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PreClinEazy X Cardiff Medsoc CASE 10 Presenter: Diya KarwaTopics Neurophysiology Pharmacology: antidepressants Pharmacology: antipsychotics Drugs of abuse Personality theories TW DISCLAIMER The content of this presentation is for educational purposes only There are many references to mental health and mental health disorders There is no intent to cause any harm and we apologies if any of the content is triggeringSynapses Neuron Dendrites Axon Soma Synapses Myelin Sheath Node of RanvierChemical Synapses Ca 2+ Ca 2+ 1. Action potential reaches the presynaptic Ca 2+ axon Ca 2+ Presynaptic 2. Voltage gates Ca2+ channels open Ca 2+ Ca 2+ neuron 3. Ca2+ influx into axon terminal causes neurotransmitter release from presynaptic vesicles Synaptic Cleft 4. Vesicles fuse with the presynaptic membrane and release neurotransmitters into the synaptic cleft Postsynaptic 5. Neurotransmitters activate receptors on neuron the post synaptic cleft altering permeability Stimulate, Na+ Whilst on placement you are testing the knee jerk reflex on a Stimulate, Cl- patient and think back to EPSPs and IPSPs from PCS. Inhibit, Cl- EPSPs ____ firing of action potentials as a result of increase ___ influx post glutamate release. Inhibit, K+ Inhibit, Na+ Stimulate, Na+ EPSPs stimulate firing of action potentials as a result of increase Na+ influx post glutamate release. Stimulate, Cl- EPSPs: membrane depolarization due to an influx of positively Inhibit, Cl- charged ions IPSPs: membrane Inhibit, K+ hyperpolarization due to an influx of negatively charged ions Inhibit, Na+Neurotransmitters Neurotransmitters Dopamine Serotonin TYROSINE L-TRYPTOPHAN Tyrosine Hydroxylase Tryptophan Hydroxylase (RLS) L-DOPA 5-HTP DOPA Decarboxylase 5-HTP decarboxylase DOPAMINE SEROTONIN (5HT) Dopamine Beta Hydroxylase Monoamine oxidase NORADRENALINE 5-HIAA GABA/ Glutamate Glycine Glucose Serine Tyrosine Hydroxylase Glutamate Serine Hydroxymethyl transferase DOPA Decarboxylase (tetrahydrofolate cycle) GABA Glycine Neurotransmitters Dopamine Serotonin • Involved in motivation, reward, arousal, • Involved in mood, emotion, motor control motivation • Produced in the substantia nigra, ventral • Produced in the raphe nuclei tegmental area (midbrain), hypothalamus Gamma amino butyric acid (GABA) Glutamate • Main inhibitory neurotransmitter • Main excitatory neurotransmitter • Produced in the hippocampus, thalamus, • Produced in the hippocampus, basal ganglia neocortex, widespread • GABAa- influx of Cl-, GABAb- efflux of K+ • Excitotoxicity- neuronal damageGlutamate cannot cross the blood Malate brain barrier therefore has to be converted to glutamine in glial cells via the enzyme glutamine Succinate synthetase. Once glutamine enters nerve terminals glutaminase converts it back to Oxaloacetate glutamate. Here it can be used for neurotransmission or assimilated back into the Krebs cycle. Alpha Ketoglutarate Which molecule in the Krebs cycle can be involved in the synthesis of glutamate? CitrateMalate Succinate Oxaloacetate Alpha Ketoglutarate Citrate Dopamine receptors A 40 year old woman comes into clinic complaining of weakness in her legs and difficulty talking and GABA Receptors swallowing. She says her symptoms usually gets worse towards the end of the day. You also notice that her eyelids are Nicotinic Acetylcholine Receptors dropping. Serotonin (5HT) receptors The production of antibodies against which receptor can cause this condition? Glutamate Receptors Dopamine receptors MYESTHENIA GRAVES GABA Receptors Acetylcholine: • Choline + Acetyl CoA (comes from pyruvate) Nicotinic Acetylcholine Receptors • Recycled via acetylcholinesterase in the synaptic cleft Serotonin (5HT) receptors PT Glutamate ReceptorsTheoretical models of depression Neurogenic Model Monoamine model • Suppression of adult hippocampal neurogenesis • Monoamines- serotonin, noradrenaline, caused by a trigger event dopamine • Patients with depression have smaller hippocampi monoamines mood Inflammatory Model therefore • Proinflammatory cytokines and reactive oxygen monoamines mood species (ROS) in various brain regions contribute to neuronal damageAntidepressants • TCAs- tricyclic antidepressants • SSRIs- selective serotonin reuptake inhibitors • SNRIs- serotonin and noradrenaline reuptake inhibitors • NRI- noradrenaline reuptake inhibitor • MOAs- monoamine oxidase inhibitors Monoamine reuptake Inhibitors SSRI TCA • Citalopram- prolonged QT • Amitriptyline- neuropathic • Fluoxetine- children and adolescents pain transporter (longer half life) • ADRs: Antimuscarinic effects • fluoxetine and paroxetine have a (dry mouth, constipation, higher propensity for drug interactions urinary retention), lengthening QT interval • Sertraline- post