OCDOCD

Neurochemical dysfunction (abnormalities in Neurochemical dysfunction (abnormalities in serotonin (5-HT), dopamine (DA), and serotonin (5-HT), dopamine (DA), and glutamatergic transmitter systems)glutamatergic transmitter systems)

Drug Therapy in OCDDrug Therapy in OCD Strategies targeting these systemsStrategies targeting these systems Role of serotonin (5-HT) neurotransmitter system Role of serotonin (5-HT) neurotransmitter system

and glutamatergic systemand glutamatergic system

SSRIsSSRIs

Block action of 5HT transporter (5-HTT) Block action of 5HT transporter (5-HTT) proteinprotein Responsible for uptake of intrasynaptic 5-HT Responsible for uptake of intrasynaptic 5-HT

released following an action potentialreleased following an action potential Prevent reuptake of 5-HT into the pre-synaptic Prevent reuptake of 5-HT into the pre-synaptic

neuronneuron More serotonin left in synapse to bind with post-More serotonin left in synapse to bind with post-

synaptic receptorssynaptic receptors

Serotonin receptors are activated by 5-HTSerotonin receptors are activated by 5-HT Receptors modulate the release of many Receptors modulate the release of many

neurotransmitters, including glutamate, GABA, neurotransmitters, including glutamate, GABA, dopamine, epinephrine/norepinephrine, and dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones.acetylcholine, as well as many hormones.

Influence biological and neurological processes Influence biological and neurological processes such as aggression, anxiety, appetite, cognition, such as aggression, anxiety, appetite, cognition, learning, and memorylearning, and memory

Targeting 5-HT receptor subtypesTargeting 5-HT receptor subtypes

Drugs that block the 5-HT2 family of receptors Augment action of SSRIs or have therapeutic

efficacy by themselves Blockade of 5-HT2A receptors and activation of

non-5HT2A receptors may have similar effects Synergistic treatment with 5-HTSynergistic treatment with 5-HT2A2A antagonist/SSRI antagonist/SSRI

combination combination

Risperidone Risperidone Potent 5-HTPotent 5-HT2A2A antagonist antagonist

blocks blocks αα22 adrenoreceptors adrenoreceptors Presynaptic heteroreceptors on 5-HT neurons that Presynaptic heteroreceptors on 5-HT neurons that

regulate release of 5-HTregulate release of 5-HT Further enhance SSRI therapy through desensitization Further enhance SSRI therapy through desensitization

of 5-HTof 5-HT1D1D terminal autoreceptor terminal autoreceptor

5-HT5-HT2C2C receptor agonism receptor agonism Psilocybin; mixed 5-HTPsilocybin; mixed 5-HT2C/2A/1A2C/2A/1A receptor agonist receptor agonist

5-H5-H1D/B1D/B receptor receptor

Regulate release of 5-HT from presynaptic Regulate release of 5-HT from presynaptic terminal by reducing 5-HT neurotransmissionterminal by reducing 5-HT neurotransmission

Activation of 5-HTActivation of 5-HT1D/B1D/B receptor by an agonist receptor by an agonist compound worsen OCD symptomscompound worsen OCD symptoms Chronic deficits in 5-HT functioningChronic deficits in 5-HT functioning Agonist m-CPPAgonist m-CPP

Silent polymorphism of G861C geneSilent polymorphism of G861C gene 5-HT5-HT1D/B1D/B receptors supersensitive, resulting in receptors supersensitive, resulting in

chronic reductions in synaptic levels of 5-HTchronic reductions in synaptic levels of 5-HT

5-HT5-HT1D/B1D/B antagonist compounds expected to antagonist compounds expected to hasten onset of therapeutic action of SSRIs in hasten onset of therapeutic action of SSRIs in OCDOCD rapidly producing state of 5-HTrapidly producing state of 5-HT1D/B1D/B receptor receptor

insensitivityinsensitivity

Glutamatergic SystemGlutamatergic System GlutamateGlutamate

most abundant excitatory neurotransmitter in the vertebrate nervous most abundant excitatory neurotransmitter in the vertebrate nervous system.system.

