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Antidepressant and Anxiolytic Drugs 12/05/20 Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20 Overview of Anxiety and Depression Proposed Mechanisms of Action for Antidepressants/Anxiolytics Major Depressive Disorder (MDD) Anxiolytic: • American Psychiatric Association definition: • BDZs: (anxiolytic) act as a sedative; enhance binding at gamma aminobutyric - Minimum of five depressive symptoms (depressed mood, having a loss acid (GABA) receptor, increasing function of GABA and slowing brain function of interest/pleasure in hobbies/activities, significant changes in appetite, weight, sleep, psychomotor activity, loss of energy or fatigue, feelings or Relevant Neurotransmitters: worthlessness, diminished ability to concentrate, or suicidal ideation) O - Symptoms occur daily for at least two weeks, and are newly presented/ HO NH2 clearly worsened prior to the onset of the episode NH2 - Depressive episodes must significantly impair social or occupational HO N functioning and must not be attributed to substance abuse or better H !-aminobutyric acid explained by other psychological disorders (schizophrenia, bipolar, etc) serotonin (GABA) • MDD affects ~17.3M people in the US annually (7.1% of population) OH • Treatment is up to 80% effective yet only 33% of depressed people HO NH HO NH2 seek/receive treatment 2 Anxiety Disorders (AD) BDZ • Feelings of intense irrational fear/panic that are difficult to control, HO HO coupled with dizziness, trembling, nausea, sweat, rapid heartbeat norepinephrine dopamine • Diagnosis: Three or more symptoms (restlessness, fatigue, inability to DOI: 10.2174/1874143601004010001 concentrate, irritability, muscle tension, sleep disturbance) majority of Antidepressants (also can act as anxiolytics): days for three months • MAOIs: inhibits monoamine oxidase (MAO) enzyme, which degrades monoamine neurotransmitters (structures above), increasing available • Most common mental disorder, affects nearly 30% of adults at some serotonin, norepinephrine, and dopamine point in their lives. ADs often progress into depression • TCAs: Non-specifically prevents reuptake of neurotransmitters • Variants of anxiety disorder: • SSRIs/SNRIs: Prevent reuptake of specific neurotransmitters - panic disorder, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), phobias, and general anxiety disorder (GAD) https://doi.org/10.1096/fj.07-1102ufm • Treatment often includes both talk therapy and medication (anxiolytics) MAOI Included in this GM: SSRI SNRI - Overview of anxiety and depression - Mechanism of action of selected drugs - Brief history of antidepressants/anxiolytics TCA - Major drug classes in this field - Atypical antidepressants - Non-pharmaceutical treatments Glossary of Abbreviations: TCA - Investigational drugs MDD: Major Depressive Disorder Not included in GM: TRD: Treatment Resistant Depression - Complete summary of all (G)AD: (General) Anxiety Disorder depression/anxiety treatments GABA: gamma amino butyric acid - Other antipsychotics (for MAOI: Monoamine Oxidase Inhibitor schizophrenia, bipolar, etc.) TCA: Tricyclic Antidepressant SNRI TCA - In-depth coverage of biology/ BDZ: Benzodiazepines mechanism of action for each drug SSRI: Selective Serotonin Reuptake Inhibitor - Medical advice or diagnosis… SNRI: Serotonin/Norepinephrine Reuptake Inhibitor Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20 Key References: Monoamine Oxidase Inhibitors (MAOI) OMe Corey’s Molecules and Medicine, 2007, drugbank.com Snakeroot plant, N H O Exp Clin Psych. 2015, 23, 1–21, Nat Rev Drug Discov. 2013, 12, 667–687 containing reserpine, OMe Brief History of Antidepressants/Anxiolytics: used as a natural remedy MeO N H O HO for ‘melancholia’ H H OMe Laudanum: tincture used to treat “pain and reserpine Reserpine: anti-hypertention drug O OMe sorrow” for over four centuries Work of N. S. Kline, 1950s: O H morphine OMe - Opium (contaning morphine) responsible for - reserpine decreased serotonin and norepinephrine, analgesic and antidepressant effects caused depression in ‘normal’ individuals H N Me - Contributed to development of monoamine oxidase (MAO) theory for HO mechanism of action of antidepressants Prior to the 1960s, the concept of “biological psychiatry” was non-existent. Me H iproniazid: antitubercular drug, seredipitously led to Since pre-WWII, psychoanalysis had little to do with psychiatry (as practiced O N in mental institutions). Freudian mentality: mental illness could be healed by N Me antidepressant development insight into previous distress that caused it, eschewing the use of drugs. H • Side effects: euphoria, psychostimulation, increased Psychiatrists used drugs as means to sedate and restrain patients appetite, and improved sleep • 1951: iproniazid