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

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. Negative Symptoms Reduction or Loss of Normal Functions 1.Affective Flattening 2.Avolition 3.Attentional Deficits Positive Symptoms Development of Abnormal Functions 1.Delusions 2.Hallucinations 3. Disorganized Speech 4. Catatonic Behavior

Psychiatric Uses Of Antipsychotic Drugs 1.Schizophrenia: Acute and Chronic Maintenance 2.Psychotic Depression (With Antidepressants) 3.Acute Mania (With Lithium) 4.Autism (For Control of Aggressive Behaviors) 5.Gilles de la Tourette’s Syndrome – Chronic Tics 6.Severe Agitation In Mentally Retarded and In Alzheimer’s Patients

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

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

Signal Transduction via Dopamine Receptors G s/q GiGi E D1D5D1D5 D 2 D 3 D 4 Second Messengers Gene Expression Physiological Responses Trophic Actions: Neuronal Morphology Synaptic Plasticity

5-HT 2 Receptor Signaling 2A

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Typical Antipsychotics Have Antagonist Actions That Are Greater for the Dopamine D2 Than the 5-HT2A Receptor Phenothiazines & Derivatives Butyrophenones 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

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

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

Dopamine Hypothesis Of Schizophrenia: An Increase in Dopaminergic Activity in CNS 1.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

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

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

Dopamine Projection Pathways 1.Neostriatal – Caudate/Putamen – Regulates Motor Function 2.Mesolimbic – Nucleus Accumbens and Amygdala – Regulates Emotions 3.Mesocortical – Limbic Cortex – Regulates Attention/Cognition 4.Tuberohypophysial – Arcuate Nucleus – Regulates Prolactin Release

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

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*

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.

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

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

DrugWeight Gain Risk for Diabetes Worsening Lipid Profile Clozapine+++++ Olanzapine+++++ Risperidone++±± Quetiapine++±± Aripiprazole±-- Ziprasidone±--

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

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

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

TypeManifestationsMechanism Autonomic nervous system Loss of accommodation, dry mouth, difficulty urinating, constipation Orthostatic hypotension, failure to ejaculate Hypotension, arrhythmia Muscarinic blockade Alpha1adrenoreceptor blockade Antiadrenergic Central nervous system Parkinson’s syndrome, acute akathisia(motor restlessness), acute dystonia (spasm of tongue, face, neck) Tardive dyskinesia, tardive dystonia (choreoathetoid movements or dystonia) Toxic-confusional state Sedation Dopamine receptor blockade (Early Onset) Supersensitivity of dopamine receptors (Late Onset) Muscarinic blockade Antihistaminergic Endocrine system Amenorrhea-galactorrhea, infertility, impotence Dopamine receptor blockade resulting in hyperprolactinemia Miscellaneo us Neuroleptic malignant syndrome Photosensitivity, heat sensitivity, cholestatic jaundice, retinal pigmentation Not known Adverse Pharmacologic Effects of Antipsychotic Drugs

Sites of production of extra pyramidal signs by antipsychotic drugs and Glu = glutamate Ach = acetylcholine GABA = γ-aminobutyric acid DA = dopamine + = excitatory synapse ▬ = inhibitory synapse Circuitry for Extrapyramidal Control of Movement 1.DA receptor blockade by antipsychotics and actions of D2 agonist bromocriptine and D1/D2 agonist pergolide 2.Antimuscarinic effect of benztropine

I n c r e a s i n g S e v e r it y Different Antipsychotics Ranked by Functional Class Side Effects DrugChemical Class CPZ Equi v DA 2 Affinity Ch-M Affinity Adr 1 Affinity Extra- pyramidal Anticholinergic Sedation Hypotension Low potency Chlorpromazine Thorazine Aliphatic phenothiazine Thioridazine Mellaril Piperidine phenothiazine Midpotency Perphenazine Trilafon Piperazine Phenothiazine 8++ Loxapine Loxitane Dibenzoxazepine 10++ High potency Haloperidol Haldol Butyrophenone Fluphenazine Prolixin Piperazine phenothiazine Atypical Clozapine Clozaril Dibenzodiazepine Very Low High Risperidone Risperdal Benzisoxazole 2++- Low

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