Nerve impulses trigger release of glutamate from pre-synaptic cellNerve impulses trigger release of glutamate from pre-synaptic cell Opposing post-synaptic cell, glutamate receptors Opposing post-synaptic cell, glutamate receptors

(NMDA receptors)(NMDA receptors) Role in synaptic plasticityRole in synaptic plasticity learning and memory in the brainlearning and memory in the brain

Glutamate transporters rapidly remove glutamate from extracellular spaceGlutamate transporters rapidly remove glutamate from extracellular space In brain injury or disease, work in reverse and excess glutamate In brain injury or disease, work in reverse and excess glutamate

accumulates outside cellsaccumulates outside cells Causes calcium ions to enter cells via NMDA receptor channelsCauses calcium ions to enter cells via NMDA receptor channels

Excitotoxicity- overstimulation of receptors leads to neuronal Excitotoxicity- overstimulation of receptors leads to neuronal damage and eventual cell deathdamage and eventual cell death

““The Combined Effects of The Combined Effects of Memantine and Fluoxetine Memantine and Fluoxetine

on an Animal Model of on an Animal Model of Obsessive Compulsive Obsessive Compulsive

Disorder”Disorder”

Effective class of drugs used to treat OCDEffective class of drugs used to treat OCD FluoxetineFluoxetine

First in a generation of SSRIs for treatment of major First in a generation of SSRIs for treatment of major depressive disorder and anxiety disorders (OCD)depressive disorder and anxiety disorders (OCD)

Good overall safety and tolerabilityGood overall safety and tolerability Better than most other antidepressantsBetter than most other antidepressants

MemantineMemantine First used in treatment of Alzheimer’s dementiaFirst used in treatment of Alzheimer’s dementia low-affinity voltage-dependent antagonist at low-affinity voltage-dependent antagonist at

glutamatergic NMDA receptorsglutamatergic NMDA receptors Uncompetitive antagonist channel blockerUncompetitive antagonist channel blocker

Aim of StudyAim of Study

Use mouse model of OCDUse mouse model of OCD Examine whether a synergistic, as opposed to Examine whether a synergistic, as opposed to

additive relationship between NMDA antagonists additive relationship between NMDA antagonists and SSRIs in treatment of OCDand SSRIs in treatment of OCD

Combining relatively low doses of both drugsCombining relatively low doses of both drugs Low enough where do not decrease compulsive behavior when Low enough where do not decrease compulsive behavior when

administered aloneadministered alone

Isobologram Graph of equally effective dose pairs

(isoboles) for a single effect level Particular effect level is selected

50% of the maximum Doses of drug A and drug B (each alone) that give

this effect are plotted as axial points in a Cartesian plot

Straight line connecting A and B is the locus of points (dose pairs) that will produce this effect in a simply additive combination

Line of additivity allows a comparison with the actual dose pair that produces this effect level experimentally

IsobologramIsobologram

Third point plotted on graphThird point plotted on graph dose combinations of two drugs necessary to produce same dose combinations of two drugs necessary to produce same

effect sizeeffect size Combination points below the line of additivity Combination points below the line of additivity

SynergismSynergism Combination points along line of additivityCombination points along line of additivity

Simply AdditiveSimply Additive Combination points above line of additivityCombination points above line of additivity

SubadditivitySubadditivity

MethodMethod

Male Swiss Webster miceMale Swiss Webster mice 18-63 g depending on age18-63 g depending on age Kept at 68 to 72 Kept at 68 to 72 °F in 12h/12h light-dark cycle°F in 12h/12h light-dark cycle Ad libitum access to water and food pelletsAd libitum access to water and food pellets

