sign in sign up
<<
Home , Antidepressant, Anxiolytic, Azapirone, Lanicemine, Rapastinel

Baran Group Meeting Kelly J. Eberle and 12/05/20

Overview of and Proposed Mechanisms of Action for / Major Depressive Disorder (MDD) Anxiolytic: • American Psychiatric Association definition: • BDZs: (anxiolytic) act as a ; enhance binding at gamma aminobutyric - Minimum of five depressive symptoms (depressed mood, having a loss acid (GABA) , increasing function of GABA and slowing function of interest/pleasure in hobbies/activities, significant changes in appetite, weight, , psychomotor activity, loss of energy or fatigue, feelings or Relevant : worthlessness, diminished ability to concentrate, or ) 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 or better H !-aminobutyric acid explained by other psychological disorders (, bipolar, etc) (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 /panic that are difficult to control, HO HO coupled with , trembling, , sweat, rapid heartbeat • 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 (MAO) enzyme, which degrades monoamine neurotransmitters (structures above), increasing available • Most common , affects nearly 30% of adults at some serotonin, norepinephrine, and dopamine point in their lives. ADs often progress into depression • TCAs: Non-specifically prevents of neurotransmitters • Variants of : • SSRIs/SNRIs: Prevent reuptake of specific neurotransmitters - , obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), , and general anxiety disorder (GAD) https://doi.org/10.1096/fj.07-1102ufm • Treatment often includes both talk therapy and (anxiolytics) MAOI Included in this GM: SSRI SNRI - Overview of anxiety and depression - of selected drugs - Brief history of antidepressants/anxiolytics TCA - Major 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 (for MAOI: Monoamine Oxidase Inhibitor schizophrenia, bipolar, etc.) TCA: Antidepressant SNRI TCA - In-depth coverage of biology/ BDZ: mechanism of action for each drug SSRI: Selective Serotonin - 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 , 2007, drugbank.com Snakeroot plant, N H O Exp Clin Psych. 2015, 23, 1–21, Nat Rev Drug Discov. 2013, 12, 667–687 containing , 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, 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 “” was non-existent. Me H : antitubercular drug, seredipitously led to Since pre-WWII, 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 • : , psychostimulation, increased Psychiatrists used drugs as means to sedate and restrain patients appetite, and improved sleep • 1951: iproniazid inhibits monoamine oxidase NH2 : 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 toxicity amphetamine was used as such in 1930s Hoffmann-La Roche amphetamine (Benzedrine) through 1950s Monoamine oxidase enzymes: degradation of neurotransmitters “old school ”

