Monoamine Oxidase in Major Depressive Disorder

Transcription

1 Handout for the Neuroscience Education Institute (NEI) online activity: Monoamine Oxidase in Major Depressive Disorder

2 Learning Objective Explain the role of monoamine oxidase in the neurobiology, etiology, and presentation of psychiatric illnesses, including depression

3 Major Depressive Disorder (MDD) Lifetime prevalence of MDD may be as high as 20% As many as 50% of patients are treatment resistant Approximately 20% of patients who do respond to treatment will relapse within 2 years Bschor T. Expert Rev Neurother 2010;10(1):77-86; Patten SB. BMC Psychiatry 2009;9:19.

4 Neural Circuits of Depression

5 The Monoamine Hypothesis of Depression Monoamine levels are reduced in patients with depression Dopamine (DA) Norepinephrine (NE) Serotonin (5HT) Decreased production, increased synaptic reuptake, or increased degradation? The most commonly used treatments (SSRIs, SNRIs) target reuptake transporters

6 Monoamine Oxidase (MAO) Primarily located on mitochondrial outer membranes in neurons, glia, and other cells ~70% of neuronal monoamine oxidase is MAO-A MAO-A is more often implicated in mental disorders Monoamine oxidase isozymes A B Substrates 5HT NE DA Tyramine DA Tyramine Phenylethylamine Tissue distribution Brain, gut, liver, placenta, skin Brain, platelets, lymphocytes The MAO Handbook. Carlsbad, CA: NEI Press; 2012; Jin Y et al. Int J Neuropsychopharmacol 2006;9:557-64; Johnson S et al. Neuropsychopharmacol 2011;36:

7 MAO-A Levels Adapt to Substrate Availability The treatment strategy of increasing monoamine availability may be counterproductive due to compensatory increases in MAO-A Sacher J et al. J Cereb Blood Flow Metab 2011; Epub ahead of print.

8 MAO is Elevated in MDD [ 11 C]-harmine positron emission tomography (PET) studies show 34% elevation in MAO-A Most prominent in prefrontal cortex and anterior cingulate cortex A significant elevation in MAO-A activity is found in the hypothalamus of suicide victims Du L et al. Neuroreport 2002;13(9):1195-8; De Luca V et al. Neurosci Lett 2005;383(1-2):151-4; Johnson S et al. Neuropsychopharmacol 2011;36: ; Meyer JH. Clin Pharm Ther 2012;91(2):201-14; Meyer JH et al. Arch Gen Psychiatry 2009;66(12):

9 MAO is Elevated in MDD Meyer JH. Clin Pharm Ther 2012;91(2):

10 SSRI Treatment Does Not Significantly Reduce MAO Levels The mismatch between monoamine levels raised by SSRI treatment and monoamine levels lowered by disease processes may contribute to a lack of response to SSRI treatment Meyer JH et al. Arch Gen Psychiatry 2009;66:

11 MAO Remains Elevated During Recovery Meyer JH et al. Arch Gen Psychiatry 2009;66:

12 MAO Elevation Predicts Depressive Relapse Meyer JH et al. Arch Gen Psychiatry 2009;66:

13 Modern Model of Extracellular Monoamine Loss During Major Depressive Disorder Healthy Untreated depression Depression treated with an SSRI Meyer JH. Clin Pharm Ther 2012;91(2): Treatment resistance? Risk of relapse?

14 Reactive Oxygen Species (ROS) MAO-A monoamine degradation produces ROS Accumulated ROS cause oxidative damage to mitochondria, leading to increased apoptosis Depressed patients show: Decreased mitochondrial ATP production Altered cerebral energy metabolism Mitochondrial dysfunction Signs of cell death and oxidative damage Some MAO inhibitors may be neuroprotective Andreazza AC et al. Arch Gen Psychiatry 2010;67(4):360-8; Johnson S et al. Frontiers Neurosci 2010;4:180.

15 MAO Polymorphisms Both MAO-A and MAO-B are located on the X chromosome Two well-studied polymorphisms in the MAO-A gene T941G Single nucleotide polymorphism MAOA-uVNTR 30 bp upstream variable number tandem repeat in the promoter region

16 T941G T allele Lower enzyme activity G allele Greater enzyme activity The G/G genotype is associated with: 75% greater MAO-A activity A greater number of depressive episodes Worse response to mirtazapine in females Pitychoutis PM et al. Curr Pharm Design 2010;16:

17 MAOA-uVNTR Short 3 repeat allele Lower expression of MAO-A Long 4 repeat allele Higher expression of MAO-A

18 MAOA-uVNTR Long Allele The long allele is: A risk factor for MDD Linked to worse outcomes in adult females exposed to severe childhood stress Associated with suicide in males with depression Predictive of worse response to fluoxetine treatment in females Du L et al. Neuroreport 2002;13(9):1195-8; Fan M et al. Psychiatr Genetics 2010;20:1-7; Gutiérrez B et al. Psychiatr Genetics 2004;14:203-8; Kinnally EL et al. Psychiatr Genetics 2009;19:126-33; Lung F-W. BMC Med Gen 2011;12(74):1-11; Pitychoutis PM et al. Curr Pharm Design 2010;16: ; Schulze TG et al. Am J Med Genetics 2000;96(6):801-3; Xu Z et al. J Affective Dis 2011;133:

