University:
West Coast University
Course:
PHAR 835 | IPC Neurology/Psychiatry
Academic year:

2024
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417

Pages:

35
Author:

Asal A.

Serotonin Pharmacology Affective Disorders Supplemental Guidance to Handout and Reading Assignment Basic & Clinical Pharmacology, 16e Katzung et al. Chapter 29-30. Parto Khansari Ph.D. 8/22/2024 (9:00-12:30) Major Depressive Disorder  Depression is a mood disorder (Affective disorder) GoGIE BIP  Genetics  Environmental Factors  Neurobiological Bases  Neurotropic Hypothesis  Neuroendocrine dysregulation( dysregulation in Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis activation  Neurotransmitters Dysregulation memory q Hippocampus in Depression glutamate INMDA Physiological Function of Hippocampus WE Consolidation of new memories Processing emotions, Navigation and spatial orientation ki factorandplaytityl growth BontaHighstress portisole Ivoumeothippocompust MDD  Small (10–15%) but significant reduction in hippocampal volume and regions of frontal  Reduction in hippocampal BNDF Neurotropic Hypothesis  Nerve growth factors such as brain-derived neurotrophic factor (BDNF) are important in the regulation of neural plasticity and neurogenesis. 538At Gaddjin A DB neuronal survival and growth by activating the  BDNF enhance tyrosine kinase receptor B in both neurons and glia  Depression is associated with the loss of synaptic connectivity in cortical areas such as the hippocampus.  Mutations in the BDNF gene have been found to be associated with altered anxiety and depressive behavior  high levels of Cortisol is hypothesized to decrease levels of BDNF Dysregulation of HPA axis É E SSM  Physiological Function of Limbic System region HipG H  Controls Emotions  Emotional Responses  Pain and Pleasure Sensations  Hormonal Regulation  Storing Memory  Motivation  MDD Dysfunction in direct and feed back interactions between Hypothalamus, pituitary, limbic system and adrenal glands weneedtoknowthem to showthese07 med Monoamine Hypothesis ►Depression is caused by functional deficit of monoamine transmission at specific site of the brain ►Serotonin ►Dopamine ►Norepinephrine Biogenic Amines Synthesized from amino acid precursors.  divided into three categories: TBenzereringardzhydroxylgrap Tynosin 1. Catecholamines: (dopamine, norepinephrine, and epinephrine) derivatives of tyrosine. 2. Indoleamine: (serotonin, melatonin) derivatives of tryptophan. 3. Histamine derivatives of histidine Catecholamines :  Dopamine  Norepinephrine  Epinephrine Monoamines:  Serotonin  Dopamine  Norepinephrine Receptor Types - MOA Effi excitatory D1, D5 Metabotropic ↑ cAMP D2, D3, D4 Metabotropic ↓ cAMP; ↑ K+, ↓ Ca2+ conductance α1 Metabotropic ↑ IP3/DAG/Ca2+ α2 Metabotropic ↓ cAMP; ↑ K+, ↓ Ca2+ conductance β1, β2, β3 Metabotropic ↑ cAMP 5-HT1 Metabotropic ↓ cAMP; ↑K+ conductance 5-HT2 Metabotropic ↑ IP3/DAG/Ca2+ 5-HT3 Ionotropic ↑ Na+, K+ conductance 5-HT4–7 Metabotropic ↑ cAMP Dopamine inhibition Norepinephrine Serotonin Serotonin (5-hydroxytryptamine: 5-HT) Produced in the Raphe nuclei of the brain stem Serotonin 1-2% Blood Cell Smooth Muscles vasoconstriction Platelets Intestinal Wall Smooth Muscles Gut Motility CNS Sleep/Wakefulness Appetite Mood Sexual behavior Pain Sensation Temperature Anger/Aggression Center of nausea Abnormalities in Serotonergic Pathway Abnormalities in Serotonin Anxiety Depression Schizophrenia Hypertension OCD Obesity Stroke Pain Vascular disorders Migraine Serotonergic Neurons Serotonin (5-HT) is synthesized from tryptophan in a two-reaction pathway: the rate-limiting enzyme is tryptophan hydroxylase. Both newly synthesized 5-HT and recycled 5-HT are transported from the cytoplasm into synaptic vesicles by the vesicular monoamine transporter (VMAT). Neurotransmission is initiated by an action potential in the presynaptic neuron, which eventually causes synaptic vesicles to fuse with the plasma membrane in a Ca2+dependent manner. 5-HT is removed from the synaptic cleft by a selective 5-HT transporter (SERT) as well as by nonselective reuptake transporters (not shown). 5-HT can stimulate 5-HT1B autoreceptors on the presynaptic membrane to provide feedback inhibition. Cytoplasmic 5-HT is either sequestered in synaptic vesicles by VMAT or degraded by mitochondrial monoamine oxidase (MAO). seriffed AADGsNotspoilt toserotonin e to See full size image Norepinephrine Norepinephrine soy products, chicken, turkey, fish, nuts, avocados, bananas, dairy products, … Phenylalanine Hormone (stress hormone) Neurotransmitter Modulates Activates Sympathetic nervous system Increase Cognition Selective attention Arousal/adaptation Executive function Heart rate Release of energy from fat Muscle readiness Tyrosine e Dopamine Norepinephrine seats Epinephrine totes comeback Norepinephrine Neurotransmission y • Dopamine synthesized from tyrosine is transported into the vesicle by the vesicular monoamine transporter (VMAT). Inside the vesicle, dopamine is converted to norepinephrine by dopamine β-hydroxylase. • NE is removed from the synaptic cleft by