Condensed timeline (see 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 , no • MAO-A: metabolizes dietary amines (i.e. ) and neurotransmitters heavy introspection, break patterns with • MAO-B: only metabolizes neurotransmitters 1937: 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 : MAOI action discovered in 1959 1939: Benzedrine approved for “mild depression” NH2 1940s: Marketed as anti- - 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 / 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 (Elavil) N O O 1961 (US) NH tranylcypromine 1. Grignard 2 second TCA NH Me O HN BrMg 2. HCl NMe2 (Nardil) 1961 (Marplan) NMe2 nonselective MAOI 1998 Hoffmann-La Roche nonselective MAOI Me R.S. Vardanyan, V.J. Hruby, Synthesis of Essential Drugs, 2006 - Before , MAOIs used sparingly N - selegiline: first MAO-B selective (at low doses) - Also used as Parkinsons treatment (1989) Me N - Dosed as for MDD (2006), selegiline (Emsam) collaboration between Somerset and Harvard Med 2006 Tricyclic Antidepressants (TCAs) (Pamelor) NHMe NHMe (Nopramin) 1963 NHMe 1964 Geigy (Vivactil) - Nonselective inhibitors of reuptake Geigy (now ) used off label for IBS Merck 1966 - Affect norepinephrine and serotonin receptors in brain, but also interact with other receptor sites (, acetylcholine, and epinephrine) leading to side (Sinequan) 1969 originally BI, then licensed to effects such as dry mouth, disorientation/dizziness, irregular heart rate O MgCl O O • Serendipitous discovery of (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 - only (Asendin) N available antidepressant for 1992 N NaNH2 years following withdrawal of N Me N iproniazid (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 on GABAA receptor O HN O N - GABA: inhibitory neurotransmitter, blocks brain signals, HN N decreases CNS activity OH OH - Binding of GABA to receptor produces anxiolytic effect N N N - Side effects: drowsiness, confusion, dizziness O N Cl - High risk of abuse and dependency Cl Cl Cl F O chlorodiazepoxide NH2 HO chlorodiazepoxide (Librium) (Tranxene) (Dalmane) !-aminobutyric acid - First BDZ synthesized, 1960 (Serax) 1967 Abbott 1968 Roche (GABA) - “Liberally” prescribed until Me 1964 treatment for O O insomnia treatment the 1970s, especially to young N withdrawal and epilepsy women and housewives HN - Basis for “Xanzolam” in O The Queen’s Gambit Cl N N HN OH O2N Cl N Original synthetic routes to Cl (Valium) Cl chlorodiazepoxide and diazepam (Klonopin) ACS Chem. Neurosci. 2014, 5, 253−260 1963 Hoffmann-La Roche Major advance 1975 Roche panic disorder treatment Leo Sternbach, “The story” in treatment of AD (Ativan) J. Med. Chem. 1979, 22, 1, 1–7 and in medicinal chemistry 1977 Wyeth (Xanax) Cl Cl N 1981 Upjohn (now Pfizer) - Panic disorder (colloquially, “the Upjohn Illness”) 1. NH OH N MeNH2 2 O Librium N Me O Me O 2. AcOH O HCl N N NO Cl HN alprazolam NH2 O 1. P S N Me N N NH2 O Cl NaOH 2 5 H Cl HN pyridine N TsOH O N N Me O N Cl 2. AcOH O O Cl Cl OEt diazepam N O Cl HN NH2 NH2 Me N N H N O Beilstein J. Org. Chem. 2011, 7, 442–495 Me SO Cl MeI Cl 2 4 NaOMe Xanax is most common recreational BDZ PCl3 or Raney Ni Street names: xannies, bars, ladders, Xanbars, Xans, Z-bars, handle bars, beans, footballs, planks, poles, blues, or blue footballs Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

Azapirones Selective Serotonin Reuptake Inhibitors (SSRI) - Serotonin receptor - Used for treatment of simultaneous depression and anxiety - No tendency for /abuse, but long - First antidepression rationally designed to target one specific - Suggested combination therapy: and BDZ neurotransmitter - Most famous in this class of anxiolytics: (BuSpar) 1986 BMS - Safe alternative to TCAs, BDZs, MAOIs, but not without side effects: N Route from original patent -, erectile disfunction, decreased (but can be used to treat J. Med. Chem. 1972, 15, 477–479 premature ejaculation) O buspirone N N N -sleep disorders: insomnia or excessive sleep N -gastrointestinal discomfort N N N -abrupt discontinuation can lead to with drawal symtoms (vertigo, electric O + N NC Cl shock sensation) O 1. N - First discovered at Eli Lilly in 1970, findings from seminal work: O 2. H2 Ra-Ni or LAH • MAOIs effective because they elevate concentrations of amine N N neurotransmitters O • (an antihisthamine) is a weak antidepressant; blocks HN NH2 reuptake of norepinephrine and serotonin O screening of OPPI 2008, 40, 391-394 Name? H diphenhydramine CO H (NH ) CO O O NH3, MeOH 2 4 2 3 NH O N analogs led to Me discovery of NC then H SO 81% OMe 2 4 O NMe2 R phenoxy CO2H O R 60% phenoxylpropylamines propylamines TBAB, K CO diphenhydramine () N Br N 2 2 Br "wave Br N H N N K2CO3, PEG-400 N O N N 94% Me HN N 96% buspirone (Zimeldine) Br - First SSRI, 1982 EU CF3 -Astra AB in Sweden (Prozac) 1987 - Withdrawn from market in 1983 not approved in US: N First SSRI in US - Caused Guillain Barré Syndrome NMe2 Nat Rev Drug Discov. 2013,12, 667–687 (autoimmune disorder leading to - Prozac is one of four antipressants O N N nerve damage) approved for use by pilots N H N (Zoloft) Pfizer N O 1992 for MDD, 1996 for OCD Me H O N O N Me Me O N (Travivo) BMS O - Development began in 1986 N N - Rejected multiple times O (Sediel) - Favorable review from FDA in 1996 Sumitomo N Cl 2016 but still not approved (Paxil) -only marketed in Japan Cl GSK 2001 F Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

