JOURNAL CLUB

Dr Ravi SoniSenior Resident

Dept. of Geriatric Mental HealthKGMC

GENERAL INFORMATION TITLE : Oestrogen receptor polymorphisms and late-life depression SOURCE:

– The British Journal of Psychiatry (2011)199, 126–131. doi: 10.1192/bjp.bp.111.091751– Impact factor: 6.606

AUTHORS:• Joanne Ryan, PhD • Jacqueline Scali, MsC• Isabelle Carrie` re, PhD • Karine Peres, PhD• Olivier Rouaud, MD• Pierre-Yves Scarabin, MD, PhD• Karen Ritchie, PhD• Marie-Laure Ancelin, PhD Joanne Ryan, PhD, Inserm U1061 and Universite´ Montpellier 1, Montpellier and Fondation

FondaMental, Hopital Albert Chenevier, Creteil, France• Correspondence: Joanne Ryan, Inserm U1061, Hoˆ pital La Colombie` re, 39 Avenue Charles

Flahault, BP 34493, 34093 Montpellier Cedex 5, France. Email: joanne.ryan@inserm.fr

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GENERAL INFORMATION • First received 11 Jan 2011• Final revision 22 Mar 2011• Accepted 17 May 2011• Reprints/Permissions: permissions@rcpsych.ac.uk• Type of article: Free PMC article (original research)• Type of study: multicenter longitudinal study• Ethical approval: Ethical Committee of the University Hospital of

Kremlin-Biceˆtre (France) • Acknowledgement: We thank the Ge´ nopoˆ le of Lille, the

Laboratories of Biochemistry of the University Hospitals of Dijon and Montpellier, the Town Council of Dijon and the Conseil Ge´ ne´ ral of Coˆ te d’Or.

• Competing interests: The authors declare that they have no competing interests.

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Abstract • Background:

– Evidence suggests a role for oestrogen in depression but the involvement of oestrogen receptor polymorphisms remains unknown.

• Aim:– To determine the association between oestrogen receptor

polymorphisms and late-life depression and the modifying effect of hormone treatment.

• Methods:– Depression was assessed using the Mini-International

Neuropsychiatric Interview, according to DSM-IV criteria and the Centre for Epidemiologic Studies – Depression Scale.

– The association between oestrogen receptor α and β (ER-α and ER-β) polymorphisms with severe depression was examined in 6017 community-dwelling elderly people using multivariate logistic regression. 4

Abstract

• Conclusions: Oestrogen receptor polymorphisms are associated with severe late-life depression risk in women only.

Results: In women, the ER-α rs2234693 and rs9340799 polymorphisms were significantly associated with the risk of late-life depression. The A allele of ER- β rs1256049 increased the risk of depression, but only for non-current users of hormone treatment. In men, only the ER-β rs4986938 polymorphism showed a weak association with depression risk.

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• Background• Methods:– Study population – Measures of depression– Oestrogen receptor polymorphism– Other measures– Statistical Analysis

• Results:• Discussion:• Conclusion:

Article in detail

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BACKGROUND

• Elderly depression and oestrogen: Depression is a major public health problem with increased risk of comorbidity and mortality, especially in elderly people.– Evidences suggest a role for oestrogen in depression.– Oestrogen has been shown to modulate neurotransmitter

turnover and enhance serotonergic activity– Oestrogen-containing hormone treatment is also effective in

improving the depressed mood of perimenopausal women

• Surprisingly, very few studies are done regarding association between oestrogen receptor polymorphism and late life depression– Polymorphisms of these receptors have been associated,

although not consistently, with oestradiol levels, vasomotor symptoms and other brain disorders such as Alzheimer’s disease.

• Elderly depression and oestrogen: Depression is a major public health problem with increased risk of comorbidity and mortality, especially in elderly people.– Evidences suggest a role for oestrogen in depression.– Oestrogen has been shown to modulate neurotransmitter

turnover and enhance serotonergic activity– Oestrogen-containing hormone treatment is also effective in

improving the depressed mood of perimenopausal women

• Surprisingly, very few studies are done regarding association between oestrogen receptor polymorphism and late life depression– Polymorphisms of these receptors have been associated,

although not consistently, with oestradiol levels, vasomotor symptoms and other brain disorders such as Alzheimer’s disease.

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BACKGROUND

• PROPOSAL BY CURRENT AUTHORS: – Genetic variation in oestrogen receptors may also

influence a person’s susceptibility to developing depression and may modify oestrogen signaling and thus the effect of hormone treatment on mood, which is still to be examined

– AIM: to investigate the association between severe late-life depression and five ER-α and ER-β polymorphisms.

