Pharmacology of Mental Disorders Lecture notes PDF

a place of mind UBC IMH Pharmacology of mental disorders Department of Psychiatry Disclosure and Mitigation 2022-2024 Consultation/Advisory Boards: AbbVie, Boehringer Ingelheim, Newron, Translationa...

a place of mind UBC IMH Pharmacology of mental disorders Department of Psychiatry Disclosure and Mitigation 2022-2024 Consultation/Advisory Boards: AbbVie, Boehringer Ingelheim, Newron, Translational Life Sciences Grants: CIHR, NIA Mitigation I create my own presentations I describe conflicts of interest prior togotany teaching, in both presentations, and in publications S - Law Engineer n lifesciences - ↳ Med Had 2 of ↳ Queens did -bour profs MD + MS2 as grad/post doc student ! Psychiatri in his lab ecolumbia Objectives Part 1: A primer on mental disorders and their treatment Discuss the clinical characteristics of mental disorders Briefly describe the role of medications Part 2: The functional anatomy of brain systems The anatomy and neurochemistry of ascending pathways in the brain The role of circuits in clinical brain disorders Part 3: Synaptic terminals and targets for drugs Le milieu intérieur “The constancy of the internal environment is the condition of a free and independent existence” Claude Bernard (1813-1878) Homeostasis: self-regulating processes that maintain constancy of “Le milieu intérieur” To Maintain balance Health Receptor Control Effector centre Walter Cannon (1871-1945) Operationalising description to diagnostic criteria Robert L. Spitzer, MD (1932-2015) (American Psychiatric Association, 1980) Concepts in Psychology compared with Medicine Scientific psychology: normal and abnormal have a statistical meaning, abnormal is uncommon or rare Medicine: abnormal is morbid or diseased, in psychiatry both frequency and severity may contribute to defining an experience as abnormal (M Hamilton ed. (1974) Fish’s Clinical Psychopathology, 2nd Edition; Figure: HE Schulz et al, 2015 DOI: 10.13140/2.1.2552.5288) Origins: an interview method to elicit experiences · Notests ↓ just talk , ask questions if A theological manual - A way to figure witch or not (Heinrich Kramer and Jacob Spenger, Malleus Malleficarum,1486) Osler and taking a patient’s history “the practice of medicine is an art based on science” “Listen to your patient, he is telling you the diagnosis” Sir William Osler 1849-1919 Early clinical concepts of symptoms Powers of observation Evolution and dissolution of the nervous system in man Application of positive and negative symptom concepts in this model Hughlings Jackson (1835-1911) From symptoms to syndrome Symptomes come together to form syndrome “... symptoms must be distinguished from one another, that common clusters of symptoms must be recognized, and that the natural course of development and remission of these clusters should be appreciated...”. Thomas Sydenham PR McHugh and PR Slavney (1986) 1624-1689 The Perspectives of Psychiatry, p34 Phenomenology: studying mental experience understandexperience apr to context putitheir past Karl Jaspers (1883-1969) “In the current clinical nomenclature, “psychotic symptom” denotes a manifestation of cognitive or perceptual dysfunction, mainly delusions or hallucinations, whereas “psychotic disorder” refers to a condition in which psychotic symptoms meet specific diagnostic criteria for a disease.” psychosis-lost connection w/ reality (NEJM 2018;379:270-280) Video: First rank symptoms patients consent from Ip All for teaching purposes-w/ Schizophrenia Pierre Trudeau sending me message over Radio L He recovered in this video fully ↳a describes his past symptoms Vic-4-s4-new Video: Hallucinations - insight How she into her disease · gain insight Clip-5 “you’re hearing voices... for 6 months I said No … I do hear voices... I thought it was real... that was just normal... ” ↑ Video: Delusions in acute psychosis Law student when he diagnosed / · became Schizophrenin ex. License plate numbers mean a message just to him vic4-s3-5new 3 Film Board of Canada Documentary by National Below 1911-1999 ir Heinz. Leihanama Delusions in acute psychosis License plate numbers on cars were “code words to me only”, indicating which cars were safe, and which might run him over “noise made outside by traffic going by had special significance” traffic He acted on these beliefs, running though National Film Board of Canada, the Mental Symptoms