MeHN O Other SSRIs Fluoxetine synthesis: selected examples * (Viibryd) O H N N US 2011 Merck/Forest Labs ACS Chem. Neurosci. 2014, 5, 14−23 2 O CF - Only for MDD not GAD 3 Me Prozac O NH2 O 1. CH2O, HNMe2 OH HCl (g) Cl NH 2. B H , THF SOCl NC 2 6 Me 2 Me (Luvox) CF3 O Me N N Solvay (now Abbott), 1994 (US) Me Me - Primarily for OCD but also MDD and 1982 Racemic CF3 anxiety disorders N CF3 - Candidate for prevention of breathing N fluoxetine 1. CNBr, problems caused by COVID-19 1988 asymmetric 2. KOH, H2O O glycol, 130 °C HO Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) Me CF3 N - Simultaneous inhibition of both serotonin and norepinephrine reuptake NaH Name? NaOH, MeOH - Used for treatment of simultaneous depression and anxiety Me reflux - Designed to interact with more than one receptor site NaI H OH H OH O - Does not interact with histaminic and cholinergic- receptors MeNH2 (+)-DIP-Cl Me and avoids adverse events such as dry mouth, , and sedation F N Cl Cl H Name? Two Generations of synthesis OPRD 2011, 15, 1392–1395 O *- Kalcat C8030-type Raney Ni NH2 CN CN NC / synthesis and impurity synthesis G1: LDA G1: Rh/Al2O3 O Org. Process Res. Dev. 2012, 16, 824−829 G2: NaOMe, G2: H Ra-Ni* NC 5-cyanopthalide HO 2, HO OH MeOH NMe2 NC MeO MeO MeO OH Grignard cyclization * O NMe G1&G2: (Pristiq) venlafaxine (Effexor) 2 HCHO, 2008 Pfizer 1993 Wyeth HCOOH F NMe2 O hydroxy analog of venlafaxine citalopram (Celexa), racemic mixture cyanodol HO Name? escitalopram (Lexapro), (S)-(+) ent. can be resolved with p-DTTA H 1998, 2002 N O MeO F Me NH2 NC E isomer + Z isomer O citalopram NC OMs S (Fetzima) N Me Me 2013 Forest Labs, MDD Me N Me Ar NMe 2 2 N (Cymbalta) racemate: (Savella) Cypress Biosciences Me O Ar 2004 Eli Lilly Ar -NDA filed in 2001 but delayed - MDD in France 1996 NMe NC 2 CN due to cGMP violations - Only approved for in US Significant impurities observed in cyclization step (0.5%) -MDD, GAD, fibromyalgia - Approved for MDD in other countries, Both were synthesized; use of tosyl suppresses formation Ar but not for fibromyalgia Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

