PHARMACODYNAMICS OF ANTIDEPRESSANTS MOOD STABILIZING AGENTS ANXIOLYTICS SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Assistant Professor of Psychiatry and Pharmacology Psychiatric Institute Department of Psychiatry University of Illinois at Chicago Email: ydwivedi@psych.uic.edu Noradrenergic (NE) Synapse Presynaptic NE Receptors (Autoreceptors) α 2 Postsynaptic NE Receptors (Heteroreceptors) α 1, α 2, β 1 Tyr: Tyrosine TH: Tyrosine hydroxylase DOPA: L-Dihydroxyphenyl alanine L-AADC: L-Aromatic amino acid decarboxylase DBH: Dopamine β hydroxylase DA: Dopamine MAO: Monoamine oxidase VMAT: Vesicular amine transporter
Noradrenergic Pathway Frontal Cortex Cerebellum Frontal Cortex Limbic Cortex Locus Coeruleus
NE Deficiency Syndrome
Serotonergic (5HT) Synapse Presynaptic 5HT Receptors (Autoreceptors) 5HT 1A, 5HT ID Postsynaptic 5HT Receptors (Heteroreceptors) 5HT 1A, 5HT 2A, 5HT 2C, 5HT 3, 5HT 4,6,7 Trp: Tryptyophan TrypOHase: Tryptophan hydroxylase 5HTP: 5-Hydroxy tryptophan L-AADC: L-AromaticAmino acid decarboxylase MAO: Monoamine oxidase VMAT: Vesicular amine transporter Serotonin Pathway Frontal Cortex Basal ganglia Raphe Nucleus Limbic Cortex Hypotalamus Brain stem
5HT Deficiency Syndrome
5HT-NE Interaction 5HT and NE Interaction
Benzodiazepine Ionotropic γ-aminobutyric acid (GABA) Receptors GABA 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 modulators to GABA neurotransmission Serotonin and Noradrenergic Signaling Systems
Monoamine Hypothesis of Depression Monoamine Receptor Hypothesis of Depression Normal functioning Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters
Gene Expression Hypothesis of Depression Brain-derived neurotrophic factor (BDNF)
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) Serotonin 2A Antagonist/Serotonin Reuptake Inhibitors (SARI)
Tricyclics All tricyclics block reuptake pumps for both 5HT and NE and 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 α 1 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
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 α 1, histamine or M cholinergic receptors or Na + pump 1 (Stahl, 2002)
2 3 4
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 α 2, postsynaptic α 1, α 2 and β adrenergic 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 active metabolite, 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
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 α 1, M 1 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 antidepressants which have little difference in efficacy at higher doses Effective in patients who are responders but not remmiters to SSRIs NE 5HT Synergy 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
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) Phenelzine Tanylcypromine Isocarboxazid Reversible and selective inhibitors of MAO-A (RIMAs) Moclobemide (antidepressant action) Selective inhibitor of MAO-B Deprenyl (neurodegenerative disorder) 5HT and NE Interaction
Noradrenergic and specific Serotonergic Antidepressant (NaSSA) (mirtazapine) α 2 receptor antagonist Increase NE and 5HT levels Blocks 5HT 2A, 5HT 3 and thus reduces side effects of anxiety, and sexual dysfunction presynaptic α 2 autoreceptor α 1 heteroreceptor 5HT 5HT postsynaptic α 2 heteroreceptor 5HT presynaptic α 2 autoreceptor 5HT But by blocking 5HT 2C, and H1 receptors cause side effects: sedation, and weight gain Stahl, 2002 Serotonin 2A Antagonist/ Serotonin Reuptake Inhibitors (SARI) (nefazodone, trazodone) Blocks 5HT uptake selectively but in a less potent manner than tricyclics This helps reduces depression However, they are powerful 5HT 2A antagonists 5HT 2A antagonists are not potent antidepressants But blockade of 5HT 2A receptors stimulate 5HT 1A receptors, which may help reduce depression 5HT 2A antagonism also reduces the risk of anxiety, sedation or sexual dysfunction which is normally associated with SSRIs
Postulated Neurotransmitter Receptor Hypothesis of Antidepressant Action Receptor Sensitivity Amount of NE Clinical Effect Antidepressants introduced (Stahl, 2002) Postulated Adaptive Mechanisms at Gene Exprerssion (Nestler, Hyman, Malenka)
Pharmacodynamics of Mood Stabilizing Agents Brain-derived neurotrophic factor
Mood Stabilizing Agents Classic Mood Stabilizer: Lithium Anticonvulsants: Valproic acid Carbamazepine Lamotrigine Gabapentin Topiramate Lithium Action-I Li Li Li MARCKS (PKC, PKA) Li Li e.g. Bcl-2 Li Neuroprotection (?) (Squire)
Lithium Action-II 5HT 2A, 5HT 2C, α 2 AR IP 3 DAG Ca2+ Inositol Lithium Action-III GSK3-β phosphorylates and thus degrades β-catenin Li blocks this degradation Brain Development (Nestler, Hyman, Malenka)
Anticonvulsants Reduces neuronal activity by: -Reducing flux of ions through voltage-gated ion channels, such as Na +, K +, Ca 2+ -Enhancing inhibitory neurotransmission with GABA, by increasing its synthesis, release, or inhibiting its breakdown -Reducing excitatory neurotransmission with glutamate by reducing its release CAI: Carbonic anhydrase inhibitor GRI: GABA reuptake inhibitor Stahl, 2002 Other Mechanisms of Action of Anticonvulsants 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)