Department of Psychiatry University of Illinois at Chicago PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Associate Professor Department of Psychiatry University of Illinois at Chicago Email: ydwivedi@psych.uic.edu

Psychosis Symptoms Positive Symptoms Delusion Hallucination Disorganized speech Disorganized behavior Agitation Negative Symptoms Passivity Apathetic social withdrawal Stereotyped thinking Anhedonia (loss of joy) Attentional impairment Emotional withdrawal Cognitive Symptoms Impaired verbal fluency Problems with serial learning Problems with focusing attention Concentration

Neurodevelopmental Hypothesis of Schizophrenia

Neurodegenerative Hypothesis of Schizophrenia (progressive loss of neuronal functions during the course of disease) Stages of Schizophrenia Over a Life Time Asymptomatic Negative symptoms Positive symptoms Negative/cognitive symptoms % of Brain Functioning Age (years) Increased excitatory glutamatergic neurotransmission

NMDA type glutamate receptor is a ligand-gated Ca2+ ion channel Binding of glutamate causes opening of the channel and thus excitatory neurotransmission

Dopamine Pathway Limbic cortex Anterior pituitary a = nigrostriatal pathway b = mesolimbic pathway: Increase in dopamine causes positive symptoms of schizophrenia c = mesocortical pathway: Deficit in dopamine causes negative and cognitive symptoms of schizophrenia d = tuberoinfundibular pathway

Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway Increased dopamine in this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal pathway Part of extrapyramidal system and controls motor movement Blockade of D2 receptors causes: -- movement disorder such as Parkinson’s disease (rigidity, akinesia, dystonia) -- hyperkinetic movement such as tardive dyskinesia Tuberoinfundibular pathway Normally neurons of this pathway are active and inhibit prolactin release Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

Pharmacodynamics of Antipsychotics

Antipsychotics First generation Second generation Chlorpromazine Acetaphenazine Fluphenazine Haloperidol Trifluoperazine Triflupromazine Second generation Clozapine Risperidone Olanzapine Quetiapine Ziprasidone

DOPAMINE SYMPTOMS Positive Negative EPS Increases prolactin release

First Generation Antipsychotics Blockade of D2 receptors in mesolimbic pathway, resulting in reduced positive symptoms of schizophrenia Blockade of D2 receptors in mesocortical pathway, which is already deficient in schizophrenia, causes cognitive symptoms or worsen negative symptoms Blockade of D2 receptors in nigrostriatal pathway, produces EPS such as motor abnormalities (parkinsonism), tardive dyskinesia or hyperkinetic movement disorder Blockade of D2 receptors in tuberoinfundibular pathway causes hyperprolactinemia side effects: dry mouth, blurred vision, drowsiness, weight gain, dizziness, low bp cholinergic properties: EPS Chlorpromazine Stahl, 2002

Anticholinergic (M1) Drugs and EPS (Acetylcholine may cause EPS) 2 3 Dopamine and acetylchilone has reciprocal relationship Stronger anticholinergic agents cause fewer EPS

Second Generation Antipsychotics 5HT2A and D2 antagonists (SDAs)

Serotonin-Dopamine Interaction 1

3 2 Key: 5HT interact with 5HT2A receptors at postsynaptic level both at DA cell bodies and at axon terminals and inhibits the release of DA or 5HT2A antagonists cause more release of DA The action of 5HT2A and D2 antagonism causes different effects in different dopamine pathways

Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway More dopamine or hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms Nigrostriatal pathway Part of extrapyramidal system and controls motor movement Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease -- hyperkinetic movement such as tardive dyskinesia Tuberoinfundibular pathway Increased neuronal activity of this pathway inhibits prolactin release Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

In mesolimbic pathway the action of D2 receptor blockade of antipsychotics are more robust than 5HT2A antagonism. This may help reducing positive symptoms

Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway Hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal pathway Part of extrapyramidal system and controls motor movement Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease -- hyperkinetic movement such as tardive dyskinesia Tuberoinfundibular pathway Increased neuronal activity of this pathway inhibits prolactin release Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

In mesocortical pathway, dopamine deficiency causes negative and cognitive symptoms. In mesocortical pathway, there is more 5HT2A receptors than D2 receptors. Thus 5HT antagonistic property is more profound than D2 receptor blocking property. This may help improve negative symptoms

Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway Hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal pathway Part of extrapyramidal system and controls motor movement Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease -- hyperkinetic movement such as tardive dyskinesia Tuberoinfundibular pathway Increased neuronal activity of this pathway inhibits prolactin release Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

In nigrostriatal pathway: 5HT2A antagonists bind to 5HT2A receptors and block the release of 5HT and thus cause more DA to be released. This may reduce EPS 1 2 3 4

Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway Hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal pathway Part of extrapyramidal system and controls motor movement Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease -- hyperkinetic movement such as tardive dyskinesia Tuberoinfundibular pathway Increased neuronal activity of this pathway inhibits prolactin release Blockade of D2 receptor increases prolactin release and causes: -- galactorrhea -- amenorrhea