Atypical Antidepressants O Alternate Indications for Antidepressants HCl H (Wellbutrin) 1985 GSK N Me Eating disorder treatment: Sleep disorder treatment: •fluoxetine for doxepine - Dual reuptake inhibitor of dopamine and norepinephrine Me (NDRI), only NDRI on market Me Me •bupropion and several SSRIs for Urinary incontenance: - Significantly lower rates of sexual disfunction (SD) than duloxetine bupropion HCl other antidepressants Cl : bupropion Hives: doxepine management: duloxetine Premature ejaculation: SSRIs - Can alleviate SD/treat SSRI-induced SD (off label) i. Br , DCM 2 prevention: ADHD: TCAs for second line - Used as anti- and smoking cessation aid t 80% - Side effects: can lead in increase in anxiety and lowers ii. BuNH2, NMP •TCAs treatment threshold for iii. HCl •SNRIs for comorbid migraine/MDD O One-pot Synthesis: (from freshman chem lab curriculum…) Me Purported Natural Remedies for MDD/GAD J. Chem. Ed. 2000, 77, 1479-1480 O Effective: Adverse effects: B9: (dosed as folate/folic extract: (Piper agomelatine N Me Cl acid) methysticum) H 2009 Servier -reduction of depression in -superior to MeO - receptor agonist concert with SSRIs - issues -approved in EU and AUS but not US Vitamin D: significant decrease in , St. John’s wort, -no significant advantage over other antidepressants depressive symptoms passionflower: Xiaobuxin-Tang: -widely used but effectiveness/ Off-Label Anxiety/Depression drugs: (Chinese herbal decoction) safety not guaranteed OH H efficacy in rats -St. John’s wort shown to have (dosed as Li2CO3) Me N O negative interactions with several - Approved for bipolar in 1970 Some efficacy: drugs including pharmaceutical - MOA not fully understood, but impacts Me Aromatherapy: in combination with antidepressants through inhibition (Inderal) massage of excitatory signaling 1965 ICI (now AstraZeneca) -temporarily improved mood No proven efficacy: - Effective in augmentation of 1988 Nobel Prize in Medicine for treatment Meditation: Acupuncture antidepressants for TRD of coronary artery disease and hypertension shown to reduce symptoms of MDD Melatonin CNS Drugs 2014, 28, 331–342 - Used for performace anxiety and PTSD and GAD Ginger : moderate effect on depressive Green tea symptoms Cl (Atarax) OH NH2 Me Omega-3: small to moderate positive 1956 Pfizer effects O O O Me S N NH N 2 O OH , Biochemistry and Behavior 2008, 89, 572–580 Phytother Res. 2005, 19, 183–188 (Provigil) (Lyrica) Am Fam Physician. 2007, 76, 549–556 1998 Cephalon 2004 Pfizer Complement Ther Nurs Midwifery. 2003, 9, 90–97 sleep disorder drug antiepileptic, fibromyalgia Database System Rev. 2006 shown to treat MDD approved for GAD in EU World Psychiatry 2019, 18, 308–324 Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

Investigational Drugs N-Methyl-D-Aspartate (NMDA) Receptor Antagonists Veranamine - NDMA receptors: -gated cation channels activated by glutamate - Recently isolated natural product - Possible mechanism of action of antagonists (such as ): - In vivo antidepressant activity and selective affinity for serotonin receptors J. Nat. Prod. 2020, 83, 1092−1098 O Me SeO 2 glutamate I2, acetone, reflux dioxane/water O O 78% Me 72% Me Br NH2 Name? Br N Me Br N Me O O H H NH N TMSCN 3 ZnI Me Me AcO TMSO CN NHAc Clinical Trial Failures: Br N Me C&EN 2020 Volume 98, Issue 3 H P2O5 1. LAH Eur. J. Pharm. 2019, 865, 172732 veranamine TsOH, DMA 2. Ac2O Translational Psychiatry 2017, 7, 1–8 Me Me "W, 200 °C Br N Me 85% Br N Me NH2 52% H (3 steps) H U.S. Patent 4,826,860 riluzole (Rilutek) Name and mechanism? KSCN Br /AcOH N 1995 Rhone-Poulenc-Rorer 2 ALS drug “Magic Mushrooms” NH2 - Very recently (JAMA Psychology, November 2020), psilocybin S - Unsuccessful in trials for TRD CF3O - Under development for GAD demonstrated to have antidepressant activity in TRD patients OCF3 Gram scale synthesis: J. Nat. Prod. 2003, 66, 885-887 H2N Me OBn Me OH N Me BnO N Me N 4 steps, 68% P OH nBuLi O (Namenda) O NH Me Me [(BnO)2PO]2O AstraZeneca 2 2013 Merz - Failed to meet endpoint, alzheimer’s treatment N THF, -78 °C - Low-to-moderate NMDA receptor H 85% terminated in 2013 N N OH blockade H H NH2 - Ineffective against MDD Int A Me O Me O O 2020 update (20 g scale): Me Me Bn O OH Me O O Process route development:HO N BnO N Me NH NH2 F - Improvements to yield P P OH N N O O O H and purity of Int A O O N N N Me - Determination of critical H2, Pd/C Allergan rislenemdaz N process parameters (CPPs) 85% - at -binding NMDA and in-process controls (IPCs) N 72% from A N site on NMDA receptor Cerecor (acquired from Merck) - Recrystalization identified H H psilocybin - FDA’s breakthrough therapy designation - Under development for TRD Synthesis 2020, 52, 688–694 gram scale in 2014, failed during Phase III - Failed in Ph II in 2016 Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

