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PHARMACODYNAMICS OF ANTIDEPRESSANTS

MOOD STABILIZING AGENTS ANXIOLYTICS

SEDATIVE-HYPNOTICS

Yogesh Dwivedi, Ph.D.Assistant Professor of Psychiatry and Pharmacology

Psychiatric InstituteDepartment of Psychiatry

University of Illinois at ChicagoEmail: ydwivedi@psych.uic.edu

Noradrenergic (NE) SynapsePresynaptic NE Receptors(Autoreceptors)

α2

Postsynaptic NE Receptors(Heteroreceptors)

α1, α2, β1

Tyr: TyrosineTH: Tyrosine hydroxylaseDOPA: L-Dihydroxyphenyl alanineL-AADC: L-Aromatic amino acid decarboxylaseDBH: Dopamine β hydroxylaseDA: DopamineMAO: Monoamine oxidaseVMAT: Vesicular amine transporter

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Noradrenergic Pathway

Locus Coeruleus

Frontal Cortex

Frontal Cortex

Limbic Cortex

Cerebellum

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NE Deficiency Syndrome

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Serotonergic (5HT) Synapse

Presynaptic 5HT Receptors(Autoreceptors)

5HT1A, 5HTID

Postsynaptic 5HT Receptors(Heteroreceptors)

5HT1A, 5HT2A, 5HT2C, 5HT3,5HT4,6,7

Trp: TryptyophanTrypOHase: Tryptophan hydroxylase5HTP: 5-Hydroxy tryptophanL-AADC: L-AromaticAmino acid decarboxylaseMAO: Monoamine oxidaseVMAT: Vesicular amine transporter

Serotonin Pathway

Frontal Cortex

Basal ganglia

Limbic CortexHypotalamus

Brain stem

Raphe Nucleus

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5HT Deficiency Syndrome

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5HT-NE Interaction

5HT and NE Interaction

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Ionotropic γ-aminobutyric acid (GABA) Receptors

α subunit

Channel pore

Barbiturates

Steroids

Picrotoxin

•Pentamers•Inhibitory in action because the associated channels are permeable to negatively charged Cl- ions•Benzodiazepines are allosteric modulatorsto GABA neurotransmission

BenzodiazepineGABA

Serotonin and Noradrenergic Signaling Systems

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Monoamine Hypothesis of Depression

Monoamine Receptor Hypothesisof Depression

Normal functioning

Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters

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Gene Expression Hypothesis of Depression

Brain-derived neurotrophic factor(BDNF)

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Pharmacodynamics of Antidepressants

Classification of Antidepressants

•Tricyclics

•Selective Serotonin Reuptake Inhibitors (SSRIs)

•Norepinephrine-Selective Reuptake Inhibitors (NRIs)

•Norepinephrine/Dopamine Reuptake Inhibitors (NDRIs)

•Mixed Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

•Monoamine Oxidase Inhibitors (MAOIs)

•Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

•Serotonin2A Antagonist/Serotonin Reuptake Inhibitors (SARI)

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Tricyclics

•All tricyclics block reuptake pumps for both 5HT and NEand they work negative allosteric modulators of neurotransmitter uptake process

•Some have more potency for inhibition of 5HT uptake pump(e.g. clomipramine, imipramine, amitryptyline)

•Others have more potency for inhibition of NE uptake pump(nortriptyline, desipramine)

•All tricyclics block α1 adrenergic, histaminergic, and M1 cholonergic receptors (causes side effects,e.g., weight gain, drowsiness, blurred vision)

•Tricyclics also block Na+ channels, thus may cause cardiac arrythmia

(Stahl, 2002)

Side Effects

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Side Effects

Selective Serotonin Reuptake Inhibitors (SSRI)•Selective and more potent inhibitors of serotonin uptake than tricyclics(fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram)

•No blockade of α1, histamine or M cholinergic receptors or Na+ pump

(Stahl, 2002)

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3

4

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NE Selective Reuptake Inhibitors (NRIs)(reboxetine, 1555U88*, tomoxetine*)

•Selective to NE uptake

•May be more effective in noradrenaline deficiency syndrome (e.g., depression associated with fatigue, apathy, cognitive disturbances), or nonresponders to SSRIs

•Also act at presynaptic α2, postsynaptic α1, α2 and βadrenergic receptors (tremor, agitation, blood pressure)

•No blockade of histamine, M cholinergic receptors or Na+

pump as with tricyclics

*under clinical trial

NE/DA Reuptake Blockers (NDRIs)(Bupropion)