19 Child Abuse, MAO-A, and Mental Health Women Nikulina V et al. Biol Psychiatry 2012;71(4):350-7.

20 MAO-A and COMT Catechol-O-methyltransferase (COMT) degrades dopamine and norepinephrine The met/met COMT genotype is associated with a 75% decrease in COMT activity Increased peripartum depression in patients with the combination of COMT (met/met) and the long MAOA-uVNTR allele COMT met/met + long MAOA-uVNTR allele is associated with an increased risk of suicide attempt in males De Luca V et al. Neurosci Lett 2005;383(1-2):151-4; Doornbos B et al. Prog Neuropsychopharmacol Biol Psychiatry 2009;33(7):

21 Regulation of MAO-A Expression R1 is an upstream transcriptional repressor of the MAO-A gene Binds to the MAO-A gene promoter Turns off the expression of MAO-A MAO-A Promoter MAO-A Gene X Chromosome Johnson S et al. Neuropsychopharmacol 2011;36: ; Thalmeier A et al. Int J Neuropsychopharmacol 2008;11(2):

22 Regulation of MAO-A Expression Reduced R1 May contribute to MAO-A-mediated cell death and monoamine deficiency Postmortem R1 levels Decreased by 37% in both treated and untreated patients with MDD Decreased in suicide victims Johnson S et al. Neuropsychopharmacol 2011;36: ; Thalmeier A et al. Int J Neuropsychopharmacol 2008;11(2):

23 MAO is Sexually Dimorphic Major depressive disorder is 2X more common in females 12-month prevalence 6.8% in women 3.4% in men MDD has a higher heritability in women (42% vs 29%) Possibly due to incomplete X-inactivation Symptom presentation Women: weight gain, hypochondriasis, somatic concerns Men: weight loss, alcohol dependence, substance abuse Kulkarnii J. Int Rev Psychiatry 2010;22(2):183-90; Pitychoutis PM, Papadopoulou-Daifoti Z. Int J Neuropsychopharmacol 2010;13:

24 Sexual Dimorphism of MAO Both testosterone and estradiol decrease MAO Leading to greater 5HT The MAO-A gene is on the X chromosome The MAO-A gene has an androgen (testosterone) response element Incomplete X-inactivation may lead to an increased expression of MAO in females Resulting in decreased 5HT MAO-A expression is regulated by a protein (SRY) produced from the Y chromosome Keating C et al. Int J Neuropsychopharmacol 2011;14:553-66; Meyers B et al. Neuroscience 2010;165:850-62; Wu JB et al. FASEB J 2009;23:

25 The Sex-Determining Region (SRY Gene) On the Y chromosome Acts as a molecular switch Triggers a cascade of molecular and cellular events Initiates the formation of male gonads Prohibits events that lead to the formation of female gonads

26 SRY Regulation of MAO-A Gene Expression S R MAO-A Promoter MAO-A Gene X Chromosome SRY Gene Y Chromosome

27 Postpartum Depression Postpartum blues affects 70% of new mothers 13% of new mothers will develop postpartum depression (PPD) During the early postpartum period, brain MAO-A increases by 43% The rise in MAO-A follows the rapid decrease in estradiol Estradiol levels drop 100- to 1000-fold following delivery Sacher J et al. Arch Gen Psychiatry 2010;67:

28 MAO is Elevated in Postpartum Depression Sacher J et al. Arch Gen Psychiatry 2010;67:

29 Monoamine Model of Postpartum Blues Pregnancy Delivery Days postpartum MAO-A levels in affect-modulating regions Estradiol levels Mood Sacher J et al. Arch Gen Psychiatry 2010;67:

30 Violence and Aggression Aggression and violent behavior are correlated with: Males High testosterone Low 5HT activity Low cortisol Hyperactivity in the amygdala Hypoactivity in the PFC Genetics account for ~50% of the risk for aggressive behavior Pavlov KA et al. J Appl Genetics 2012;53:61-82.

31 MAO-A: Warrior Gene? MAO-A gene expression is regulated by both testosterone and glucocorticoids MAO-A knockout mice and humans with an inactivating mutation in the MAO-A gene display increased aggression Males with the MAOA-uVNTR short allele have an increased risk for violent behavior Especially subsequent to childhood maltreatment The opposite is true for females Åslund C et al. Behav Genetics 2011;41:262-72; Fergusson DM et al. Br J Psychiatry 2011;198:457-63; Pavlov KA et al. J Appl Genetics 2012;53:61-82.

32 Sexual Dimorphism in the Relationship Between MAOA-uVNTR and Violence Åslund C et al. Behav Genetics 2011;41:

33 Response to Increased Testosterone Depends on MAOA-uVNTR Genotype MAOA short allele ASPD: antisocial personality disorder Testosterone may act on the MAO-A promoter The promoter region contains the MAOA-uVNTR polymorphism MAOA long allele Sjöberg L et al. Neuropsychopharmacol 2008;33:

34 Summary One of the leading hypotheses of depression suggests that monoamine levels are reduced in MDD Increased degradation of monoamines by MAO-A may underlie the reduction of monoamines seen in MDD Current treatments for MDD are focused on reducing monoamine reuptake; however, this strategy does not address the underlying problem of MAO-A hyperactivity Polymorphisms in the gene for MAO-A and sexual dimorphism have been shown to influence the etiology, presentation, and treatment of MDD