Ketamine: “Special K” Synthesis of - Approved as an in 1970, - Previous entantiospecific syntheses: lack of efficient method for the commonly prescribed off label for MDD installation of the α-tertiary amine center Org. Lett. 2019, 21, 6575−6578 Esketamine: - Recently approved for TRD, Unsuccessful strategy: 4X antidepressant effect of racemate CCl3 - NMDA-type antagonist - Exact mechanism of action is unknown OMe O NH N ketamine Me NHCOCCl Cl C O NH 3 OMe 3 NaH Me Δ NH Name? Synthetic approaches to ketamine O Reason for failure? X J. Chem. Sci. 2020, 132, 133-139 Cl Cl Original Route (Stevens Method) Cl esketamine O Cl Cl MgBr O OH CN THF Br2 66% O OMe [Ru] OMe

then NH Cl (racemic alcohol) 4 or NBS OMe TEA-HCO H Cl 77% [Pd] 2 (OH)2B Me 88% 88%, 98% ee N O Br Cl Mechanism? OH Br Cl Cl MeNH2 Δ NH2 N 1. O yield not 84% reported Cl Cl O O O Cl3C NCO H OMe TFAA OMe ketamine 2. K2CO3 Me TEA O Ar Me OMe O N O HN N Δ MeNH2 OH Cl Cl Cl OH 91% 73% Cl Cl MeO C O MeO Me O Me New Route KMnO4 N HN HN - Improved yields, avoids use of Br 2 85% LAH HCl Cl O 93% Mg HO acidic 80% Br THF ionic liquid Cl 98% ee Cl Cl + esketamine 82% 97% 99.9% ee Cl Cl Allyl cyanate/isocyanate rearr. Eur. J. Org. Chem. 2017, 1295–1307 Baran Group Meeting Kelly J. Eberle Antidepressant and Anxiolytic Drugs 12/05/20

Endocannabinoids Current Psychiatry Reports 2019, 21, 37−46 Relevant GM: Cannabinoids, Harwood 2020 - THC is , but effect is diminished when co-administered with CBD - CBD given alone has anxiolytic properties, particularly under circumstances or in response to stimuli which normally provoke anxiety, but still a need for large scale placebo-controlled studies Me Me

OH H OH H

H H Me Me O Me HO Me Me (CBD) tetrahydrocannabidiol (THC) - Previously, interest in studying cannabinoid receptor CB1 , “Mental pain is less dramatic than physical but rimonabant when used for anti-obesity lead to depression, anxiety, pain, but it is more common and also more and suicidal ideation hard to bear. The frequent attempt to Me O conceal mental pain increases the burden: N it is easier to say “My tooth is aching” than Cl N H to say “My heart is broken.” N N C.S. Lewis, The Problem of Pain Cl rimonabant (Acomplia) Cl inverse CB1 receptor agonist Approved in 2006 (EU) Withdrawn in 2008

Personal Resources • National Prevention Lifeline 1-800-273-8255 • Substance Abuse and Mental Health Services Administration (SAMHSA) - National Helpline 1-800-662-HELP (4357) - https://www.samhsa.gov/ • Scripps CAPS (free services for employees) • Services through TSRI grad student health insurance: - In-network mental health services covered at 100% - 20 acupuncture sessions/year covered at 100% • Your primary care doctor; 85% of MDD/AD drugs are prescribed by GPs