• PROPOSAL BY CURRENT AUTHORS: – Genetic variation in oestrogen receptors may also

influence a person’s susceptibility to developing depression and may modify oestrogen signaling and thus the effect of hormone treatment on mood, which is still to be examined

– AIM: to investigate the association between severe late-life depression and five ER-α and ER-β polymorphisms.

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METHODS: Patients selectionPatients • Data collected at baseline from the Three City

(3C) Study, an ongoing multicentre longitudinal study•Recruitment of the cohort took place between 1999 and 2001 •Eligible participants (aged over 65 years and non-institutionalized) •Randomly selected from the electoral polls in three cities

37% of the individuals contacted agreed to participate

Total 9097 dementia free participants recruited

• Exclusion: – Those who were not assessed for current and previous psychiatric symptomatology [n=953]– Those who did not provide blood samples for genotyping analysis [n=1291]– Those who have incomplete genotypic data [n=237]– Those who have missing data covering key covariates [n=599]

Participants excluded from this analysis were significantly more likely to have current depression (chi sq. = 73.9, P<0.0001) and were more likely to be female (chi sq. = 38.7, P<0.001); however, there was no significant difference in terms of the distribution of oestrogen receptor polymorphism genotypes.

Total 6017 remain after exclusion

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METHODS: interview • After consent, interview using structure proforma• Diagnosis: MINI-INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW for diagnosis of

current and previous episode of major depressive disorder according to DSM-IV TR • Severity: Centre for Epidemiology Studies – Depression Scale (CES-D).• Participants with a DSM-IV diagnosis of current major depressive disorder or those

scoring above the clinical cut-off for ‘probable’ depression (CES-D≥23) were classified as having current severe depression in this analysis.

• Current use of antidepressants, validated by presentation of the prescription or the medication itself, was also considered as a covariate in the analysis.

Oestrogen receptor polymorphism: •DNA was extracted from white blood cells and stored at -80 C•Genotyping was performed by competitive allele-specific polymerase chain reaction (PCR) single-nucleotide polymorphism (SNP) genotyping system(KASPar).•The amplified PCR products were analysed by fluorescence scanning in a BMG labtech Pherastar scanner•Five SNPs with potential causal associations with the diseases are: ER-α rs2234693 (otherwise known as PvuII) and rs9340799 (XbaI), ER-β rs1256049 (AluI), rs4986938 (RsaI) and rs1271572 (in the promoter region of the gene). 10

METHODS: interview • Other assessments:

– BMI was calculated– Physical limitations counted– Socio-economic factors: Education, Economic class, Council Tax

Band, and living arrangement– Mini Mental State Examination (MMSE)- score of ≤26– Questionnaire for sleeping habits to define insomnia– Current use hormone treatment, baseline – Detailed medical history through questionnaires– All the drugs used within previous month– Fasting blood samples– Questionnaires for their vascular disease, chronic illnesses,

hypercholesterolemia, hypertension and thyroid problems or cancer diagnosis within previous two years

Participants were classified as having comorbidity if they suffered from vascular disease, more than one chronic illness or a recent cancer. 11

METHODS: statistical analysis– Chi Sq. test was used to compare the observed allele frequencies with

those expected – t-test, ANOVA and chi sq. Tests were used to examine the association

between baseline socio-demographic and clinical variables with both depression and oestrogen receptor polymorphisms

– Due to statistically significant interaction with gender and depression, all subsequent analyses were undertaken separately for males and females

– Logistic regression method- Genotype frequencies of the oestrogen receptor polymorphisms were compared for participants with depression and those without using logistic regression models

– Adjustment was made for covariates that were significantly associated with depression in this sample and remain significant in the final multivariate models

– The potential interaction between oestrogen receptor polymorphisms and the use of oestrogen-containing hormone treatment in women was also considered

– Used SAS version 9.1 for Windows for all of the analyses and all tests were two-tailed, with a significance level of P<0.05.

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RESULTS: Study Profile 37% of the individuals

contacted agreed to participate

Total 9097

N=6017

Men n=2492 Women n=3525

Exclusion

• Women were significantly more likely to use antidepressants, to have current depressive symptoms and to have a current or previous diagnosis of major depressive disorder

Overall, 564 participants were diagnosed with current severedepression (CES-D≥23 or current major depressive disorder), with a higher prevalence rate in women compared with men

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RESULTS: Study Profile

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RESULTS: Study ProfileTABLE:1• Participants ranged in age from 65 to 96 years with a mean of

73 years. • Men and women differed significantly on all socio-

demographic and health variables examined, with the exception of age.