inhibits monoamine oxidase NH2 Amphetamine: the first antidepressant? N • Antidepressant activity discovered by Kline in 1952 • Approved in 1958 (US), used off label to treat MDD Although not developed as an antidepressant, Me iproniazid (Marsilid) • Withdrawn from market in 1961 due to liver toxicity amphetamine was used as such in 1930s Hoffmann-La Roche amphetamine (Benzedrine) through 1950s Monoamine oxidase enzymes: degradation of neurotransmitters “old school Adderall” Condensed timeline (see Amphetamines GM, Harwood 2020) NH2 OH 1927: Gordon Alles reports “feeling of well-being” from amphetamine 1935: Benzedrine reported to enhance “pep” and “energy-feeling” O 1936: Market with neurologists and psychiatrists increased in part due to HO MAO HO studies of psychiatrist Abraham Myerson (Professor of Clin. Psych. Harvard Medical School). N N - Myerson considered an authority on depression, author of The Nervous H H Housewife (1920) and When Life Loses Its Zest (1925) serotonin 5-Hydroxyindole acetic acid - Referred to depression as ‘anhedonia’ (lack of pleasure) Two forms of MAO: - Myerson’s treatment regimen: wholesome diet, moderate exercise, no • MAO-A: metabolizes dietary amines (i.e. tyramine) and neurotransmitters heavy introspection, break insomnia patterns with sedatives • MAO-B: only metabolizes neurotransmitters 1937: Clinical trial for amphetamine. Neurasthenics (depressed patients) - Early MAOIs non-selective, inhibit both MAO-A and MAO-B, leading to improved but anxious patients became more anxious. Benzedrine at buildup of dietary amines which causes hypertension first is only approved or use in psychiatric institutions tranylcypromine: MAOI action discovered in 1959 1939: Benzedrine approved for “mild depression” NH2 1940s: Marketed as anti-depressant - Inhibits MAO-A and MAO-B, leading to 1960s: Tricyclic antidepressants (TCAs) reinforced biological understanding tyramine build up unless foods containing tyramine and drug treatment of minor psychiatric conditions, concept of (cheese, beer, wine) are avoided, “the cheese effect” tranylcypromine “biological psychiatry” is born - Still used for treatment resistant depression (TRD) (Parnate) Rasmussen’s Journal of the History of Medicine, 2006 SKF 1961 (US) Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20 Monoamine Oxidase Inhibitors continued 1st Generation TCAs: tertiary amine chain inhibit serotonin and norepinephrine reuptake O Δ OEt EtOH/-OH OH 2nd Generation TCAs: secondary amine chain selective for inhibition of N2 norepinephrine reuptake OEt O trans isomer O separated - Dangers: cause arrhythmia/cardiac arrest at high doses 1. SOCl2 - Largely replaced by SSRIs Vardanyan & Hruby’s Synthesis of Essential Drugs Name step 2? 2. NaN3 3. HCl H N amitriptyline (Elavil) N O O 1961 (US) NH tranylcypromine 1. Grignard 2 second TCA NH Me O HN BrMg 2. HCl NMe2 phenelzine (Nardil) 1961 isocarboxazid (Marplan) NMe2 nonselective MAOI 1998 Hoffmann-La Roche nonselective MAOI Me R.S. Vardanyan, V.J. Hruby, Synthesis of Essential Drugs, 2006 - Before selegiline, MAOIs used sparingly N - selegiline: first MAO-B selective (at low doses) - Also used as Parkinsons treatment (1989) Me N - Dosed as transdermal patch for MDD (2006), selegiline (Emsam) collaboration between Somerset and Harvard Med 2006 nortriptyline desipramine protriptyline Tricyclic Antidepressants (TCAs) (Pamelor) NHMe NHMe (Nopramin) 1963 NHMe 1964 Geigy (Vivactil) - Nonselective inhibitors of neurotransmitter reuptake Geigy (now Novartis) used off label for IBS Merck 1966 - Affect norepinephrine and serotonin receptors in brain, but also interact with other receptor sites (histamine, acetylcholine, and epinephrine) leading to side doxepin (Sinequan) 1969 originally BI, then licensed to Pfizer effects such as dry mouth, disorientation/dizziness, irregular heart rate O MgCl O O • Serendipitous discovery of chlorpromazine (Thorazine) FeCl2, DCME TCAs from antischizophrenic 1953 Rhone-Poulenc OH 88% Me N activity of chlorpromazine S O 2 • Explored by Swiss psychiatrist Roland then HCl Kuhn in 1950s at Ciba-Geigy 71% from O 70% • Amine side chain key to activity Cl N phenol and isobenzofuranone Tetrahedron 2007, 73, 2913-2922 Me2N See GPCR Drug GM, Barton 2019 NMe2 NH N - imipramine only amoxapine (Asendin) N available antidepressant for 1992 N NaNH2 years following withdrawal of N Me N iproniazid trimipramine (Surmontil) H NMe - Drawback: numerous side 2 Cl EU 1966, US 1980 NMe imipramine (Tofranil) effects and narrow therapeutic 2 Cl NMe2 O Rhone-Poulenc 1959 Ciba (now Novartis) window (can lead to overdose) Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20 Benzodiazepines (BDZs) Other selected BDZ examples: O Et2N HN Me O - BDZs act as modulators
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