12 Antidepressant Agents - FINAL.pptx

Antidepressant Agents Antiepileptic drugs Anupam Bishayee, M.Pharm., Ph.D. Professor of Pharmacology Lake Erie College of Osteopathic Medicine 941-782-5950 [email protected] 1 MMS1070: October 27, 2023 Reference Basic and Clinical Pharmacology 15th Edition Chapter 30 MMS1070: October 27, 2023...

Antidepressant Agents Antiepileptic drugs Anupam Bishayee, M.Pharm., Ph.D. Professor of Pharmacology Lake Erie College of Osteopathic Medicine 941-782-5950 [email protected] 1 MMS1070: October 27, 2023 Reference Basic and Clinical Pharmacology 15th Edition Chapter 30 MMS1070: October 27, 2023 2 Learning objectives • At the end of this session, you should be able to: – Describe the current neurochemical and neurotrophic theories regarding depression and how it can be altered by drugs. – List the major classes of antidepressant drugs (tricyclic ADs, SSRIs, SNRIs, hetrocyclics antidepressants, and MAO inhibitors) and their primary cellular targets. – Discuss the mechanisms of actions and pharmacokinetics of antidepressants. – Describe the most common therapeutic indications. – Describe and compare the most common adverse effects of the classical antidepressants. – Discuss the use of herbal antidepressants, such as St. John’s wort, and its possible interaction with other antidepressant drugs. MMS1070: October 27, 2023 3 Introduction • The diagnosis of depression still rests primarily on the clinical interview. • According to a 2007 report by the Centers for Disease Control and Prevention, antidepressant drugs were the most commonly prescribed medications in the USA. • The primary indication for antidepressant agents is the treatment of major depressive disorder (MDD). • Major depression, with a lifetime prevalence of around 17% in the USA and a point prevalence* of 5%, is associated with substantial morbidity and mortality. *Point prevalence refers to the prevalence measured at a particular point in time. MMS1070: October 27, 2023 4 Introduction • Antidepressants have also received Food and Drug Administration (FDA) approvals for the treatment of: – panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). – pain disorders, such as neuropathic pain and the pain associated with fibromyalgia – premenstrual dysphoric disorder (PMDD) – vasomotor symptoms of menopause – stress urinary incontinence MMS1070: October 27, 2023 5 Pathophysiology of Major Depression • There has been a marked shift in the last decade in our understanding of the pathophysiology of major depression. • In addition to the older idea that a deficit in function or amount of monoamines (the monoamine hypothesis) is central to the biology of depression, there is evidence that neurotrophic and endocrine factors play a major role (the neurotrophic hypothesis). – Monoamine hypothesis – Neurotrophic hypothesis • Histologic studies, structural and functional brain imaging research, genetic findings, and steroid research all suggest a complex pathophysiology for MDD with important implications for drug treatment. MMS1070: October 27, 2023 6 Mechanisms of Antidepressant Action • By different mechanisms, almost all antidepressants result in a potentiation of the neurotransmitter actions of nor­ epinephrine, serotonin, or both. • The only exception is bupropion, which has an unknown mechanism of action. • The most common mechanism is inhibition of the activity of serotonin transporter (SERT), norepinephrine transporter (NET), or both monoamine transporters. – Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs. • Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (by the MAOIs). • MMS1070: October 27, 2023 Additional strategies for enhancing monoamine tone include7 Classes of Antidepressant Drugs MAO Inhibitors (MAOIs) Phenelzine Selegiline Tranycyprom ine Tricyclic Heterocycli Antidepress c ants Antidepress (TCAs) ants (tetracyclic, unicyclic) Amitriptylin e Clomiprami ne Imipramine Amoxapine Bupropion Mirtazepine Vilazodone 5-HT-NE reuptake Inhibitors (SNRIs) 5-HT receptor modulato rs Selective serotonin reuptake inhibitors (SSRIs) Duloxetine Venlafaxine Levomilnacip ran Nefazodo ne Trazodon e Vortioxeti ne Escitalopr am Fluoxetine Fluvoxami ne Paroxetine Sertraline MMS1070: October 27, 2023 8 General Pharmacokinetics • Majority have rapid oral absorption • Achieve peak plasma levels within 2–3 hours • Are tightly bound to plasma proteins • Undergo hepatic metabolism • Cleared by the kidneys MMS1070: October 27, 2023 9 Pharmacokinetics • Selective Serotonin