MI PT Interactions: SNRI • If on warfarin/heparin- Mirtazapine (alpha 2 antagonist) • Duloxetine, venlafaxine • NSAIDs- prescribe a PPI NRI • Memory aid: • Triptans and MOAs- serotonin • Reboxetine • ‘Dulo’ sounds like dual syndrome PT Discontinuation of SSRIs Review of SSRIs • Review 2 weeks post initiation unless: • <25 or at increased risk of suicide- review after Discontinuation symptoms: 1 week • If good response to treatment- continue for at least 6 months after remission to reduce • Gastrointestinal side effects: pain, relapse risk cramping diarrhea, vomiting • Increased mood change Protocol when stopping SSRIs: • Difficulty sleeping • When stopping - SSRI dose should be gradually • Unsteadiness reduced over a 4 week period • sweating • Paroxetine has a higher incidence of • paresthesia discontinuation symptoms Mirtazapine A 65 year old man with hypercholesterolemia takes atorvastatin for lipid modification Reboxetine and citalopram for depression. He has recently suffered an MI. The registrar in charge is Fluoxetine considering changing citalopram for another drug. Sertraline What is the name of this drug? Moclobemide Mirtazapine A 65 year old man with hypercholesterolemia takes atorvastatin for lipid modification Reboxetine and citalopram for depression. He has recently suffered an MI. The registrar in charge is Fluoxetine considering changing citalopram for another drug. What is the name of this drug? Sertraline Moclobemide MOAs- monoamine oxidase inhibitors • Used to treat atypical depression (hyperphagia) • MAO A- oxidizes serotonin and norepinephrine • MAO B- oxidizes phenylethylamine (dopamine) MOA Hypertensive crisis: • Eating tyramine-rich foods (aged cheeses, cured meats, wine, chocolate) while taking MAOIs • Tyramine displaces other neurotransmitters in the synaptic cleftà sympathetic stimulation (flushing/ headache) Serotonin and noradrenaline are broken down by Treatment: Phentolamine monoamine oxidase A in the presynaptic cleftDopaminergic pathways NA ts of dopamine Caudate MesoLimbic Mesocortical VTA to cortex VTA to nucleus accumbens putamen eward related Mediates schizophrenia- earning and motivation and negative symptoms ehavioural emotional (anergia, daptations processes anhedonia, chizophrenia- avolition, ositive ymptoms- alogia) hallucination VTA nd psychosis) dopamine +ve symptoms dopamine -ve symptoms Nigrostriatal Tuberoinfundibular Substantia nigra to striatum Hypothalamus to pituitary sential for the ntrol of ovement Substantia nigra dopamine prolactin ntipsychotics à Dopamine à Parkinson- like Antipsychotics à symptoms (parkinsonism) Hyperprolactinemia à Amenorrhea ( reduced FSH), galactorrhea Mesolimbic A 78 year old man taking clozapine Mesocortical to manage his schizophrenia presents to clinic with difficulty walking, stiffness, a tremor and Tuberoinfundibular balance problems. Which pathway is his medication likely effecting to Nigrostriatal cause these side effects? Spinothalamic tract Mesolimbic A 78 year old man taking clozapine Mesocortical to manage his schizophrenia presents to clinic with difficulty walking, stiffness, a tremor and Tuberoinfundibular balance problems. Which pathway is his medication likely effecting to Nigrostriatal cause these side effects? Spinothalamic tractAntipsychotics Antipsychotics 1 Generation/ Typical 2 Generation/ Atypical • D2 receptor antagonists: lower dopamine in • 5HT and D2 receptor antagonist work on BOTH mesolimbic and mesocortical pathways the mesolimbic pathway to reduce positive symptoms reduce positive and negative symptoms • Examples: Haloperidol, fluphenazine, • Examples: clozapine, olanzapine, risperidone, aripiprazole (partial dopamine agonist) chlorpromazine, thioridazine NA Caudate Mesolimbic Mesocortical VTA to nucleus accumbens VTA to cortex putamen D2 Antipsychotics 5HT VTA Blockade of D2 receptors decreases dopamine Inhibition of serotonin increases dopamine dopamine +ve symptoms dopamine -ve symptomsIncreased risk of stroke and venous thromboembolism in PT elderly patients Antipsychotic ADRs 1 Generation/ Typical 2 Generation/ Atypical • Extrapyramidal side effects (ADAPT) • Fewer extrapyramidal side effects • Acute Dystonia Akathisia Parkinsonism Traditive • Less significant hyperprolactinemia dyskinesia • METABOLIC SYNDROME- high risk • Prolonged QT interval, Sedation (quetiapine- anti-H1) • HYPERPROLACTINEMIA • Prolonged QT interval ( block repolarization of K+ • Risk of neuroleptic malignant syndrome • CLOZAPINE- agranulocytosis, myocarditis, channels in myocardium) • Risk of neuroleptic malignant syndrome cardiomyopathy Serotonin syndrome Neuroleptic Malignant syndrome • Causes: SSRIs, MOAs, tramadol/ St. Johns • Causes: antipsychotics, levodopa wart interaction with