Antipsychotics

1. Antipsychotics John A. Harvey, Ph.D. Department of Pharmacology and Physiology

2. Neurobiology of Schizophrenia Schizophrenia represents a major mental illness, or possibly a group of Illnesses, manifested chiefly by disordered thought processes including disturbances in attention and associations. This leads to difficulties in communication, interpersonal relationships and reality testing. Studies Indicate that schizophrenia occurs 4-times more frequently among biological relatives than in the general population. • Positive Symptoms • Development of Abnormal Functions • Delusions • Hallucinations • 3. Disorganized Speech • 4. Catatonic Behavior • Negative Symptoms • Reduction or Loss of Normal Functions • Affective Flattening • Avolition • Attentional Deficits

3. Psychiatric Uses Of Antipsychotic Drugs • Schizophrenia: Acute and Chronic Maintenance • Psychotic Depression (With Antidepressants) • Acute Mania (With Lithium) • Autism (For Control of Aggressive Behaviors) • Gilles de la Tourette’s Syndrome – Chronic Tics • Severe Agitation In Mentally Retarded and In • Alzheimer’s Patients

4. Pharmacological Actions of Antipsychotics At CNS Receptors • Dopamine: Antagonists at D2 or Partial Agonist at D2 (aripiprazole) • Serotonin: Antagonists at 5-HT2A • Histamine: Antagonists at H1 • Cholinergic: Antagonists at muscarinic M1-4 • Noradrenergic: Antagonists at α1

5. Therapeutic Targets of Antipsychotics • Dopamine: Antagonists at D2 • Serotonin: Antagonists at 5-HT2A

6. Signal Transduction via Dopamine Receptors D2 D3 D4 D1 D5 Gs/q Gi E Physiological Responses Second Messengers Trophic Actions: Neuronal Morphology Synaptic Plasticity Gene Expression

8. 5-HT2 Receptor Signaling 2A

9. Scientific Name: Rauwolfia serpentinaCommon Name:  RauwolfiaOther Common Names: Plant Type: PerennialWhere To Plant: Full Sun to Partly ShadySoil Types: AverageZones (See US Zone map): 11+ or GreenhouseGermination: HardNumber of Seeds Per Pack: 15Uses: MedicinalNotes: Famous tranquilizer plant of India. Powerful hypnotic and sedative properties. Slow to germinate needs bottom heat 75 degree F. RAUWOLFIA SERPENTINA. Famous tranquilizer plant of India, where for 3000 years it has been used to treat mental illness. Long ignored by the West, until the 1950s, but now its active constituent, reserpine, is prescribed for its powerful hypnotic and sedative properties. Slow to germinate; bottom heat essential.

10. Typical Antipsychotics Have Antagonist Actions That Are Greater for the Dopamine D2 Than the 5-HT2A Receptor Phenothiazines & DerivativesButyrophenones Chlorpromazine Haloperidol Thioridazine Fluphenazine Perphenazine A Newer Antipsychotic Is a Partial Agonist at the Dopamine D2 Receptor And A Serotonin 5-HT2A Receptor Antagonist Aripiprazole

11. Atypical Antipsychotics Have Antagonist Actions that are Greater for 5-HT2A than D2 Risperidone Olanzapine Quetiapine Clozapine Ziprasidone A Newer Antipsychotic Is a Partial Agonist at the Dopamine D2 Receptor And A Serotonin 5-HT2A Receptor Antagonist Aripiprazole

12. Large Effect Dopamine DA Agonist Large Effect DA Antagonist No Effect DA Partial Agonist Small Effect Aripiprazole

13. Dopamine Hypothesis Of Schizophrenia: An Increase in Dopaminergic Activity in CNS • All Antipsychotics are DA Receptor Antagonists • 2. Therapeutic effects correlated with D2 affinity • 3. Dopamine Agonists (e.g., Amphetamines) Exacerbate Schizophrenic Symptoms at Low Doses • 4. Higher Doses of Amphetamines Induce Paranoid Psychotic Reactions in Normal Individuals • 5. Evidence of Changes in Dopamine Receptors in Schizophrenia is Still Controversial