Reuptake Inhibitors (SSRIs) – The prototype SSRI, fluoxetine (T1/2 of 2.5 days) is metabolized to an active product, norfluoxetine (T1/2 of 8 days), which has elimination half-life of about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs. – This long duration of action can be a disadvantage if severe adverse effects occur or in patient with hepatic disease. – Due to long half-life, fluoxetine has to be discontinued 4 weeks or longer before an MAOI/TCA/SNRI can be administered to mitigate the risk of serotonin syndrome. – Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this to potential drug MMS1070: Octobercontributes 27, 2023 10 interactions. Pharmacokinetics • Tricyclic Antidepressants (TCAs) – The TCAs are well absorbed and along with their active metabolites have relatively long half-lives, ranging from 18 to 70 hours. • TCAs are extensively metabolized and only about 5% of TCAs are excreted unchanged in the urine. They have high volumes of distribution and are not readily dialyzable. • The TCAs are substrates of the CYP2D6 system, and the serum levels of these agents tend to be substantially influenced by concurrent administration of drugs such as fluoxetine. • Genetic polymorphism for CYP2D6 may result in low or extensive metabolism of the TCAs. • TCAs have a wide therapeutic window, and serum levels are reliable in predicting response and toxicity. MMS1070: October 27, 2023 11 Pharmacokinetics • MAO inhibitors (MAOIs) – The MAOIs are well absorbed from the gastrointestinal tract. – Have extensive first-pass effects that may substantially decrease bioavailability. – Because of the prominent first-pass effects and their tendency to inhibit MAO in the gut, alternative routes of administration are being developed which decrease the risk of food interactions and provide substantially increased bioavailability. MMS1070: October 27, 2023 12 Selective Serotonin Reuptake Inhibitors (SSRIs) • Fluoxetine (PROZAC), Fluvoxamine (LUVOX), Paroxetine (PAXIL), Sertraline (ZOLOFT), Citalopram (CELEXA), Escitalopram (LEXAPRO) • Most widely prescribed drugs for depression and certain anxiety disorders, such as panic disorder and Obsessive Compulsive Disorder (OCD). • They have few side effects and seem to be rather safe. More rational prescribing and better patient compliance. • Most common side effects include GI upset, sexual dysfunction (30%+!), anxiety, restlessness, nervousness, insomnia, fatigue or sedation, dizziness. Very little risk of cardiotoxicity in overdose. • Can develop a discontinuation syndrome with agitation, nausea, disequilibrium and dysphoria. MMS1070: October 27, 2023 13 Selective Serotonin Reuptake Inhibitors (SSRIs) • Fluoxetine (PROZAC), is one of the most popular drugs for the treatment of depression, and one of the first drugs from this group approved for the treatment of bulimia nervosa. • The drug is well absorbed orally and is converted to an active metabolite, norfluoxetine. – The parent compound has a half-life of 2.5 days, but its active metabolite has a half-life of about 8 days. This long duration of action can be a disadvantage if severe adverse effects occur or in patient with hepatic disease, more likely to induce mania than some of the other SSRIs, but the benefit of having a long half life is a decreased incidence of discontinuation syndromes. • Fluoxetine causes more drug interactions than do other SSRIs. – Fluoxetine and paroxetine inhibit liver enzymes, particularly CYP2D6. – It can impair the regulation of blood glucose levels in diabetic patients. • It can also cause syndrome of inappropriate antidiuretic hormone secretion (SIADH), characterized by persistent hyponatremia and elevated urine osmolality. MMS1070: October 27, 2023 14 SSRI Discontinuation Syndrome • Interruption, cessation, or reduction of dosage in an SSRI treatment that has lasted four or more weeks. • The symptoms are widely variable in description and are of unknown etiology: 1. Dizziness, 2. Electric shock like sensations (“brain zaps", "brain shocks", "brain shivers", or "cranial zings“) 3. Sweating 4. Nausea 5. Insomnia 6. Tremor, confusion, nightmares, and vertigo MMS1070: October 27, 2023 15 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Inhibit both serotonin and noradrenergic reuptake like the TCAS, but without the antihistaminic, antiadrenergic or anticholinergic side effects • Used for depression, anxiety and possibly neuropathic pain – Venlafaxine (Effexor) – Duloxetine (Cymbalta) – Desvenlafaxine (Pristiq) – Milnacipran (Dalcipran, Ixel, Savella) – Levomilnacipran (Fetzima) • MOA: – SNRIs bind to transporters for both serotonin and NE, presumably enhancing the actions of both neurotransmitters. – Venlafaxine has less affinity for the NE transporter than desvenlafaxine or duloxetine. MMS1070: October 27, 2023 16 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Venlafaxine – Pros • Minimal drug interactions and almost no P450 activity • Short half life and fast renal clearance avoids build-up (good for geriatric populations) – Cons • Can cause a 10-15 mmHG dose dependent increase in diastolic BP (dose dependent) • May cause significant nausea, primarily with immediate-release (IR) tabs • Can cause a bad discontinuation syndrome, and taper recommended after 2 weeks of administration • Noted to cause QT prolongation • Sexual side effects in about 30% MMS1070: October 27, 2023 17 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Desvenlafaxine (Pristiq) – Pros • Minimal drug interactions • Short half life and fast renal clearance avoids build-up (good for geriatric populations) – Cons • GI distress in 20%+ • Dose-related increase in total cholesterol, LDL and triglycerides • Dose-related increase in BP MMS1070: October 27, 2023 18 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Duloxetine (Cymbalta) • It is indicated for major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. – Pros • Thus far less BP increase as compared to venlafaxine. – Cons • CYP2D6 and CYP1A2 inhibitor • Cannot break capsule, as active ingredient not stable within the stomach • In pooled analysis had higher drop out rate MMS1070: October 27, 2023 19 Tricyclic Antidepressants (TCAs) • Structurally related to the phenothiazine antipsychotics and share certain of their pharmacologic effects. • Very effective, but potentially unacceptable side effect profiles, i.e., antihistaminic, anticholinergic, antiadrenergic effects • Lethal in overdose – Hypotension, seizure, QRS prolongation(due to Na channel blockade), broad complex dysrhythmias, coma etc. – Can cause QT lengthening even at a therapeutic serum level • At the present time, the TCAs are used primarily in depression that is unresponsive to more commonly used antidepressants, such as the SSRIs or SNRIs. Are dosed once daily at night because of their sedating effects. MMS1070: October 27, 2023 20 Tricyclic Antidepressants (TCAs) Tertiary TCAs • Have tertiary amine side chains • Side chains are prone to cross react with other types of receptors which leads to more side effects including: – antihistaminic (sedation and weight gain), – Anticholinergic (dry mouth, dry eyes, constipation, memory deficits & potentially delirium, and seizure), – Antiadrenergic (orthostatic hypotension, sedation, sexual dysfunction) • Act predominantly on serotonin receptors • Examples: – Amitriptyline (Elavil) – Clomipramine (Anafranil) – Doxepine (Sinequan) – Imipramine (Tofranil) – Trimipramine (Surmontil) • Have active metabolites including desipramine and nortriptyline 21 MMS1070: October 27, 2023 Tricyclic Antidepressants (TCAs) Secondary TCAs • Are often metabolites of tertiary amines. • Primarily block norepinephrine. • Side effects are the same as tertiary TCAs, but generally are less severe • Examples: – Amoxapine (Asendin) – Desipramine (Norpramin) – Nortriptyline (Aventyl, Pamelor) – Protrypyline (Vivactil) MMS1070: October 27, 2023 22 Tricyclic Antidepressants (TCAs) Side Effects • Most common uncomfortable side effects – Histamine receptor blockade: Drowsiness, sedation and weight gain – Alpha1 receptor blockade: Orthostatic hypotension & reflex tachycardia – Anticholinergic: dry mouth, paradoxical excessive perspiration, constipation, blurred vision, mydriasis, metallic taste & urine retention • Others – Tremors, restlessness, insomnia, confusion, pedal edema, headache, blood dyscrasias, sexual dysfunction – Can lower seizure threshold • Adverse – Most serious is cardiotoxicity, coma, and seizures – Taking an overdose of a TCA can cause life-threatening cardiac arrhythmia, which frequently presents as a wide QRS complex tachycardia (due to Na channel blockade) and/or a prolonged QT interval MMS1070: October 27, 2023 23 5-HT2 Receptor Modulators • Trazodone – Serotonin antagonist and reuptake inhibitor (SARI) class. – Antagonist of 5-HT2A or 2C receptors, partial agonist at 5HT1A and 5-HT uptake inhibitor. – Highly sedative (hypnotic) [antagonist of the H1 receptor], but minimal antimuscarinic action. – Also associated with