•Weak dopamine and weak NE reuptake blocker

•But is potent blocker of NE and dopamine neurotransmission

•Bupropion is metabolized into its hydroxylated activemetabolite, which is a potent NE reuptake blocker

•Effective for patients who can not tolerate side effects of SSRIs such as sexual dysfunction or nonresponders of SSRIs

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Mixed 5HT/NE Reuptake Inhibitors (SNRIs)(venlafaxine)

•Combines the action of SSRI and NRI

•Selective 5HT and NE uptake blockers

•Weak DA uptake blocker as with TCA

•But without α1, M1 cholinergic or H receptor blocking properties

•Causes dual action on serotonin and adrenergic systems, thus amplifying these two systems synergistically

•Greater NE action at higher doses, thus greater efficacy at increased doses,as opposed to other antidepressantswhich have little difference in efficacy at higher doses

•Effective in patients who are responders but not remmiters to SSRIs Synergy

NE5HT

Monoamine Oxidase Inhibitors (MAOIs)-I

Two types of MAO

MAO-A --- metabolizes 5HT and NE selectively--- metabolizes certain amines, linked to

blood pressure

MAO-B --- protects neurons by metabolizing certain amines such as protoxins into toxins that may cause neuronal damage

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Monoamine Oxidase Inhibitors (MAOIs)-II

•Classic MAOIs--irreversible and nonselective(MAO-A and B enzyme activity can not be restored unless new enzyme is synthesized)

PhenelzineTanylcypromineIsocarboxazid

•Reversible and selective inhibitors of MAO-A (RIMAs)

Moclobemide (antidepressant action)

•Selective inhibitor of MAO-B

Deprenyl (neurodegenerative disorder)

5HT and NE Interaction

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Noradrenergic and specific SerotonergicAntidepressant (NaSSA)

(mirtazapine)

Stahl, 2002

• α2 receptor antagonist

•Increase NE and 5HT levels

•Blocks 5HT2A, 5HT3 and thus reduces side effects of anxiety, and sexual dysfunction

•But by blocking 5HT2C, and H1receptors cause sideeffects: sedation, and weight gain

α1 heteroreceptor

presynapticα2 autoreceptor

postsynapticα2 heteroreceptor

presynapticα2 autoreceptor

5HT5HT

5HT5HT

Serotonin2A Antagonist/ Serotonin ReuptakeInhibitors (SARI)

(nefazodone, trazodone)

•Blocks 5HT uptake selectively but in a less potent manner than tricyclics

•This helps reduces depression

•However, they are powerful 5HT2A antagonists

•5HT2A antagonists are not potent antidepressants

•But blockade of 5HT2A receptors stimulate 5HT1A receptors, which may help reduce depression

•5HT2A antagonism also reduces the risk of anxiety, sedation or sexual dysfunction which is normally associated with SSRIs

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Receptor Sensitivity

Antidepressants introduced

Clinical Effect

Amount of NE

Postulated Neurotransmitter Receptor Hypothesis of Antidepressant Action

(Stahl, 2002)

Postulated Adaptive Mechanisms at Gene Exprerssion

(Nestler, Hyman, Malenka)

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Brain-derived neurotrophic factor

Pharmacodynamics of Mood Stabilizing Agents

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Mood Stabilizing Agents

Classic Mood Stabilizer:

Lithium

Anticonvulsants:

Valproic acidCarbamazepine

LamotrigineGabapentinTopiramate

MARCKS (PKC, PKA)

Li

LiLi

Li

Li

e.g. Bcl-2 Li

Neuroprotection (?)

Lithium Action-I

(Squire)

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Ca2+

5HT2A, 5HT2C, α2AR

Lithium Action-II

Inositol

IP3 DAG

Brain Development

•GSK3-β phosphorylates and thus degrades β-catenin

•Li blocks this degradation

Lithium Action-III

(Nestler, Hyman, Malenka)

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Reduces neuronal activity by:-Reducing flux of ions through voltage-gated ion channels, such as Na+, K+, Ca2+

-Enhancing inhibitory neurotransmission with GABA, by increasing its synthesis,release, or inhibiting its breakdown

-Reducing excitatory neurotransmission with glutamate by reducing its release

Anticonvulsants

Stahl, 2002

CAI: Carbonic anhydraseinhibitor

GRI: GABA reuptake inhibitor

•Inhibit PKC (carbamazepine)

•Inhibit adenylyl cyclase activity (carbamazepine)

•Decreases inositol monophospahte activity (carbamazepine)

•Increase neurogenesis (valproic acid)

•Increase expression of Bcl-2, thus cause neuroprotection(valproic acid)

Other Mechanisms of Action ofAnticonvulsants