after seizures induced by magnetic seizure therapy and ECT were compared.
Seizures could be elicited in 10 of the 11 patients. Stimulation over the vertex produced tonic-clonic activity on 9 out of 11 occasions. Stimulation over the prefrontal midpoint elicited seizures on 3 out of 7 occasions. The mean duration of magnetically induced seizures was 31.3s, ranging from 10 to 86s. All patients had an exceptionally quick recovery of orientation: mean of 7 min 12s (s.d.=2 min 7 s, range 4 min 20s to 9 min 41 s). The recovery times were on average 15 min 35s shorter with magnetic seizure therapy than with ECT in the same patients (paired-samples t-test: P<0.0001). Patients reported feeling less confused after magnetic seizure therapy. Side-effects were confined to myoclonic movements, associated with the use of etomidate.
The new 100Hz magnetic stimulator elicits seizures in the majority of patients when administered over the vertex. Magnetic seizure therapy was associated with shorter recovery times and less confusion following treatment. Subsequent work will be required to assess the safety and effectiveness of magnetic seizure therapy in the treatment of depression.
Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: Case-control study of over 3000 individuals from the UK
Elaine K. Green, Rachel Raybould, Stuart Macgregor, Sally Hyde, Allan H. Young, Michael C. O'Donovan, Michael J. Owen, George Kirov, Lisa Jones, Ian Jones, Nick Craddock
Journal: The British Journal of Psychiatry / Volume 188 / Issue 1 / January 2006
Brain-derived neurotrophic factor (BDNF) influences neuronal survival, proliferation and plasticity Three family-based studies have shown association of the common Valine (Val) allele of the Val66Met polymorphism of the BDNF gene with susceptibility to bipolar disorder.
To replicate this finding.
We genotyped the Val66Met polymorphism in our UK White bipolar case-control sample (n=3062).
We found no overall evidence of allele or genotype association. However, we found association with disease status in the subset of 131 individuals that had experienced rapid cycling at some time (P=0.004). We found a similar association on re-analysis of our previously reported family-based association sample (P<0.03, one-tailed test).
Variation at the Val66Met polymorphism of BDNF does not play a major role in influencing susceptibility to bipolar disorder as a whole, but is associated with susceptibility to the rapid-cycling subset of the disorder.
Randomised controlled trial of compliance therapy: 18-month follow-up
Roisin Kemp, George Kirov, Brian Everitt, Peter Hayward, Anthony David
A randomised controlled trial was conducted in an acute treatment setting to examine the effectiveness of compliance therapy, a brief pragmatic intervention targeting treatment adherence in psychotic disorders, based on motivational interviewing and recent cognitive approaches to psychosis.
Seventy-four patients with psychotic disorders according to DSM–III–R criteria recruited from consecutive admissions to an acute in-patient unit, received 4–6 sessions of either compliance therapy or non-specific counselling, and were followed-up over 18 months. The principal outcome measures were observer-rated compliance, attitudes to treatment, insight and social functioning.
Significant advantages were found for the compliance therapy group post-treatment on measures of insight, attitudes to treatment and observer-rated compliance which were retained over the follow-up period. Global social functioning improved relatively more over time in the compliance therapy group compared with the control group. Survival in the community prior to readmission was significantly longer in the compliance therapy group.
The results support the effectiveness of compliance therapy in improving functioning and community tenure after an acute psychotic episode.
Cost-effectiveness evaluation of compliance therapy for people with psychosis
Andrew Healey, Martin Knapp, Jack Astin, Jennifer Beecham, Roisin Kemp, Anthony David, George Kirov
Non-compliance rates with antipsychotic medication can be high, and the personal and societal costs are considerable. A new psychological intervention, compliance therapy seeks to improve compliance and patient outcomes and reduce treatment costs.
A randomised controlled study examined the cost-effectiveness of compliance therapy compared to nonspecific counselling over 18 months for 74 people with psychosis admitted as inpatients at the Maudsley Hospital. Bivariate and multivariate analyses were conducted to test for differences and to explore inter-patient cost variations.
Compliance therapy is more effective and is no more expensive. Consequently, compliance therapy is more cost-effective than non-specific counselling at six, 12 and 18 months.
There are compliance, outcome and cost-effectiveness arguments in favour of compliance therapy in preference to non-specific counselling.
No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene
Nick Craddock, Gillian Spurlock, Peter Mcguffin, Michael J. Owen, Marika Nosten-Bertrand, Frank Bellivier, Rolando Meloni, Marion Leboyer, Jacques Mallet, Lesley Mynett-Johnson, Valerie Murphy, Patrick Mckeon, George Kirov, John Powell, Hiroshi Kunugi, David Collier, Monica Larosa, Benedetta Nacmias, Sandro Sorbi, Sibylle Schwab, Manfred Ackenheil, Wolfgang Maier, Biomed European Bipolar Collaborative Group
Journal: The British Journal of Psychiatry / Volume 170 / Issue 6 / June 1997
There is compelling evidence for the existence of susceptibility genes for bipolar disorder. Association studies using functional DNA variations are an important approach for identifying these genes. The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters and is a candidate for involvement in bipolar disorder. Recently a common functional genetic polymorphism that underlies population variation in COM Tactivity has been elucidated and a simple assay developed.
In a collaboration involving seven European centres, we have undertaken an association study of this functional polymorphism in 412 unrelated West European caucasian DSM - III-R bipolar patients and 368 ethnically matched controls.
We found no evidence of allelic or genotypic association.
We can conclude that variation at this functional polymorphism does not make an important contribution to bipolar disorder in the Western European population. Future studies using this powerful experimental approach can be expected to contribute to identification of bipolar susceptibility genes.
'Slowly progressive schizophrenia'
George Kirov
Journal: The British Journal of Psychiatry / Volume 157 / Issue 3 / September 1990