Antipsychotics neuroleptics Alexandra Sulcová, M.D., Ph.D., Professor of Pharmacology Central European Institute of Technology (CEITEC) MU, Group: Experimental and Applied Neuropsychopharmacology PSYCHOSIS • a person's capacity, affective response to recognize reality, communicate, and relate to others is impaired schizophrenia, mania. depression, Alzheimer's dementia cognitive disorders hallucinations (auditory, visual, olfactory, gustatory, tactile) delusions (misinterpretations of perceptions or experiences) anxiety / depresssion Ideal antipsychotic drug effects "Dopaminergic hypothesis of schizophrenia" DA r« - partly sensitive to Adrenaline and Noradrenaline, too Family Dl: D15 - coupled to adenylylcyclase —» | cAMP - excitatory influence Family D2: D 2 3 4 - coupled to phosphodiesterase (cAMP degradation) —» si cAMP - inhibitory influence Dopamine receptors Possible modulation of dopaminergic transmistter functions The 4 Dopaminergic Pathways of the Brain^^^ ^ —^ Basal ganglia Nigrostriatal dopamine pathway X / imhir * / Mesolimbic dopamine pajliway ^Substantial A niqra f LS* \. Mesocortical dopamine pathway Hypothalamus egmentum Tubei oinfudibulai dopamine pathway 4 DAerqic brain oathwavs NIGROSTRIATAL (subt. nigra - basal ganglia) control of movements MESOLIMBIC (midbrain VTA - ncl. accumbens) - positive symptoms, euphoria ; MESOCORTICAL (midbrain - limbic cortex) ■ negative symptoms, : cognitive side effects - TUBEROINFUNDIBULAR (hypothalamus - anterior pituitary gland) control of prolactine secretion MAIN SYMPTOMS OF SCHIZOPHRENIA POSITIVE SYMPTOMS delusions hallucinations disorganised speech disorganized behaviour catatonic behaviour The Dopamine Hypothesis of Schizophrenia Mesofrontal and Mesolimbic Dopamine Pathways -J Limbic syste yperactivit MAIN SYMPTOMS OF SCHIZOPHRENIA POSITIVE SYMPTOMS NEGATIVE SYMPTOMS delusions hallucinations disorganised speech disorganized behaviour catatonic behaviour affective flattening (restriction of emotional expression) alogia avolition (general lack of desire, motivation, difficulty, or inability to initiate and persist in goal-directed behaviour) anhedonia (lack of pleasure) attention impairment The Dopamine Hypothesis of Schizophrenia Mesofrontal and Mesolimbic Dopamine Pathways Frontal corti Hypoactivit' -J Limbic syste yperactivit Positive torn P P Couses of hypoactivity of mesocortical DAergic pathway PP The 4 Dopaminergic Pathways of the Brain^^^ ^ —^ Bazálni ganglia Nigrostnatai extrapyramidal effects Mesolimbická Substantia niqra V. Mesokortjkální Hypothalamus egmentum Tuheroinfundihulární nigrostriatal pathway —> DA inhibits Ach activity blockade of DA function —► Ach hyperactive DA Ach • antipsych • anti-Ach consolidation of Ach hyperactivity Ill Si s . D2 antagonist Blockade of D2 recept. in nigrostriatal pathway Tardive dyskinesia D2 receptor up-regulation Stephen M. Stahl, 2000 The 4 Dopaminergic Pathways of the Brain^^^ ^ —^ Bazálni ganglia Nigrostriatální Mesolimbická /O. - ' Substantia niqra V. Mesokortjkální Hypothalamus egmentum Tuberoinfundibular endocrinological efects Tuberoinf undibular dopaminergic pathway Development of antipsychotics 1930 '40 '50 '60 70 '90 '00 '05 TCA t tioridazine trifluoperazine flufenazine perfenazine haloperidol chlorpromazine Typical antipsychotics t clozapine risperidone olanzapine quetiapine ziprasidon Atypical antipsychotics Dopamine-Serotonin system stabiliser a r ■ i p ■ i p r a z 0 1 ANTIPSYCHOTICS (neuroleptics) Typical (I- generation) Basic (sedative): (lower efficacy - doses in hundreds of mg) chlorpromazine, levomepromazine, chlorprothixen, thioridazine, clopenthixol Incisive: (higher efficacy - doses in mg or tens of mg) prochloperazine, phluphenazine, perphenazine, pimozide, haloperidol, flupenthixole DEPOT (1x /1 - 3 weeks) - penfluridole, fluphenazine ANTIPSYCHOTICS D2 blockade = antipsychotic effects Mj blockade = dry mouth, diplopia, constipation ax blockade = 4- BP, dizziness Hj blockade = drowsiness, weight gain Stephen M. stahl, 2000 ANTIPSYCHOTICS (neuroleptics) Typical (I- generation) Basic (sedative): (lower efficacy - doses in hundreds of mg) chlorpromazine, levomepromazine, chlorprothixen, thioridazine, clopenthixol Incisive: (higher efficacy - doses in mg or tens of mg) prochloperazine, phluphenazine, perphenazine, pimozide, haloperidol, flupenthixole DEPOT (1x /1 - 3 weeks) - penfluridole, fluphenazine Neuroleptic Malignant Syndrom idiosyncratic response (20-30% mortality; in 1-2% treated patients) 5-10 day persistence after the withdrawal of p.o. treatment, (3-30 days after injections) HYPERTERMIA; EPS (rigidity, dysartria, dysforia, tremor), VEGETATIVE SY. (tachycardia, T BP, tachypnoe, urinary incontinence); DISORDERS OF BEHAVIOUR & CONSCIOUSNESS (delirium, somnolence, epileptic paroxysms); leukocytosis, homeostatic disturbance, Themocoagulation .... ANTIPSYCHOTICS (neuroleptics) ... cont. Atypical (II. generation) (without EPS, tardive dyskinesia, prolactinemia, malignant neuroleptic syndrom) • MARTA (Multi-Acting Receptor Targeted Agents) clozapine, olanzapine, quetiapine • SDA (Serotonin-Dopamine Antagonist) risperidone, ziprasidone, sertindole • D2/D3 antagonists sulpiride, amisulpride • DSSS (Dopamine-Serotonin System Stabilizers) aripiprazole ANTIPSYCHOTICS D2 blockade = antipsychotic effects Mj blockade = dry mouth, diplopia, constipation = vl BP, dizziness = drowsiness, weight gain at blockade Hj blockade More selective for mesolimbic pathways i less EPS therapeutic efects D 1,2,3,4 5-HT side effects av a2, Ml Hx 2A Stephen M. Stahl, 2000 SDA (Serotonin-Dopamin Antagonist) risperidone, olanzapine, sertindol, seroquel I better effect on negative symptoms, less of EPS (especially at lower dosage) DA realease 5-HT r. blockade —> T release of DA = suppression of impact of D2 blockade Stephen M. stahl, 2000 ■ ■ -t-» 11.111 ■ ■ -t-» 11.111 T Mm clozapine 5HT2 amisulpride risperidone 2 Alphil SHT2 Alpha1/5HT2 olanzapine 5HT2 haloperidol D2 ziprasidone 5HT2 D2 5HT1 □ HTI A From Richelson 1996; Schoernaker et al 1997; Seeger et al 1995 Comparative Side Effect Profiles of the New Antipsychotics er Sedation ++ + ++ + + EPS - + + + (+) + Orthostatic hypotension ++ + - + + Weight gain ++ +(+) + + + + (+) (+) Prolactin increase (+) ++ (+) ++ (+) + Salivation/dry mouth + (+) + - (+) (+) Haematological effects ++ (+) + (+) (+) (+) General Review of Literature + mild ++ moderate blockade of D23 postsynaptic receptors lockade of D3/D2 autoreceptors in the limbic region LIMBIC REGIO DA FRONTAL CORTEX D X 3^y 3r ^D2 Activatioon in the cortex Suppression of negative (cognitive) symptoms DA autoreceptors blockade Suppression of Dopaminergic D2 receptor ligands "INTRINSIC ACTIVITY" ability of ligand to activate receptor full AGONIST (dopamin) ANTAGONIST (napr. haloperidol...) PARTIAL AGONIST (aripiprazole) D2receptor full activation