videos The National Film Board (NFB) is a public organization and an agency of the Government of Canada The mandate is “to create, produce and distribute distinctive and original audiovisual works that reflect the diverse realities and perspectives of Canadians” The works produced span: a) Documentary, b) Animation, c) Interactive, d) Education In 1951, the NFB created nine short films on Mental Symptoms, intended to be used by educational institutions Each features Dr. Heinz Lehmann interviewing one or more patients The films were made before antidepressant or antipsychotic drugs were available – some of the patients are seriously ill, and have been for many years A Canadian psychiatrist and Lasker Award winner Heinz Lehmann was born in Berlin, Germany. His father was Jewish and a chest physician, his mother was Protestant. With the rise of Adolph Hitler and Nazism in Germany, Lehmann and his father faced extermination in a death camp, the fate of 6 million other Jews in the Holocaust. Anticipating this near extermination, in 1937 Lehmann applied to the German secret police, the Gestapo, to go to Canada for a 2- week ski vacation. The vacation trip allowed him to come to Canada, then stay as a refugee. He worked, practiced, taught, and researched in psychiatry for the next 62 Heinz Lehmann (1911-1999) years. “For his demonstrations of the clinical uses of chlorpromazine in the treatment of mental disorders” Mental symptoms video: Depressive states Part 1 (12:07) Dr. Lehmann interviews a 60-year old man presenting with his fourth episode of major depression. The interview is presented in two parts, to explore diurnal variation. The first section is in the afternoon, the second in the morning. 2 Section " "Im full of the devic, I must be section ↓ · · restless ! ! · Hopeless still used today ↳ physical anxiety! , ShockTreatment Previous Electric changes · low self-esteem very · Not responding to reassurance NegativeThoughts about future · sad "lonesome" very , crying · , A Major Depressive Episode as a syndrome diagnosis in the DSM Requires five or more symptoms, one of which must be: Depressed mood (e.g. sad, empty, hopeless, tearful) Loss of interest or pleasure In addition, from the following: Worthlessness or excessive or inappropriate guilt Somatic symptoms Weight loss/gain or decrease/increase in appetite Insomnia or hypersomnia Agitation or retardation Fatigue or loss of energy Cognitive Decreased thinking Impaired concentration Indecisiveness Suicidal ideation, plans Mental symptoms #8 video: Manic state (13:07) ↳Part of Bipolar Disorder Dr. Lehmann interviews a older woman presenting with a recurrent manic episode. but irratable bit Appear happy a · distrated very · from idea to idea Jumps · always making sense · Not · Expression constantly changing Stages and associated symptoms in a manic episode Ili¬ ce CD CO ° e Dysphoria, j-, XD-. Mania V' ' Psychosis -4—^^^ -!^-·" Hospital Days 20 Stage I Stage Stage Stage II Stage Distractable, More manic and No sleep, religious Coherent, tired, Labile, numerous racing thoughts, hyperverbal, delusions, still paranoid, phone calls, feels joking, intrusive, hyperactive, "hearing God" difficulty good, laughing and happy, can't concentrate, impulsive, much fragmented, restless, concentrating, joking, hyperverbal, impulsive, pressure of speech, confused, racing thoughts, irritable, changing hyperverbal, still responding disruptive, loud, depressed, labile moods quickly, singing to limits, racing more talkative, insightful thoughts, paranoid, severely agitated, delusions and grandiose, labile "Going downhill at hallucinations 190 MPH," singing loudly, crying Fig 3.—Relationship between stages of a manic episode and daily behavior ratings (patient 72). (Carlson GA, Goodwin FK, Arch Gen Psychiatry 1973;28:221) Treatment response in acute psychosis more resistant a FE-S-SA Ref-S-SA-clozpine 160 140 Treat Acute 120 · stages PANSS total 100 80 60 40 base f/u adm dc Emil Kraepelin on his round at the Psychiatric Department of the University of Munich Emil Kraepelin - Chairman of the Psychiatric Department of the University of Munich 1903-1922 In 1891 Kraepelin began a research programme to quantify psychiatric disorders and eliminate any subjective biases on the part of the researcher. His aim was to place psychiatry on a more scientific foundation. Data were collected about every new patient