• Women were significantly more likely to use antidepressants, to have current depressive symptoms and to have a current or previous diagnosis of major depressive disorder

• Overall, 564 participants were diagnosed with current severe depression (CES-D≥23 or current major depressive disorder), with a higher prevalence rate in women compared with men

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RESULTS: oestrogen receptor polymorphism genotype frequencies according to current depression status

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RESULTS: oestrogen receptor polymorphism genotype frequencies according to current depression status

TABLE-2– The overall distribution of genotypes in both genders was

not significantly different except in the case of the ER-b rs1271572 polymorphisms in women (chi sq. = 5.7, P= 0.02).

There was no significant difference in the genotype distribution between men and women, although women were more likely to be heterozygous for ER-b rs4986938 (49.6% of women overall had the GA genotype compared with 46.6% of men, chi sq.=5.7, P=0.06)

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RESULTS:

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RESULTS: Adjusted logistic regression model for association between oestrogen receptor polymorphisms and current severe depression

• In men, the only borderline significant association was a 1.7 times increase in current severe depression with the AA versus the GG genotype of ER-β rs4986938. • None of the other polymorphisms showed any significant association with depression in men.

• Among women however, those homozygous CC for the ER-α rs2234693 polymorphism were 40% less likely to have current severe depression compared with homozygous TT women. • The findings concerning the rs9340799 polymorphism were almost identical, with women having the GG genotype significantly less likely to have late-life depression compared with women with the AA genotype.

• In terms of the ER-β, women with at least one A allele of the rs1256049 polymorphism were more likely to have current severe depression, but this was at the limit of statistical significance. • The other two ER- β polymorphisms were not associated with late-life depression. 19

RESULTS: Oestrogen receptor vs hormone treatment interaction

• There was a non-significant trend for an interaction between ER-β rs1256049 and current hormone treatment

Subsequent analysis stratified by current hormone treatment use revealed that women who were not using treatment (n = 2986) were significantly more likely to have current severe depression with the GA/AA genotype (odds ratio (OR) = 1.72, 95% CI 1.17–2.50, P = 0.005)

In contrast, among women who were using hormone treatment (n = 539), the GA/AA genotype was not associated with the risk of severe depression (OR = 0.69, 95% CI 0.23–2.08, P= 0.51).

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DISCUSSION

• Main study result: – found significant gender-specific associations between polymorphisms of ER-a

and ER-b with severe late-life depression. – The results also provide some evidence of an interaction between hormone

treatment and one of the ER-b polymorphisms, which modified a woman’s risk of depression.

• Association between ER-a polymorphisms and severe depression in women – Results of the previous studies were mixed (study size, population and

depression criteria)– In SWAN and Rotterdam – no significant association (moderate depression)– Study of 106 korean women and 126 chinese midlife women studies have

shown significant associations.– In this study of 3525 elderly women, the CC and GG genotypes of the

rs2234693 and rs9340799 polymorphisms respectively were associated with a significant decrease in current severe depression

– In post hoc analysis, study did not find a significant association with these ER-a polymorphisms and moderate depressive symptoms alone (CES-D≥16).

– The findings thus relate specifically to a severe clinical level of current depression.

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DISCUSSION

• Potential interaction between ER-b polymorphism and hormone treatment– There is one report of a non-significant association between another polymorphism (rs1256030) and

moderate depressive symptoms (CES-D516) in 1435 midlife women– in a Korean study of 43 women with postmenopausal depression and 63 controls no significant

association was found with rs1256049 or rs4986938.– In our study we find that the ER-b rs1256049 polymorphism was significantly associated with an

increased likelihood of severe depression in women, but only for those who were non-hormone treatment users.

– No significant association was observed for women who were currently using hormone treatment.

– finding provides some preliminary evidence that hormone treatment could be beneficial for certain genetically vulnerable women, by reducing the risk of depression associated with the ER-b

rs1256049 polymorphism.

• Oestrogen receptor polymorphisms and depression in men– Study found no significant association between ER-a polymorphisms and moderate or

severe depression in men, in accordance with the two previous studies that have been conducted.

– Study reports here that the AA allele of the ER-b rs4986938 may increase the likelihood of depression specifically in men, although this was of borderline significance.

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DISCUSSION

• Biological hypothesis linking oestrogen receptors and depression– ER-a polymorphisms examined in this study have been associated with other

brain disorders, such as cognitive decline and Alzheimer’s disease, although not consistently

– These polymorphisms have also shown significant associations with oestradiol levels in postmenopausal women (lower oestradiol with the T (rs2234693) and A (rs9340799) alleles), and in a similar manner with bone density and fractures (higher bone mass density and lower fractures for the rs9340799 genotype GG).

– Distinct genetic vulnerability to depression for men and women.– Different polymorphisms of ER-b increased the likelihood of severe

depression in men and women, whereas in women, only ER-a polymorphisms were associated with late-life depression.