Scratching AssayScratching Assay

Established as effective modelEstablished as effective model compulsive behavior in dogs with allergic compulsive behavior in dogs with allergic

dermatitisdermatitis Intradermal injection in miceIntradermal injection in mice

SerotoninSerotonin Compound 48-80Compound 48-80

Promotes histamine release and mast cell degranulationPromotes histamine release and mast cell degranulation

Effect of fluoxetine on serotonin-induced scratching Effect of fluoxetine on serotonin-induced scratching compared to controlscompared to controls 5,10,15,30 mg/kg5,10,15,30 mg/kg

Effect of memantine on serotonin-induced scratching Effect of memantine on serotonin-induced scratching compared to controlscompared to controls 5,10,15,30 mg/kg5,10,15,30 mg/kg

Effect of combination fluoxetine and memantine on Effect of combination fluoxetine and memantine on serotonin-induced scratchingserotonin-induced scratching 5mg/kg fluoxetine5mg/kg fluoxetine 5mg/kg memantine5mg/kg memantine

Effect of fluoxetine (10 mg/kg) and memantine (5 Effect of fluoxetine (10 mg/kg) and memantine (5 mg/kg) by compound 48-80 both alone and in mg/kg) by compound 48-80 both alone and in combinationcombination

Experimental miceExperimental mice intraperitoneal injection of varying doses of intraperitoneal injection of varying doses of

fluoxetine and/or memantine in saline (0.9% NaCl) fluoxetine and/or memantine in saline (0.9% NaCl) containing ascorbic acid (1mg/ml)containing ascorbic acid (1mg/ml)

Control miceControl mice Intraperitoneal injection of varying doses of saline Intraperitoneal injection of varying doses of saline

and ascorbic acidand ascorbic acid 0.1ml/10g of body weight0.1ml/10g of body weight

5 minutes later5 minutes later Control and experimental mice subcutaneously Control and experimental mice subcutaneously

injected behind neckinjected behind neck 0.1 ml of 0.4 mg/ml serotonin or 0.1 ml of compound 0.1 ml of 0.4 mg/ml serotonin or 0.1 ml of compound

48-80 1 mg/ml in saline and ascorbic acid to induce 48-80 1 mg/ml in saline and ascorbic acid to induce scratchingscratching

Each mouse then placed individually in Each mouse then placed individually in separate cage paired with control mouse in separate cage paired with control mouse in separate cage given saline pretreatmentseparate cage given saline pretreatment

Cumulative number of scratches counted Cumulative number of scratches counted continuously using manual countercontinuously using manual counter

Cumulative scratches recorded every 5 Cumulative scratches recorded every 5 minutes for 30 minutesminutes for 30 minutes Other behaviors noted Other behaviors noted

motor activity, sedation, licking, and rearingmotor activity, sedation, licking, and rearing

Statistical AnalysisStatistical Analysis

Mean scratching scores for pretreated mice Mean scratching scores for pretreated mice compared to their saline controlscompared to their saline controls

Cumulative scratches in mice injected with Cumulative scratches in mice injected with drug were expressed as % of scratches drug were expressed as % of scratches compared to saline controlscompared to saline controls

ResultsResults

DiscussionDiscussion

Combined doses of fluoxetine and memantine Combined doses of fluoxetine and memantine required to produce 90% reduction in required to produce 90% reduction in scratchingscratching much lower than doses of either drug alone much lower than doses of either drug alone

necessary to produce same effectnecessary to produce same effect Synergistic relationshipSynergistic relationship

Present study mechanisms most likely serotonergic and Present study mechanisms most likely serotonergic and glutamatergicglutamatergic

Basis for synergism between fluoxetine and Basis for synergism between fluoxetine and memantinememantine SSRIs increase amount of serotonin in synapses and SSRIs increase amount of serotonin in synapses and

NMDA antagonist block glutamate binding at NMDA NMDA antagonist block glutamate binding at NMDA receptorsreceptors

Both decreased serotonergic activity and increased Both decreased serotonergic activity and increased glutamatergic activity have been linked to the glutamatergic activity have been linked to the expression of impulsive behaviorsexpression of impulsive behaviors