SSRIs, ecstasy, (dopaminergic)- dopamine blockade à amphetamines glutamate release à neurotoxicity • Neuromuscular: hyperreflexia, rigidity, • Pyrexia, rigidity, tachycardia, hypertension, monoclonus confusion • ANS: sweating, hyperthermia • RAISED CREATININE KINASE, LEUKOCYTOSIS • Mental state: confusion • Management: 3Ds • NON-SPECIFIC BLOODS 1. Discontinue antipsychotic • Management: IV CRYPROHEPADIDINE (5HT 2. DANTROLENE receptor antagonist) if severe, IV fluids 3. Dopamine agonist (bromocriptine) • ONSET with 24 hours PT Depression A 28 year old man with schizophrenia is started on Metabolic syndrome olanzapine and FBCs, U&Es, LFTs, lipids, weight, fasting blood glucose, prolactin and blood pressure are Psychosis monitored. He also has an ECG and cardiovascular assessment done. Renal failure Which is a possible side effect of this medication? HyperthyroidismMetabolic syndrome: Depression Increased risk of developing T2DM, cardiovascular disease and stroke Associated with: Metabolic syndrome •Abdominal obesity •Insulin resistance •Dyslipidemia Psychosis •Hypertension Renal failure Apiprazole- can reduce clozapine related side effects HyperthyroidismDrugs of abuse KETAMINE (Class B) COCAIN (Class A) MDMA/ Ecstasy (Class A) • Anesthesia/Analgesia: • Blocks the dopamine reuptake • Blocks serotonin, dopamine, Ketamine antagonizes NMDA transporter increasing the half receptors à prevents noradrenaline reuptake life of dopamine sensitization of dorsal horn • Blocks voltage gated Na+ transporters or causes transport reversal neurons channels as a LA • Antidepressant: stimulates AMPA receptor CANNABIS (Class B) FENTANYL (Class A) NICOTINE (psychoactive) • Mimics anandamide • Activates mu opioid receptors • Feeling of relaxation, (PA causing hyperpolarization • Increases mesolimbic euphoria, introspection (PAG). Suppresses GABA- dopamine levels • THC causes dopamine release activating anti-nociceptive • Reduces monoamine oxidase by agonizing CB1- pathways activity, increasing serotonin psychoactive effects, CB2- • NALOXONE- respiratory analgesia depressionPersonality TheoriesOCEAN (5 personality traits) Personality theories Environment and response to a stimulus shapes Behavioral theory behavior Heritable traits Biological theory Unconscious mind and childhood experiences shape ideas about sex, aggression and conflict Psychodynamic theories (Freud) Cognitive expectations about the world shape Social Learning theory personality Freewill and individual experience impacts personality Humanistic theories Conservative management for PT common psychiatric disorders Post traumatic stress disorder Eye movement desensitization and reprocessing Obsessive compulsive disorder Exposure and response prevention Personality disorders, substance abuse, self-harm Dialectical behavior therapy Cognitive behavior therapy or functional analytic Depression and anxiety psychotherapy Schizophrenia Psychoeducation Cognitive behavioral therapy or functional analytical psychotherapy A 22 year old woman has recently had an uncomplicated pregnancy. She comes into clinic because she's in constantly Exposure and response prevention afraid she might unintentionally do something to cause harm to the child. Her partner has also noticed that she is always Dialectical behavior therapy worried about hygiene and excessively washes her hands and showers multiple times a day. She is also checks locks and appliances multiple times a day. Eye movement desensitization and reprocessing What conservative management would you consider for her diagnosis? Psychoeducation Cognitive behavioral therapy or functional analytical psychotherapy A 22 year old woman has recently had an uncomplicated pregnancy. She comes into clinic because she's in constantly Exposure and response prevention afraid she might unintentionally do something to cause harm to the child. Her partner has also noticed that she is always Dialectical behavior therapy worried about hygiene and excessively washes her hands and showers multiple times a day. She also checks locks and appliances multiple times a day. Eye movement desensitization and reprocessing What conservative management would you consider for her diagnosis? PsychoeducationPLEASE FILL OUT THE FEEDBACK FORM PLEASE TUNE IN TO OUR REMAINING SESSIONS THIS WEEK SOURCES https://www.ncbi.nlm.nih.gov/books/NBK11106/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177794/ https://www.ncbi.nlm.nih.gov/books/NBK539894/#:~:text=Neurotransmitters%20are%20 endogenous%20chemicals%20that,process%20of%20chemical%20synaptic%20transmissio n. https://www.nice.org.uk/guidance/ng222/chapter/Recommendations https://cks.nice.org.uk/topics/bipolar-disorder/prescribing-information/antipsychotics/ https://casereports.bmj.com/content/2014/bcr-2014-204154