SERT, SUBTYPES OF DEPRESSION AND MORE…

ANDREA MARQUEZ LOPEZ MATOINSTITUTE OF BIOLOGICAL PSYCHIATRY

BUENOS AIRES. ARGENTINA www.ipbi.com.ar

SERT o NO SERT DEPRESIVO

International Congress of Affective Disorders Mendoza, Argentina. 2007

To be or not to be depressed

The author declares no

conflicts of interest

including any financial, personal

or other relationship

with other people or organizations

that could have inappropriately influenced her work

SERT and subtypes of Depression

• The objective of this presentation is to determine if SERT allelic variations are related to stress triggered depression and may prone to the presentation of any particular subtype of depression or may influence the therapeutical response to antidepressants families

• Published studies are discussed and compared

Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, Mc Clay J, Mill J, Martin J, Braithwaite A, Poulton R.Science. 2003 Jul 18;301(5631):291-3

The Bible of enviroment-gene interaction

THE BIBLE OF E-G INTERACTION

- M&M• 847 (age 3-18) in a long-term study • Separated into groups based on their

SERT promoter genotype: -147 homozygous for the short ("s") allele -265 homozygous for the long ("l") allele -435 heterozygous

-Histories of 14 stressful life events at ages 21-26 were determined (finances, housing, health, relationships, etc)

Caspi 2003

THE BIBLE OF E-G INTERACTION

- R & D• The 3 genotype groups had experienced similar

exposure to stress

• The effect of life events on self-reports of depressive symptoms at age 26 was significantly stronger in individuals carrying at least one "s" allele

• Carriers of the "s" allele, but not “l/l" homozygotes, who had stresful life events between ages 21 and 26 had increased depressive symptoms

Caspi 2003

Stolen fromAPA 2009

What does this pioneer work reveals ?

• Stressful life events predicted major-depression diagnoses among "s"-allele carriers

• Childhood maltreatment predicted adult depression only among "s"-allele carriers

• Environment-gene interaction increases vulnerability to major depression

Association between SERT gene promoter and Association between SERT gene promoter and behavioral responses to tryptophan depletion in behavioral responses to tryptophan depletion in healthy women with and without family history of healthy women with and without family history of

depressiondepression-M & M

• 24 women with familial history of depression • 21 women without familial history of depression• Tryptophan free diet

-R & D• All had lower plasmatic tryptophan• x/x allele had depression (non dependant on FTD)• x/l had depression, only when having FTD• x allele and family history are aditive factors

Neumeister A; Konstantinidis A . Arch Gen Psychiatry 2002

A polimorphism (5-HTTLPR) in SERT A polimorphism (5-HTTLPR) in SERT gene is associated with depression gene is associated with depression

subtypes in SADsubtypes in SAD

-M & M • 138 seasonal depressive patients• 146 normal controls

-R & D• Melancholic subtype is associated with l allele

( P= 0,0038)• Atypical subtype is associated with x allele

(P= 0, 207)Willeit M; Praschak-Rieder N Kasper S. Mol Psychiatry 2003

Association between violent suicidal Association between violent suicidal behavior and low activity allele of the behavior and low activity allele of the

SERTSERT

-M & M• 51 caucasian with violent suicidal attempts• 139 depressives without suicidal attempts

-R & D• x/x allele associated only with first group• Odd ratio between x/x vs l/l is 3.46 (95% CI)

Courter P. Mol Psychiatry 2001

A polymorphism in the 5HTTLPR gene is not associated with suicidal behavior

-M & M • 124 depressive inpatients• 185 controls free of DSM axis I/II diagnosis

-R & D• No difference between SERT alleles in both groups• No difference according to suicidal subtype, clinical severity, unipolar, bipolar or Pers Disorder

-Opossite conclusion to other studies

Rujescu D; Giegling A . Psychiatry Genet 2001

Possible association between SERT gene polymorphism and violent suicidal behavior in

mood disorders

Bellivier F; Szoke A. Biol Psychiatry 2000

-M & M •237 unipolar or bipolar depressives•99 with suicidal attempts•26 with violent suicidal attempts •187 normal controls

-R & D•No difference between depressives with or without suicidal attempts•Clear relation between x/x allele and violence

Enhancement of serotonin uptake by cortisol: a possible link between stress and depression

-Rationale• Hypercortisolemia in depression may be

related to serotonin uptake in vivo and in vitro (rats, neuronal models in rabbit, peripherical lymphocytes in humans)

-M &M• Comparison between cortisol levels and SERT

alleles-R & D

• No relation found

Tafet GE; Toister-Achituv M . Cogn Affect Behav NSc 2001

Ovarian steroid regulation of SERT binding, distribution, and function in

female macaques

-M &M

• Ovariectomized female monkeys

• E2, PG, both or placebo administered to rafe (IM)

-R & D

• No change in number of serotonin nucleus

• Only E2 increased serotonin binding sites (measured by citalopram) in different hypo-thalamic & extrahypothalamic structures

-Ovaric horm. induce expression & distribution of SERTLu NZ; Eshleman AJ Mol Psychiatry 2003

SERT gene polymorphism and antidepressant response

-M & M • 120 corean depressive patients • 252 corean controls • Fluoxetine or paroxetine treatment for

6 weeks

-R & D• Only x/x allele patients respond succesfully • 83.3% with x/l did not improve

Kim DK; Lim SW Neuroreport 2000

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI

treatment trial outcome-M & M

• 51 fluoxetine treated depressive patients (10 to 40 mgs)

• 50 placebo treated patients • HAM D at start point and at 18 weeks

(evaluation each 2 weeks)

