Therapeutic targets and biomarkers of epilepsy comorbidities: lessons from animal models December 10, 2013

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1 Therapeutic targets and biomarkers of epilepsy comorbidities: lessons from animal models December 10, 2013 Andréy M Mazarati, MD, PhD Department of Pediatrics, Children s Discovery and Innovation Institute, David Geffen School of UCLA American Epilepsy Society Annual Meeting

2 Disclosure NIH/NINDS: Research grant R01 NS UCLA Children s Discovery and Innovation Institute/ Today's and Tomorrow's Children Fund: Research grant. American Epilepsy Society Annual Meeting

3 Learning Objectives Identify therapeutic targets for epilepsy-associated depression and attention deficit / hyperactivity disorder (ADHD). Identify biomarkers and therapeutic targets for epilepsy-associated autism stemming from maternal infection. Epilepsy comorbidity Major Depressive Disorder Patients with epilepsy General population 30-50% 5-17% ADHD 25% 3-5% Autism 30% 0.1-1% American Epilepsy Society Annual Meeting

4 Disclosure (pt. II) Role of monoamine transmitters in mechanisms of epilepsy, depression and ADHD Disorder Norepinephrine Serotonin Dopamine Epilepsy Yes! ДА! You bet! Depression Aber ja! Absolutely! Totally! ADHD Sure! M-m-m.. Yep! יא!

5 NE 5-HT PFC Glu LC NE

6 Andres M. Kanner Lancet Neurology 2012; 11:

Struggle, s 150 125 Depressive behavior in rats with epilepsy Naive

minutes total Active swimming 100 75 Epilepsy:?

Depressed 0 25 50 75 100 125 150 Immobility, s Mazarati et al.

7 Struggle, s Depressive behavior in rats with epilepsy Naive Epilepsy "struggling" Epilepsy "immobile" Forced swimming test 5 minutes total Active swimming Epilepsy:? Active= 300 s-immobility-struggle Immobility Normal Epilepsy: Depressed Immobility, s Mazarati et al., Brain 2008;131: Pineda et al., Epilepsy & Behavior, 2014, In Press Depression Non-cued struggle

8 5HT current, na PFC RN LC Mood regulation by ascending monoaminergic pathways 5-HT: Raphe nucleus-prefrontal cortex NE: Locus coeruleus-prefrontal cortex Diminished serotonergic tone in depression Naive 2.0 Epilepsy, "struggling" Epilepsy, "immobile" 5-HT is suppressed in all depressed 1.5 NE is suppressed in some depressed NE is suppressed in all struggling 5-HT is normal in all struggling Mazarati et al., Brain 2008;131: NE current, na Pineda et al., Epilepsy & Behavior, 2014, In Press

Percent correct choices Percent impulsive responses Lateralized Reaction Time Task Measures impulsivity and attention (food reward after temporally and spatially correct response to the light signal)

10 Percent correct choices Percent impulsive responses Lateralized Reaction Time Task Measures impulsivity and attention (food reward after temporally and spatially correct response to the light signal) Impulsivity * * Naive Post-SE "non-impulsive" Epilepsy "impulsive" 0 Naive All "Impulsive" "Nonimpulsive" Epilepsy Attention deficit Percent impulsive responses Pineda et al., Epilepsy & Behavior, 2014, In Press Food Lightnose poke Lustig et al., Neurosci Biobehav Rev 2012; In Press

11 5-HT current, NA PFC RN LC Diminished Noradrenergic tone Serotonergic tone in ADHD NE is suppressed in all impulsive These animals are struggling in the forced swimming test 5-HT is suppressed in all non-impulsive These animals are immobile in the forced swimming test Pineda et al., Epilepsy & Behavior, 2014, In Press Naive 2.0 Epilepsy, "impulsive" Epilepsy, "non-impulsive" NE current, na

Immobility, s Is triple-morbidity possible? 5HT current, na 12-50% Neuropsychiatric Disease and Treatment 2009:5; 1370159 Depression frequently masks ADHD 150 120 90 60?