14. The therapeutic dose of antipsychotics is related to dopamine D2 receptor antagonism Decreasing affinity Increasing dose of drug

15. Cognitive deficits can be due to too little as well as too much receptor activation Normal Psychosis Level of Cognitive Functioning DA Receptor Activation

16. Dopamine Projection Pathways • Neostriatal – Caudate/Putamen – Regulates Motor Function • Mesolimbic – Nucleus Accumbens and Amygdala – Regulates Emotions • Mesocortical – Limbic Cortex – Regulates Attention/Cognition • Tuberohypophysial – Arcuate Nucleus – Regulates Prolactin Release

17. Blockade of Dopamine D2 Receptors • Emotion - Reduces expression of emotion • Cognitive functions – Decreases cognitive processes in prefrontal cortex • Motor functions – Produces akinesia and symptoms of Parkinsonism • Endocrine function – Produces increased release of prolactin

18. The New England Journal of Medicine Established in 1812 September 22, 2005, Vol. 353 no. 12 Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., and John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators*

19. Conclusions • The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. • Olanzapine was the most effective in terms of the rates of discontinuation, however it was associated with greater weight gain and increases in measures of glucose and lipid metabolism. • The efficacy of the typical antipsychotic agent perphenazine appeared similar to that of the atypical antipsychotics, quetiapine, risperidone, and ziprasidone. • Although atypical antipsychotics tended to have less extrapyramidal effects they were not free of them.

20. Typical Antipsychotics Have Antagonist Actions That Are Greater for the Dopamine D2 Than the 5-HT2A Receptor Phenothiazines & Derivatives Chlorpromazine: First drug Thioridazine: Fluphenazine Perphenazine: Equally Effective with Atypicals Butyrophenones Haloperidol: Still Widely Used

21. Atypical Antipsychotics Have Antagonist Actions that are Equal or Greater for 5-HT2A than D2 Risperidone: Widely Used Olanzapine: Well tolerated but greater weight gain Quetiapine Clozapine: Agranulocytosis in 2% of patients

23. Absorption and Distribution • Readily but incompletely absorbed • Significant first-pass metabolism • Highly lipid soluble and protein bound • Large volume of distribution • Long clinical duration (e.g., 6 weeks or more to full relapse) • Metqbolism • Cytochrome P450 Enzymes • CYP 3A4: Inhibitors are erythromycin, fluvoxamine • Inducers are carbamazepine, phenytoin, phenobarbital • CYP 2D6: Inhibitors are buproprion, fluoxetine, paroxetine, quinidine • CYP 1A2: Inhibitors are fluvoxamine, omeprazole

24. Metabolism Thioridazine metabolized to more potent compound – mesoridazine Aripiprazole metabolized to active compound dehydro- aripiprazole with a half-life of 96 hours Clozapine metabolized to active compound N-desmethylclozapine Excretion Little excreted unchanged

25. Adverse Effects of Antipsychotics At CNS Receptors • Dopamine: Antagonists at D2 • Serotonin: Antagonists at 5-HT2A • Histamine: Antagonists at H1 • Cholinergic: Antagonists at muscarinic M1 • Noradrenergic: Antagonists at α1

26. Adverse Pharmacologic Effects of Antipsychotic Drugs

27. Sites of production of extra pyramidal signs by antipsychotic drugs and • DA receptor blockade by • antipsychotics and actions • of D2 agonist bromocriptine • and D1/D2 agonist pergolide • Antimuscarinic effect of • benztropine Glu = glutamate Ach = acetylcholine GABA = γ-aminobutyric acid DA = dopamine + = excitatory synapse ▬ = inhibitory synapse Circuitry for Extrapyramidal Control of Movement

28. Different Antipsychotics Ranked by Functional Class Increasing Severity Increasing Severity

29. THE END