In tuberoinfundibular pathway: D2 blockade causes release of prolactin, whereas, blocking 5HT2A inhibits release of prolactin. Antagonistic properties of antipsychotics cancel DA and 5HT2A action 1 2 3 4

Other Actions of Second Generation Antipsychotics Clozapine: Very few EPS No prolactin release Causes agranulocytosis Weight gain Seizures Sedative Risperidone: EPS at high dose Low TD Less weight gain Ziprasidone: Very few EPS No prolactin release No weight gain SRI and NRI, thus act as AD and anxiolytic Quetiapine: No EPS No prolactin release Weight gain Olanzapine: No prolactin release Nonsedative Weight gain Low level of TD Stahl, 2002

Pharmacodynamics of Anxiolytics/ Sedative-Hypnotics

Ionotropic GABA Receptors Benzodiazepine GABA a subunit Channel pore Barbiturates Steroids Pentamers Inhibitory in action because the associated channels are permeable to negatively charged Cl- ions Benzodiazepines are allosteric modulators to GABA neurotransmission Picrotoxin

Benzodiazepine Anxiolytics Chlordiazepoxide Diazepam Oxazepam Chlorazepate Lorazepam Prazepam Halazepam Flumazil Alprazolam Midazolam (Agonists)

The Agonist Spectrum

Action of Agonist A balance between open and close

Antagonist Acting Alone A balance between open and close No action

Antagonist Acting in Presence of Agonist

Action of Inverse Agonist Complete blockade A balance between open and close

Action of Antagonist in Presence of Inverse Agonist Acts like agonist

Action of Partial Agonist Partially opens the channel

Antagonist Acting in the Presence Partial Agonist

Action of Partial Inverse Agonist

BZD Receptor Activity Full Agonist Partial Antagonist Partial Inverse Full Inverse Anxiolytic Sed-Hypnotic Myorelaxant Anticonvulsant Amnestic Dependency No clinical effect Promnestic (memory enhancing) Anxiogenic Pro- convulsant Pro-convulsant

Serotonergic Anxiolytics (buspirone, gepirone,* tandospirone*) Partial 5HT1A agonist Cause upregulation of presynaptic somatodendritic 5HT1A receptors (anxiolytic action) and postsynaptic 5HT1A receptors (nausea, dizziness) As compared with benzodiazepines, lacks interaction with alcohol, benzodiazepines, and thus cause no drug dependence, withdrawal symptoms Delayed effect like antidepressants *under development/clinical trial

Noradrenergic Anxiolytics-I neuronal firing, Anxiety Cerebral cortex

Clonidine: a2 receptor agonist Binds to a2 presynaptic autoreceptors Decreases firing and release of NE which may reduces anxiety

Noradrenergic Anxiolytics-II Blocking the postsynaptic b receptors reduces anxiety Overactivity at postsynaptic b receptors increase anxiety Beta-blockers : Antagonist to postsynaptic b adrenergic receptors Decreases postsynaptic b receptor-mediated signaling

Cholecystokinin (CCK)* and CRF* Antagonists as Anxiolytics Tetra-peptide CCK causes panic attacks CCK antagonists are anxiolytic in panic disorder Cortotropin-releasing factor is a neuropeptide which mediates anxiety behavior. Antagonists to CRF are anxiolytics *under development

Sedative-Hypnotics-I (Treatment for insomnia) Benzodiazepines: Rapid onset, short acting triazolam Delayed onset, intermediate acting temazepam, estazolam Rapid onset, long acting flurazepam quazepam Nonbenzodiazepines: Rapid-onset, short acting Zaleplon Zolpidem Zopiclone Act at benzodiazepine receptors and increase the inhibitory action of GABA High doses required Develop tolerance Binds to omega-1 benzodizepine receptors Less cognitive, memory and motor side effects Shorter half life No dependence, tolerance or withdrawal symptoms

Sedative-Hypnotics II Sedative antidepressants: tricyclics (anticholinergic/antihistaminergic) trazodone (5HT2A antagonist) mirtazapine (5HT2A antagonist) nefazodone (5HT2A antagonist) Sedative antihistamines: diphenylhydramine doxylamine hydroxyzine Other sedative: chloral hydrate Natural products: melatonin Good choice with AD properties Safe with other psychotropic drugs which disrupts sleep, such as SSRIs Short-term use Causes dependency Tolerance

Suggeted Readings Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press, NY Nestler EJ, Hyman SE, Malenka RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. McGraw-Hill Publications Squire LR, Bloom FE, McConnel SK, Roberts JL, Spizer NC, Zigmond MJ. Fundamental Neuroscience. Academic Press Dwivedi Y. ey al. Chronic Treatment of Psychoactive Drugs Modulates Phosphoinositide-Specific Phospholipase C (PLC) Activity and mRNA and protein Expression of Selective PLC 1 Isozyme in Rat Brain. Neuropharmacology, 43:1269-1279, 2002 Dwivedi Y. et al. Effect of subchronic administration of antidepressants and anxiolytics on the levels a subunits of G-proteins in rat brain J Neural Transm, 104:747, 1997