a selective norepinephrine transporter (NET) specific • NE can stimulate α2-adrenergic autoreceptors to provide feedback inhibition. Dopaminergic Neurons Dopamine role in cognition and behavior Motivation / Reward Sleep Mood Attention Learning Inhibition of prolactin Monoamine Neurotransmitters • For all monoamines, the first synthetic step is rate-limiting. • 5-HT: tryptophan hydroxylase (TPH) • DA and NE: tyrosine hydroxylase (TH). • Vesicular monoamine transporter (VMAT) is nonspecific for the vesicular packaging of DA, NE, EPI and 5-HT. • The selective monoamine transporters, serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), are capable of transporting the other monoamines with efficiently. Monoamine degradation Potential Site of Action Site of Action of Antidepressant at  Tricyclic antidepressants (TCAs) (Norpramine) effect on defeat sastemof toe body n ofgood for ebay cordiwaswelt problem  Selective serotonin reuptake inhibitors (SSRIs) Prozac, Zoloft more ofsynapticaett  Norepinephrine-dopamine reuptake inhibitors Wellbutrin neat  Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) Cymbalta  Monoamine oxidase inhibitor (MAOIs) Phenelzine depredate monoamine Antidepressants April 10th, 2017 PBS 602 Tricyclic antidepressants (TCAs)      Amitriptyline Desipramine Doxepin Imipramine Nortriptyline Elavil Norpramin Sinequan Tofranil Pamelor Reuptake Inhibitors  Selective Serotonin Reuptake Inhibitors (SSRIs)  Citalopram Celexa  Escitalopram Lexapro  Fluoxetine Prozac  Fluvoxamine Luvox  Paroxetine Paxil  Sertraline Zoloft  Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)  Desvenlafaxine Pristiq  Duloxetine Cymbalta  Venlafaxine Effexor  Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)  Bupropion Wellbutrin Atypical Antidepressants  Mixed Serotonergic Effects (Mixed 5-HT)  Nefazodone Serzone  Trazodone Oleptro  Vilazodone Viibryd  Serotonin and α2-Adrenergic Antagonist  Mirtazapine Remeron Monoamine Oxidase Inhibitors (MAOIs)    Phenelzine (Nardil) Selegiline (transdermal) (Emsam) Tranylcypromine (Parnate) Atypicallove life half longer Tricyclic Antidepressants  Oldest class of antidepressants developed in the 1950s.  Consist of three rings: two aromatic rings attached to a cycloheptane ring  Block the reuptake of NE, 5-HT and to some extent dopamine.  TCAs with secondary amines preferentially affect the NE system, with tertiary amines primarily affect the 5-HT system.  Minimal effect on dopamine reuptake  Net effect to increase the levels of the neurotransmitters in the synaptic cleft Tricyclic Antidepressants Adverse Effect  Block muscarinic acetylcholine receptors, α1 adrenergic receptors and histamine H1 receptors, which underlie many of their side-effects.  Anticholinergic effects : nausea, vomiting, anorexia, dry mouth, blurred vision, confusion, constipation, tachycardia, and urinary retention. The  Antihistaminergic effects: sedation, weight gain, and confusion (in the elderly).  Antiadrenergic effects include orthostatic hypotension, reflex tachycardia, drowsiness, and dizziness.  Effects sodium channels include potentially lethal conduction delays in heart  Orthostatic hypotension is an especially significant risk for elderly patients, and TCA use must be monitored carefully in such patients  May also precipitate mania in patients with BD. SSRI Antidepressants  Significantly more selective for 5-HT transporters  inhibit norepinephrine and dopamine transporters at the higher end of their therapeutic doses.  No effects on other receptors hence higher therapeutic index and greater safety profile than the TCAs  Adverse effect:  Sexual dysfunction  GI distress; sertraline is more often associated with diarrhea, while paroxetine is associated with constipation. Serotonin Syndrome A rare but dangerous elevation of 5-HT levels that can occur when both an SSRI and an MAOI are administered concurrently. The clinical manifestations of serotonin syndrome twich include hyperthermia, muscle rigidity, myoclonus, and rapid fluctuations in mental status and vital signs. sudden SNRI Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) • Newer class of antidepressants • Block the 5-HT reuptake transporter and the NE reuptake transporter in a concentration-dependent manner; at low doses, they behave as SSRIs, but at higher doses, they also increase extracellular NE levels. • Duloxetine also inhibits NE and 5-HT reuptake specifically and has been approved for the treatment of depression as well as neuropathic pain and other pain syndromes. Atypical Antidepressants Bupropion, effects on nicotinic acetylcholine (nACh) receptors fewest sexual adverse effects. contraindicated in patients with seizure disorders, electrolyte abnormalities, or eating disorders (since these can cause electrolyte imbalances). receptors auto I Mirtazapine, a tetracyclic molecule, blocks postsynaptic 5-HT2A and 5-HT2C receptors and the presynaptic α2-adrenergic autoreceptors and presumably decreases neurotransmission at 5-HT2 synapses while increasing NE neurotransmission. (appetite stimulant), making it a particularly