no activation partial activation Influence of dopamine antagonist on positive symptoms and EPS DA inhibition Hyperprolactinemia Suppression of positive symptoms Pharmacological mechanisms of antipsychotics There is need to suppress positive symptoms 65 - 70% occupation of D2 receptors by antipsychotic. EPS occurs up to 80% occupation of D2 receptors by antipsychotic. Farde L, et al.: Arch Gen Psychiatry 1992; 49:538-544 Increase in prolactine release is dose dependent (occupation of D2-receptors). Schlegel S, et al.: Psychopharmacology (Berl) 1996; 124:285-287 Influence of dopamine antagonist on negative symptoms DA I inhibition negative symptoms Pharmacological mechanisms of antipsychotics Negative symptoms and affectivity are influenced by antipsychotics with antagonistic activity at 5-HT2A receptors. Blockade of other receptors is source of adverse effects. Farde L, et al.: Arch Gen Psychiatry 1992; 49:538-544 Influence of DAergic partial antagonism on: positive symptoms and EPS Influence of DA partial antagonism on: negative symptoms negative symptoms, cognition, motivation Impact of receptor activities on effects of antipsychotics Receptor Therapeutic effects Adverse effects D2 positive symptoms EPS, endocrinological effects 5-HT2A negative symptoms • • 5-HT1A negative symptoms cognitive symptoms anxiety/depres s sion • ai • • hypotension «2 • • antihypertensive effects H, sedation sedation, weight increase suppression of EPS anticholinergic effects DSSS [Dopamine-Serotonin System Stabilizers) ARIPIPRAZOLE suggested mechanisms of action: - partial agonist at Dj autoreceptors and 5-HTj^ somatodendritic receptors - antaponist at heterorecejjtors of dopaminergic neurons (Burris at al., 2002; Jordan et al., 2002) DSSS [Dopamine-Serotonin System Stabilizers) ARIPIPRAZOLE suggested mechanisms of action: partial agonist at Dj autoreceptors and 5-HTj^ somatodendritic receptors antaponist at heterorecejjtors of dopaminergic neurons (Burris at al., 2002; Jordan et al., 2002) - partial agonist at D2 autoreceptors —> inhibition of DA release - antagonist at 5-HT2A heteroreceptors of dopaminergic neurons I desinhibition of DA pcarons (nigrostriatum, mesocortical region) suppression of negative sy/aptoms of schizophrenia preceptor aripiprazole o dopamine (DA) o serotonin I5-HT1 ARIPIPRAZOL - main indications: ] 1. Schizophrenia in adults and adolescents (age 13-17) 2. Acute manic or mixed episodes of bipolar disorder I. (as monotherapy or with valproate in adults or adolescents of age 10-17) 3. Adjunctive therapy in major depression 4. Irritability associated with autistic disorder in pediatric patients (age 6-17) 5. Acute agitation associated with schizophrenia or bipolar disorder (intramuscularly) Kantrowitz J.T., Citrome L. From MedscapeCME Psychiatry & Mental Health Antipsychotics A-Z, 2010, www.medscape.org/viewarticle/718207 Aripiprazole its high affinity for D2 receptor can displace from that binding other antipsychotic with lower affinity Cits partial agonistic actvity can produce at least some of DAergic effects Cthis can explain exacerbation of psychosis in some patients on exchange of other antipsychotic pharmacotherapy to aripiprazole Ramaswamy S, et al. Int Clin Psychopharmacol. 2004;19:45-48. INDICATIONS FOR ANTIPSYCHOTICS • psychoses • sleeping disorders • anxiety • Huntington disease • Touretf s syndrome • anesthesiology / neuroleptanalgesia • nausea, vomitus