that was admitted to the clinic and summarized on specially prepared index cards, his famous Zahlkarten. In his posthumously published Memoirs (first published in German 61 years after his death) Kraepelin described his method: „... after the first thorough examination of a new patient, each of us had to throw in a note [in a "diagnosis box"] with his diagnosis written on it. After a while, the notes were taken out of the box, the diagnoses were listed, and the case was closed, the final interpretation of the disease was added to the original diagnosis. In this way, we were able to see what kind of mistakes had been made and were able to follow up the reasons for the wrong original diagnosis (p. 61).“ KLINIKUM DER UNIVERSITÄT MÜNCHEN® http://www.klinikum.uni-muenchen.de/Klinik-und-Poliklinik-fuer- Psychiatrie-und-Psychotherapie/de/index.html Kraepelin‘s „Zählkarten“ (‚counting cards‘) formed the basis for a psychopathological documentation system KLINIKUM DER UNIVERSITÄT MÜNCHEN® http://www.klinikum.uni-muenchen.de/Klinik-und-Poliklinik-fuer- Psychiatrie-und-Psychotherapie/de/index.html A Resident's charting note for a case of schizoaffective disorder Hosp-2 Hosp-1 Hosp-3 Hosp-2 Rehab farm Hosp-5 Hosp-6 Hosp-7 Hosp-4 Hosp-8 Jail Hosp-7 Hosp-7 Course and phases of illness: schizophrenia (an der Heiden and Häfner, Eur Arch Psych 2000;250:292) Illness phase and course of schizophrenia First episode Relapse 10-yr outcome ! · PreventRelapse Acute episode 15% Treatment 15% 15% resistant 39% 45% Chronic 65% 26% Functional 40% 85% recovery 6% 20% 14% (Honer WG et al., Am J Psychiatry, 2021;178:369; based on Agid O et al., J Clin Psychiatry 2011;72:1439, Chan SWK et al., Schizophr Bull 2021;47:485, Chan SWK et al., Schizophr Res 2019;204:65, Hui CL et al., Psychol Med 2019;49:2206) ) First episode and First relapse or How long does the first episode schizophrenia patient need to be on antipsychotic medication? (Chen et al., Brit Med J 2010;341:c4024) Relapse prevention in First Episode Psychosis What meds MT: Quetiapine 400 mg/d · t How to maintain meds long · ≥12 mon antipsychotic (actual mean = 22 mon) Switch to PL: Placebo study med Relapse Prevention in First Episode Psychosis MT: 32% (19%-45%) PL: 76% (66%-86%) 1 Probability of remaining relapse-free 0.9 of had a l chance 0.8 ↳ relapse 0.7 Quetiapine 0.6 0.5 -had / chance of 0.4 relapse Placebo 0.3 0.2 0.1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days Summary: Part 1 Mental disorders are characterised by identifiable symptoms that cluster into syndromes Mental disorders frequently have acute episodes Mental disorders may have a pattern of relapses S episodes and remissions, or may be chronic Medications ameliorate the severity of symptoms in the acute phase, and may decrease the duration of acute episodes (shorter acute episodes depression episode - Medications can help prevent relapses  a place of mind UBC IMH Functional Anatomy of Brain Systems Neurotransmitters: a focused list Acetylcholine Noradrenaline Serotonin Dopamine Glutamate GABA Drug classes Antidepressants Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRI) Monoamine oxidase inhibitors Mood stabilisers prevent relapse -> Lithium Anticonvulsants: lamotrigine, valproic acid Antipsychotics First generation (dopamine antagonists) Block receptors - D2 Second generation (dopamine antagonists or partial agonists) Clozapine Sedative-hypnotics-antianxiety - OLD, panir disorders Benzodiazepines - Short term banxiety Z-drugs Stimulants (amphetamine-like) -Children W/ADHD Neurotransmission and drug action Receptor Control Effector centre Control centre: a neuron, Control a group of interconnected Effector Receptor neurons, a group of centre interconnected brain regions 2 inputs.Bas ex on ex. Cholinergic ex - Popanergic  Mapping control centres: Cholinergic ↳ Ach A and B sections modified from Martin JH. 1996. Neuroanatomy: Text and Atlas.2nd Ed. McGraw-Hill, New York 39 Source: Blumenfeld, H. (2010) Neuroanatomy through Clinical Cases 2nd Edition. Sinauer Associates, Inc., Sunderland MA  Mapping control centres: Noradrenergic I NE Brainstem sections modified from [top] the University of Washington Digital Anatomist Project and [bottom] Martin JH. 1996. 40 Neuroanatomy: Text and Atlas. 2nd Ed. McGraw-Hill, New York Source: Blumenfeld, H. (2010) Neuroanatomy through Clinical Cases 2nd Edition. Sinauer Associates, Inc., Sunderland MA  Mapping control centres: Serotonergic Brainstem section modified from Martin JH. 1996. Neuroanatomy: Text and Atlas. 