– Although males and females have a similar distribution of ER-a and ER-b in the brain, there appear to be differences in the level of expression of these receptors in various regions.

– Study results may partly account for gender differences in depression prevalence and highlight the need for a gender-specific approach to the development of novel hormone-based therapies.

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Study limitations and strengths• Limitations:

– The relatively low response rate, • which limits the ability to generalize these findings as study volunteers tend to be

better educated and healthier than the overall population

– Participants diagnosed with probable/possible dementia at inclusion (n = 217) were excluded from this analysis to minimize recall bias.• Such individuals may also have higher rates of depressive symptoms this could

have decreased the overall power of the study, possibly underestimating the associations found.

– Possible prescription bias in relation to women who are given hormone treatment

– Study reports associations between oestrogen receptor polymorphisms and the prevalence of late-life depression, but have not differentiated the independent associations with depression incidence and disease duration.

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Study limitations and strengths• Strengths:

– strengthened by its sample size and population based design, as well as the inclusion of both men and women to enable the assessment of independent gender-specific associations.

– Depression was assessed by trained staff using two distinct measures, including a structured diagnostic interview, which have been validated in the general population.

– Severity ratings allowed us to examine separately the relationship between moderate depressive symptoms and severe depression, with oestrogen receptor genotypes.

• findings suggest the possibility that some women may be genetically more susceptible than others to the psycho-protective effects of hormone treatment.• This could have important clinical applications, suggesting the potential for offering tailored hormonal therapies based on genetic markers for the treatment of mood disorders in women, and perhaps men, via the development of oestrogen-receptor selective effectors. 25

Critical appraisal

• TITLE OF ARTICLE:– Appear confusing– Title does not say about what they want to study– There is no mention of hormone treatment

interaction with polymorphism

TITLE Oestrogen receptor polymorphisms and late-lifedepression

SUGGESTION Association between Oestrogen receptor polymorphisms and late-lifedepression

Interaction of oestrogen receptor polymorphism with both late life depression and current hormone treatment

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Critical appraisal

• Authors: – Conflict of interest declared– Funding is done from multiple sources like, universities, pharma

industry and national research foundations

• Topic: – less likely to be helpful in clinical practice, it proposes for the

identification of the genetic markers for detection of polymorphism and possible hormone treatment interaction

– It can be foundation for further research in same topic

• Abstract:– Concise and comprehensive – Easy to follow

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Critical appraisal

Background of the study:– Relevant literature reviewed, improvised on previous

studies– ‘Several lines of evidence suggest a role for oestrogen in

depression.’-reference not given– Similar lack of references for 2 more statements in

background

Critical appraisal: • No clear cut hypothesis and support from other studies

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Critical appraisal

• Methodology:– Informative but too long– Well designed multicenter longitudinal cohort study– 599 participants are excluded on the basis of missing data about

key covariates- source of bias– Interview: done by trained staff and underwent multiple clinical

examination and blood sampling– Adequate blood sampling and storage measures were taken for

transport of sample to the laboratory– Probable depression defined– Comorbidity is very well defined– Other variables have been taken care of– Statistics is done very well

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Critical appraisal

• Result:– Concise and easily understandable– Well arranged results in tables– Results are explained adequately according to tables,

however it looks complicated– Data of current hormone treatment interaction with

polymorphism is lacking in the tabular form, though mentioned in text?

– Overall, 564 participants were diagnosed with current severe depression

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Critical appraisal

• Discussion: – Study finding explained very precisely– Results are discussed under proper headings– Previous study findings quoted – Appropriate reasons are given for the counter intuitive

results.– In discussion under this ‘Biological hypothesis linking

oestrogen receptors and depression’ heading for 2 discussion findings references are not quoted.

– Authors have suggested their finding as unique and foundation for further research for similar hypothesis

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Critical appraisal

Limitations and strengths– Authors are aware of their study limitations and strengths– Various limitations given, that looks relevant – They have also said that exclusion of participants is a

source of bias– Independent association of depression incidence and

disease duration to the polymorphism is not studied– Population based design and study size are major

strengths

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Final comments

• Research finding is not helpful for the clinical practice, results require replication of findings and support from the future studies

• Title is confusing and lacking the relevance• Various statements in background information and discussion are not

given references• Data is missing for multivariate analysis in tabular form for interaction

between polymorphism and current hormone treatment• Population cohort is recruited in 1999-2001 and study published in 2011.

what take so long? Analysis of data?• Exclusion of large number of participants?

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C.S.M. Medical University UP, Lucknow C.S.M. Medical University UP, Lucknow INDIA INDIA

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