12 Immobility, s Is triple-morbidity possible? 5HT current, na 12-50% Neuropsychiatric Disease and Treatment 2009:5; Depression frequently masks ADHD ? Naive Epilepsy "non-impulsive" Epilepsy "impulsive" Some hyperimpulsive rats are also depressed Percent impulsive responses Naive 2.0 Epilepsy, "struggling" Epilepsy, "immobile" Some rats show both NE and 5-HT deficits NE current, na Pineda et al., Epilepsy & Behavior, 2014, In Press

13 Epilepsy 5-HT NE RN LC SE Depression ADHD SSRI Fluoxetine SNRI Venlafaxine NRI Atomoxetine J. Child Adolesc. Pharm 2007;17:

Infection during pregnancy as a risk factor for autism in the offspring PEDIATRICS Volume 130, Number 6, December 2012 maternal influenza was associated with a twofold increased risk of autism;

15 Infection during pregnancy as a risk factor for autism in the offspring PEDIATRICS Volume 130, Number 6, December 2012 maternal influenza was associated with a twofold increased risk of autism; prolonged episodes of fever caused a threefold increased risk of autism. maternal viral infection in the 1 st trimester and bacterial infection in the 2 nd trimester were associated with ASDs in the offspring, with hazard ratios 2.98 and 1.42.

, Brain Behavior and Immunity, 2012; 26: 607-16 Pineda et al.

16 Offspring Autism Pregnant mouse Viral (Poly I:C) or Gram-negative (LPS) infection Epilepsy Sociability test normal autism Malkova et al., Brain Behavior and Immunity, 2012; 26: Pineda et al., Annals of Neurology, 2013; 74:11-19 Yin et al., Brain Res, 2013; 1519:78-86 Kirschman et al., Metab Brain Dis, 2011; 26:91-93

17 pg/ml of plasma IL-6 IL-1b TNFa IL-3 IL-9 IL-8 IL-10 IL-12 Saline Maternal Immune Activation * * Poly I:C Infection *- Anti-IL6 monoclonal antibody (Clinical trials for NHL, Multiple Myeloma, Castleman's Disease) - Anti-IL-1b monoclonal antibody (Clinical trials for COPD, CAD, gout) Increased plasma levels in pregnancy/infection IL-6 - risk for autism IL-6+IL-1b - risk for autism+epilepsy in the offspring Pregnant mice in Poly lieu IC of + Poly antibody I:C Offspring IL-6 IL-1b Siltuximab* Canakinumab Autism Epilepsy Smith et al., J Neurosci 2007; 27: Pineda et al., Annals of Neurology, 2013; 74:11-19

SNRI may be particularly effective. Seminars in neurology 2008 ;28:379-88 Do not underestimate environmental causes of autism and comorbid epilepsy.

18 Impact on Clinical Care and Practice Epilepsy-associated depression is linked to 5-HT deficiency; SSRI are prompted. Epilepsy-associated ADHD is linked to NE deficiency; NRI should be considered. Triple-morbidity between epilepsy, depression and ADHD is possible. Diagnosis of ADHD may be complicated. SNRI may be particularly effective. Seminars in neurology 2008 ;28: Do not underestimate environmental causes of autism and comorbid epilepsy. Detrimental effects of maternal infection on the offspring may be predicted using a simple blood test during pregnancy (IL-6- autism; IL-6+IL-1b- epilepsy). Active prevention of autism and epilepsy caused by maternal infection may be achieved by treating viral infections during pregnancy with IL-6 (and IL-1b) MAB.

ADHD Medications & How They Work. Gail C. Rodin, Ph.D. January 21, 2008

ADHD Medications & How They Work Gail C. Rodin, Ph.D. January 21, 2008 Agenda How the (ADHD) Brain Works (or doesn t) Neurons and neurotransmitters NE & DA: the major players in ADHD Channel vs. state