2nd Ed. McGraw-Hill, New York 41 Source: Blumenfeld, H. (2010) Neuroanatomy through Clinical Cases 2nd Edition. Sinauer Associates, Inc., Sunderland MA Mapping control centres: Dopaminergic *All from Brainstem but travel to dif areas of brain Source: Blumenfeld, H. (2010) Neuroanatomy through Clinical Cases 2nd Edition. Sinauer Associates, Inc., Sunderland MA Thinking about a disease as affecting a single neurotransmitter system: Parkinson’s disease Receptor Control Effector centre Movements short video #6, 7.3.3 (58) Disease Parkinsons Advanced) Movements short video #6, 7.3.3 (58) Hypokinetic - bradykinesia ↳ slow movenment Turning difficulty SNegativeSymptoms Freezing Other features Hyperkinetic: “pill-rolling tremor” Facial impassivity “masking" Negative Symptone - Parkinson’s disease (advanced) Negative symptom pathway Positive symptom pathway Tremor BG BG blu to a relative Ach] change huge Balance ACh Blow Dopamine + ! (Ratio&4) Movements 7.1 (54) Parkinson’s disease A treated patient with Parkinson’s disease describes his symptoms, and persistent abnormal movements can be observed. Thinking about the effects of treatment Symptoms is · Tremors stiffness in muscle TreatmentTo est - whenstarted 1-3 times dry - a d Now9 Sinemetplos + 3 Sinemet · Can't more when not enough dopamine ↳ moving a lot when too much Dopa · Mood swings -I says he can get aggressive Movements 7.1 (54) Parkinson’s disease Movements 7.1 (54) Parkinson’s disease Chorea / dystonia (left hand and ankle) Craniocervical dystonia (right rotational torticollis) Akathisia FromAkathisia the interview history Tremor and stiffness - Restless too much dopaminea certain times “Off” periods - Mood symptoms Negative symptom pathway Positive symptom pathway BG BG BG  a place of mind UBC IMH Circuits in clinical brain disorders A reversible change in consciousness: Sleep Sleep as an active process rather than a lack of stimuli neurons in the brainstem Awake-promoting action from Brainstem reticular formation-to-thalamus Sleep-promoting action from neurons in the hypothalamus movement (REM) sleep Discovery of rapid eye Requires process a fast switching Constantin von Economo Mental state: dreaming - requires loss of muscle tone (1876-1931) Image by Max Schneider (except eyes and breathing) (Sandi MS, Brain 2019;142:2888)  sleep for months ?? Von Economo encephalitis, or encephalitis lethargica O FH Lewy, 1925; Wellcome Library (YouTube.com/@WellcomeFilm) An illness linking brain and mind: von Economo’s disease inflame (von Economo C, J Nerv Ment Dis 1930;249)  Switching between REM and non-REM sleep control phases of sleep GABAergic Cholinergic Glutamatergic Neuron 2019 103980-1004DOI: (10.1016/j.neuron.2019.07.009) Copyright © 2019 Elsevier Inc. Terms and Conditions A cortical microcircuit balances excitation and inhibition (Smucny J et al., Neuropsychopharmacol 2022;47:292-308)  automatically undertaken (ie, shaking hands or saluting muscle Functional circuitry for cortex and basal ganglia at a distance). When the sequence involves different is incr rapid typical A Motor circuit B Associative circuit C Limbic circuit long-la stretch cortex this st proxim also pr correla Caudate Caudate clear.60 Thalamus Thalamus Thalamus The by find as de GPe GPe GPe Stimu GPi GPi GPi in the cortex Putamen Putamen Putamen contro STN STN STN medic monke Figure 4: Functional organisation of the basal ganglia tetrahy The basal ganglia are divided into motor (A), associative (B), and limbic (C) subregions, which are topographically segregated, as highlighted by areas coloured in red (motor cortex), green (prefrontal cortex), and blue (anterior neuron cingulate cortex). Figure reprinted from Obeso and colleagues. GPe=globus pallidus pars externa. GPi=globus 4 specifi pallidus pars interna. STN=subthalamic nucleus. firing (Rodriguez-Oroz M et al. Lancet Neurol 2009;8:1128) Summary: Part 2 Ascending monoamine neurotransmitter pathways are the focus of study of multiple mental and neurological disorders Ascending systems impact on multiple subcortical and cortical targets creating circuits of activation and inhibition The cortex itself contains microcircuits, balancing excitation and inhibition to create output effects  a place of mind UBC IMH Synaptic terminals and