cardiac arrhythmias (antagonizes alpha adrenergic receptors a property which may be associated with postural hypotension). – Priapism is an uncommon but serious side effect requiring surgical intervention in one-third of the cases reported. – Used in unipolar depression, anxiety disorder and insomnia. MMS1070: October 27, 2023 24 5-HT2 Receptor Modulators • Nefazodone – Is a weak inhibitor of both SERT and NET, but is a potent antagonist of the postsynaptic 5-HT 2A receptor. – Nefazodone received an FDA black box warning in 2001 for hepatotoxicity, including lethal cases of hepatic failure. Still available generically, nefazodone is no longer commonly prescribed. – The primary indications are major depression and in the treatment of anxiety disorders. MMS1070: October 27, 2023 25 Tetracyclic and Unicyclic Antidepressants • Tetracyclic and Unicyclic Antidepressants – Bupropion (WELLBUTRIN, ZYBAN), – Mirtazapine (REMERON), – Amoxapine (Asendin, Asendis, Defanyl, Demolox, Moxadil), – Vilazodone (Viibryd) – Maprotiline (Deprilept, Ludiomil, Psymion) MMS1070: October 27, 2023 26 Tetracyclic and Unicyclic Antidepressants • Amoxapine – Metabolite of Loxapine (an antipsychotic) -- retains some antipsychotic activity and DA receptor antagonism => Parkinson's-like symptoms. – MOA: Alteration of NE output – May be useful if psychosis is present. • Maprotiline – A tetracyclic drug, resembles desipramine with less sedative and antimuscarinic side effects. – Evokes seizures at high doses. – Blocks NT reuptake. MMS1070: October 27, 2023 27 Tetracyclic and Unicyclic Antidepressants • Bupropion – Is an atypical antidepressant and smoking cessation aid. – It acts as a norepinephrine and dopamine reuptake inhibitor. – The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. – It lowers seizure threshold. Can induce psychotic symptoms at high doses. – It reduces the severity of nicotine cravings and withdrawal symptoms; used as second line attention deficit hyperactivity disorder (ADHD) agent. – Potential for abuse/less likely to cause weight gain. MMS1070: October 27, 2023 28 Tetracyclic and Unicyclic Antidepressants • Mirtazapine. – Antagonist at central presynaptic α2 adrenergic inhibitory autoreceptors and heteroreceptors – Potent antagonist of 5-HT2 and 5-HT3 receptors. – Potent antagonist of histamine (H1) receptors (very sedating). – “Weight gain” (used in Anorexia) – Cons • Increases serum cholesterol and triglycerides in certain patients • Very sedating at lower doses (30 mg) • Associated with weight gain (particularly at doses below 45 mg) MMS1070: October 27, 2023 29 Monoamine Oxidase Inhibitors (MAOIs) • Irreversible, non-selective inhibitors – Phenelzine (Nardil), Tranylcypromine (PARNATE) • Reversible inhibitors of MAO-B – Selegiline (l-Deprenyl), Rasagiline • Emsam patch • Acute administration causes – An increase in brain amine levels by interfering with their metabolism in the nerve endings, resulting in an increase in the vesicular stores of NE and 5-HT. • Chronic administration causes – Down-regulation of auto-receptors. – Up-regulation or enhancement of post synaptic transmission at 5HT1A receptors. MMS1070: October 27, 2023 30 Monoamine Oxidase Inhibitors (MAOIs) • Are very effective for depression, but use have declined due to side effects and drug/food interaction. • They are generally used as alternative therapy when patients have failed to respond adequately to other drugs and patients with atypical depression. • Effects persist even after these drugs are no longer detectable in plasma (1-3 weeks). • Side effects include orthostatic hypotension, weight gain, dry mouth, sedation, sexual dysfunction (phenelzine) and sleep disturbance • Hypertensive crisis can develop when MAOIs are taken with tyramine-rich foods or sympathomimetics. • Serotonin syndrome can develop if taken with drugs that increase serotonin levels. Drugs commonly implicated are: – SSRIs, TCAs, Mepridine & St. John’s Wort MMS1070: October 27, 2023 31 Antidepressant Drug-Herb Interactions • St. John’s Wort – Extracts of the plant called St. John's wort (Hypericum perforatum) exhibit antidepressant activity – Products containing these extracts are available in health food stores. – The extracts contain a substance called hypericin and several flavones. – Some of these compounds inhibit MAOI, whereas others appear to block the neuronal reuptake of serotonin. – Hypericum extracts appear to cause fewer adverse effects than but 32 MMS1070:other October 27,antidepressants, 2023