-R & D• l/l SERT allele had a better response both to

fluoxetine and to placebo • No dose relation

Rausch JL; Johnson ME. Biol Psychiatry 2002

Efficacy of paroxetine in depression is influenced by a functional polymorphism in

the promoter of SERT gene

- M & M • 102 patients with paroxetine treatment at variable dosing • HAM D at start point and week 12

-R & D• x/x allele was associated to non remission at

week 12

Zanrdi R; Benedetti F J . Clin Psycopharmacol 2000

Efficacy of fluvoxamine in depression is influenced by a functional polymorphism in

the promoter of SERT gene

- M & M

• 102 major depressive patients treated with fluvoxamine

-R & D• Less clinical improvement at 6 weeks if

predominance of x allele

Smeraldi E. Psychiatric Research 1997

Investigation of 5HT-related genes in antidepresssant response

-M & M • 96 depressive patients on fluoxetine

treatment for 12 weeks• Candidate genes studied : HTR1A, HTR2A,

HTR2C, MAO, SLC6A4, TPH1, TPH2-R & D

• HTR2A, TPH2 y MAO A predict better response to fluoxetine

• Allelic variances of SERT had less predictive trend on a better response to fluoxetine

Peters EJ; Slager SL. Mol Psychiatry 2004

5-HTTLPR polymorphism predicts non-remission in major depression treated with

citalopram

-M & M • 131 hispanic depressives • HAM D administered at start point and after

treatment (weeks 4 and 12 )

-R & D• x/x allele was strongly associated to non

remission at week 12• x/x allele was moderatly associated to non

response at week 4Arias B; Catalan R.J. Clin Psychopharmacol 2003

Alteration of serotonin transporter density and activity in Fibromyalgia

-M & M • 40 fibromyalgic patients• 38 normal controls • Platelet SERT expression and paroxetine binding

-R & D• Bmax was less in fibromyalgic• Kd had no variation between groups• Platelet Vmax was increased in fibromyalgia• Clinical severity correlated with Bmax and Vmax

alterations

5HTP alleles and anxiety trait

Hariri AR; Weinberger D 2003

Individuals with the hypofunctioning (s/s) allele have a five fold increase in sensitivity of the amygdala to fearful or threatening stimuli

Individuals with at least one copy of the short (x/x, x/l) allele have increased coupling of the amygdala and the prefrontal activity

Heinz R 2005

Change in fear responsiveness due to short alleles may underline an increased risk for anxiety disorders Mc Naughan; Corr 2004

Stolen fromAPA 2009

Stolen fromAPA 2009

SERT alleles and ThalamusNegative Emotions I

-M&M• 49 dead persons• With or without psychiatric pathologies

-R & D• SERT x/x allele had a 20% greater pulvinar

nucleus with 20 % more cells• SERT x/l allele or SERT l/l allele had less

pulvinar size with less cell count

Dwight German, Biological Psychiatry 2006

SERT alleles and ThalamusNegative Emotions II

• Depressive patients had 31% more cells (neurons and connective cells) in the pulvinar nucleus

• Whole pulvinar was 16 % greater in depressed patients

• Both studies back the hypothesis that there are thalamic abnormalites in depression which are related to x/x alleles

Dwight German, Biological Psychiatry 2006

Association between thalamus volume and SERT

-M&M

• 54 thalamus tissue cuts• With or without psychiatric pathologies

-R & D• SERT s/s in 14 people• SERT I/I in 16• SERT s/s had 11% increase in pulvinar

British Journal of Psychiatry, 2008

Association between thalamus volume and SERT

• Major Depressives had 12% increase in lymbic thalamus

• Suicide was associated with increase in total thalamic volume (8%)

• Antidepressant treatment was associated with reduction of thalamicus volume (18%)

British Journal of Psychiatry, 2008

Interaction between SERTPR and stressful life events on response to antidepressant treatment

• 159 MDD and bipolar depressive inpatients• Had received venlafaxine for 6 weeks• Wash out and fluvoxamine 150 a 300 mgs/d• Improvement (50% in HAMD: response)

• SERTPR l/l without SLE• SERT l/l with previous SLE• SERT x/l or x/x without SLE• SERT x/x or x/l with previous SLE

Mandelli L, Marino E, et al. Eur Neuropsychopharmacol. 2009

Serotonin transporter polymorphism predicts waking cortisol in young girls

• 84 never disordered girls (1/3 at elevated risk for depression)

• Girls homozygous for the short allele had higher levels of waking (but not afternoon or evening) cortisol than did their long-allele counterparts

• Suggests genetic susceptibility to HPA-axis dysregulation is detectable in individuals as young as 9 years of age

Chen M, Joormann J, Hallmayer J, Gotlib I. Psychoneuroendocrinology 2009

SERT studies SUMMARY

• 70% of population has x/x or x/l SERT alleles• 70% has vulnerability to stress-triggered depression• SERT hypofunction is observed in several

pathologies with depressive symptomatology• SERT transcription is related to several hormonal

factors • SERT hypofunction is predictor to poor response to

SSRI• SERT hypofunction leads to vulnerability to anxiety• SERT hypofunction leads to vulnerability to MDD

ArtificialFertilization world

Discharge embryos with

genetic predisposition to

•Bipolar• ADD

• other mental

disorders• CVD

• Miopia

DNA per se does not explain

evolution

Enviromental cues

are always necessary

•

•

GATTACAGATTACA

THANK YOU

ANDREA MARQUEZ LOPEZ MATOINSTITUTE OF BIOLOGICAL PSYCHIATRY

BUENOS AIRES. ARGENTINA www.ipbi.com.ar

www.aapb.org.ar