targets for pharmacotherapies of mental disorders (NEJM 2018;379:270-280) Synaptic terminal and neurotransmission Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Vesicular Neurotransmitter Synaptic terminal and neurotransmission Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Synaptic terminal and neurotransmission Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Synaptic terminal and neurotransmission Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Vesicular Neurotransmitter Synaptic terminal and neurotransmission Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Vesicular Neurotransmitter  a place of mind UBC IMH Points of contact to modify synaptic neurotransmission Postsynaptic receptor antagonist (risperidone) Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Reuptake inhibitor (cocaine) Postsynaptic receptor + Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Agonist at the autoreceptor (clonidine) Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Vesicular Neurotransmitter Inhibit the vesicular transporter (tetrabenazine) Postsynaptic receptor Postsynaptic receptor Transporter Presynaptic Cytoplasmic (auto)receptor Neurotransmitter Inhibit vesicular reuptake + transporter reversal (methamphetamine) Postsynaptic receptor + Transporter umps reverse ! into Synapse Cytoplasmic A Presynaptic (auto)receptor Neurotransmitter Neurotransmitter degradation Postsynaptic receptor + (Transporter) Cytoplasmic Neurotransmitter Neurotransmitter degradation Postsynaptic receptor (Transporter) Cytoplasmic Neurotransmitter Neurotransmitter degradation inhibitor (donepezil) Postsynaptic receptor + (Transporter) Cytoplasmic Neurotransmitter (NEJM 2018;379:270-280) Schizophrenia: Treatment response “About 20 percent of patients have complete remission of their symptoms... for 30 percent of patients who do not have a response to other treatments, clozapine has substantially enhanced therapeutic effects...” (New Engl J Med 2003:349:1738-1749) Antipsychotic drugs and receptor affinity (McCutcheon RA, Biol Psychiatry, 2023:94:561-568) Clustering antipsychotic drugs according to receptor affinity (McCutcheon RA, Biol Psychiatry, 2023:94:561-568) PET: clozapine and risperidone Risperidone Clozapine 100 100 80 80 Percent occupancy 60 60 40 40 20 20 0 0 D2 D2 -20 -20 5HT2 5HT2 -40 -40 0 2 4 6 8 10 12 0 200 400 600 800 1000 (Kapur et al., Am J Psychiatry 156:286, 1999)  Add another drug if Clozapine + Haloperidol doesn't respond to clozapine 100 90 D2 receptor percent occupancy 80 70 60 50 40 30 20 cloz cloz+hal 10 0 0 1 2 3 4 5 6 (Kapur et al., Am J Psychiatry 158:311, 2001)  Receptor target Neurotransmitter A ⍺ Neurotransmitter B β Neurotransmitter C Ɣ Receptor profile target Drug A A Drug B B Ɣ Devising an intervention according to drug cluster (McCutcheon RA, Biol Psychiatry, 2023:94:561-568) (Taylor et al., Schiz Res 48:155, 2001) (Honer et al., NEJM 354:472, 2006) 110 110 105 105 pbo risp 100 100 PANSS Total 95 95 90 90 85 85 80 80 75 75 Cloz Cloz+risp 0 10 20 30 40 50 60 70 Days (NEJM 2006;354:472) (NEJM 2006;354:472)  Antipsychotic polypharmacy is common,20-80% worldwide A rationale can be made for adding a high potency D2 antagonist to clozapine There was no symptomatic benefit of risperidone augmentation of clozapine in controlled trial (NEJM 2006;354:472) Summary Individual drugs used to treat mental disorders are almost always affecting multiple receptors, each to a variable extent A control system has multiple receptors where interventions may be targeted Depending on the chosen receptor and control centre pathway, the desired effect may differ in magnitude, or in nature due to concurrent (side) effects Receptor Control Effector centre Pharmacotherapy of mental disorders Patient engagement and cooperation D Patient engagement &!! History Has enough information been collected? Examination Testing Communication of the Consultation diagnosis Treatment (Balogh, Miller and Ball eds, “Improving Diagnosis in Health Care” IoM, 2015) Comments on pharmacotherapy # Patient engagement and cooperationD Initiating medication treatment Establishing the effective dose Changing or stopping a treatment: withdrawal effects Duration of treatment Placebo effects DF Klein, R Gittelman, F Quitkin, A Rifkin “Diagnosis and Drug Treatment of Psychiatric Disorders: Adults and Children, 2nd Ed., Williams & Wilkins, 1980 Receptor Control Effector centre