useful antidepressant for the elderly population (who often present with insomnia and weight loss) Trazodone, a phenylpiperazine, blocks postsynaptic 5-HT2A and 5-HT2C receptors while also inhibiting the serotonin transporter Tianeptine is a tricyclic antidepressant with anxiolytic effects. possible mechanisms include effects on neuroplasticity through increasing BDNF, effects on glutamate e receptors, and modulation of μ and δ opioid receptors. Tianeptine is currently approved for human use in Europe. Antidepressants –MAO Inhibitors D Block the activity of monoamine oxidase, enzymes that are responsible for the catabolism of monoamine neurotransmitters. There are two isoforms of this enzyme, MOA type A and type B, and drugs can block both or only one of them. MAOIs can potentially cause serious complications if taken with certain food or beverages which results in tyramine toxicity.  The older MAOIs are nonselective and irreversible inhibitors  iproniazid,  phenelzine  isocarboxazid  Newer MAOIs are selective for MOA-A and reversible  moclobemide,  Befloxatone  Brofaromine Drug-interactions Involving Antidepressants Antidepressant Taken With Consequence Fluoxetine Lithium, TCAs, warfarin Increased blood levels of second drug Fluvoxamine Alprazolam, theophylline, TCAs, warfarin Increased blood levels of second drug MAO inhibitors SSRIs, sympathomimetics, tyramine-containing foods Hypertensive crisis, serotonin syndrome Nefazodone Alprazolam, triazolam Increased blood levels of second drug Paroxetine Theophylline, TCAs, warfarin Increased blood levels of second drug Sertraline TCAs, warfarin Increased effects of second drug TCAs Ethanol, sedative hypnotics Increased CNS depression Delayed Response Antidepressants treatment A. Before treatment, neurotransmitters are released at pathologically low levels and abnormally low baseline level of postsynaptic receptor activity (signaling). B. Short-term use of antidepressant medication results in increased release of neurotransmitter and/or increased duration of neurotransmitter action in the synaptic cleft. Both effects cause increased stimulation of inhibitory autoreceptors, with increased inhibition of neurotransmitter synthesis and increased inhibition of exocytosis. The net effect is to dampen the initial effect of the medication, and postsynaptic receptor activity remains at pretreatment levels. C. Chronic use of antidepressant medication results in desensitization of the presynaptic autoreceptors. Thus, the inhibition of neurotransmitter synthesis and exocytosis is reduced. The net effect is enhanced postsynaptic receptor activity, leading to a therapeutic response. Summary of SSRI, SNRI Bipolar Disorder 08 23 2029 • Refers to as manic-depressive disorder with similarities to components of schizophrenia and major depressive disorder. • The underlying pathogenesis includes neurotransmitters and neuroendocrine dysregulation and abnormalities in signal transduction. • One hypothesis is that the depression and mania are caused by two different mechanisms. • .The alternative theory is that bipolar disorder is a result of a specific type of neurotransmission dysregulation that results in the loss of mood stabilization. • Both models focus on serotonin, norepinephrine and dopamine in in hormones and and support the hypothesis that fluctuation neurotransmitters are associated with bipolar disorders. Tortisol adBDNF volume atHipoampus memory SND anurallossin Hypothesis I Mt Bipolar Disorder Bo all I 19 3 molecherabnorm phosphgelicondon sus • Imaging studies support the hypothesis that there are some structural changes associated with bipolar disorders which include neural loss in basal ganglia, temporal and cortical regions as well as ventricle’s enlargement. information inputsfrom their backtodiftentdiffautpartofbrain portofbrain Chapothalamus context • some evidence supports molecular abnormalities in the signal transduction system such as phosphoinositol, and altered circadian system in bipolar patients Inositol Phosphate Pathway Improve important to mediators I once a the activate produced isbeing ithaste bereachetoberaadytonexttime inbred acting deplatephospholy me inostilphosphate mfreemostic T Lithium as Ip3 brainiheart  Monovalent cation similar in electrochemical properties to sodium and potassium  Blocks the conversion of Inositol Phosphate to free inositol  Hence reduce the activity of brain inositol phosphate dependent pathways.  It is hypothesized that the second messenger system involving inositol activity is greatly increased during manic phase of bipolar disorders.  increases glutamate re-uptake, which reduces the excitability of neurons Pharmacological Treatment for Bipolar Disorder     Lithium Tag Carbamazepine Valproic Acid 11 Lamotrigineas Bipolar lamical list of antipsychotics used to treat bipolar depression:  Lurasidone (Latuda)  Quetiapine (Seroquel®) greisen  Olanzapine/fluoxetine (Symbyax®)  Clozapine (treatment refractory patients) clozaril Site of Action of Antipsychotic agents and Lithium

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