Psychopharmacology - Antipsychotic drugs Dr. Subhash Gupta

The objectives of this session 1. To understand the mechanisms of action of antipsychotic drugs used in psychiatric practice 2. To understand therapeutic indications of antipsychotic drugs and their effectiveness 3. To understand factors influencing drug tolerability and adverse effects

Dopaminergic dysregulation is a core neurotransmitter abnormality in schizophrenia although other neurotransmitters are also thought to be involved Dopamine Glutamate Acetylcholine Serotonin Norepinephrine -Aminobutyric acid (GABA) Neuropeptides (eg, cholecystokinin) Others? Goff et al. Med Clin North Am. 2001;85:663. Crismon and Dorson. Pharmcotherapy: a pathophysiologic approach. 1999.

Neurotransmitters and Neuromodulators Monoamines Dopamine Dopamine: A neurotransmitter; one of the catecholamine. Implicated roles in movement, attention, learning, reinforcing effects of abused drugs. Synthesized from tyrosine that we obtain from our diet.

Neurotransmitters and Neuromodulators Monoamines Dopamine L-Dopa: The levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson’s disease because of its as a dopamine agonist.

Neurotransmitters and Neuromodulators Monoamines Dopamine Nigrostriatal system: A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen of the basal ganglia); appears to play a role in the control of movement.

Neurotransmitters and Neuromodulators Monoamines Dopamine Mesolimbic system: A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus; appears to play a role in the reinforcing effects of drugs that are commonly abused.

Neurotransmitters and Neuromodulators Monoamines Dopamine Mesocortical system: A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex; appears to influence formation of short-term memories, planning, and preparing strategies for problem solving.

Copyright © 2004 Allyn and Bacon

Neurotransmitters and Neuromodulators Monoamines Dopamine Parkinson’s Disease: A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system; Parkinson’s disease has been treated with L-DOPA.

Neurotransmitters and Neuromodulators Monoamines Dopamine Monoamine oxidase (MAO): A class of enzymes that destroy the monoamines; dopamine, norepinephrine, and serotonin.

Neurotransmitters and Neuromodulators Cocaine and Amphetamine Dopamine agonists Cocaine blocks DA transporters Amphetamine increase DA release and reverses transporter

Extrapyramidal side effects Caused by blocking dopamine receptors in the basal ganglia Muscle spasms Tremor Dystonia Akathisia Parkinsonism Tardive dyskinesia

What is atypical? Unlike typical antipsychotics (neuroleptics), atypical antipsychotics decreased amphetamine induced hyperactivity in rats in doses that did not produce catalepsy (immobility). Classically, an antipsychotic is said to be atypical when it improves both positive and negative symptoms of schizophrenia but: Produces minimal or no EPS Causes minimal or no sustained prolactin elevation Many researchers have proposed greater efficacy in treating negative symptoms, mood changes and cognitive deficits, giving rise to broader definitions of atypicality.

Class Efficacy EPS Prolactin 1st generation (HPL, CPZ) Limited to positive symptoms High Elevating 2nd generation (risperidone) Both positive and negative symptoms Dose dependent 3rd generation (clozapine, olanzapine, quetiapine) Broad spectrum (both positive and negative symptoms + mood and cognition effects) Low Sparing

Why they are atypical? Serotonin – Dopamine Hypothesis Fast-off D2 hypothesis – Low affinity and fast dissociation from D2 receptors Dopamine D4 hypothesis In this presentation I will be covering … 5 important receptors implicated in schizophrenia Refreshing our minds of the 4 dopamine pathways implicated in schizophrenia Then a brief mention about the close relationship between dopamine and serotonin Finally will put the basic science covered into a clinical context by looking at 1st, 2nd and 3rd generation antipsychotics

Serotonin–Dopamine Hypothesis Greater affinity and antagonism at serotonin 5HT2 receptors than at D2 receptors So, the name Serotonin – Dopamine Antagonists (SDA) was coined.

Contradictions to Serotonin Dopamine Hypothesis Typical antipsychotics such as loxapine and chlorpromazine show equally high 5HT2A occupancy. Amisulpride is an effective atypical antipsychotic drugs but doesn’t have 5HT2A affinity.

Other Dopamine theories ‘Limbic Specific’ Extent of D2 blockade: Antipsychotic action occurs at a D2-receptor occupancy rate of 60–70%, whereas a D2 occupancy rate greater than 80% is believed to increase the risk of EPSs without increasing efficacy. Usual doses of typical antipsychotics occupy 70–90% of D2- receptors. Clozapine, the prototypic atypical agent, occupies only 38–63% of D2-receptors at usual dosages. Olanzapine and risperidone may lose their “atypicality” at higher dosages because of increased binding affinity for D2-receptors

Fast-off D2 hypothesis Atypical antipsychotics are loosely and transiently bound to and rapidly released from D2 receptor. They continually go on and off D2 receptors, allowing extensive access of endogenous dopamine to these receptors. Clozapine and quetiapine are most loosely bound and rapidly dissociated. This explains efficacy in controlling psychosis without worsening of motor symptoms in parkinsonism Quetiapine (Seroquel): Most atypical?

Relative binding to D2 receptors Quetiapine Loose (fastest dissociation) Clozapine Olanzapine Intermediate Sertindole Dopamine Ziprasidone Chlorpromazine Haloperidol Tight (least dissociation) Risperidone

Dopamine D4 hypothesis This concept gained popularity based on 2 findings: Clozapine's greater D4Vs D2 affinity Elevated D4 receptors in brains of schizophrenic patients. But, not applicable to other atypical antipsychotics

Dopamine System stabilisers Prescribing information available on last slide

Partial agonism at D2 receptors Intrinsic activity Receptor binding Molecular profile Full agonist (Dopamine) Full activation Antagonist (Typicals/ Atypicals) No activation Stabilises activity Partial agonist (Aripiprazole) D2 Receptor Stahl, J Clin Psychiatry 2001; 62(11): 841-842; Stahl, J Clin Psychiatry 2001; 62 (12): 923-024

Side Effects of atypicals Weight gain Dyslipidemia Increased glucose levels Metabolic syndrome Risk of stroke EPS, prolactin related side effects

ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS 1135 - 1205 approx Please divide into two groups. The left hand side of the room (your left) will be Group One and right hand side of the room will be Group Two. Look at both clinical scenarios. I will invite each group to feedback in turn

ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario One A 16 year old boy has an 18 month history of self neglect, social withdrawal and has been very suspicious of his friends. He has complained of depressed mood. Two weeks ago his G.P. sent him for urgent psychiatric assessment. He was given chlorpromazine 100mg t.d.s by the doctor he saw. He has been re-referred after a serious episode of self harm (neck laceration) and complains of feeling more depressed and agitated. Discuss the appropriateness of his medication. Would you change this and if so why?

ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario Two A 56 year old man has a 6 month history of hearing voices in the 3rd person. He has previously seen one of your colleagues and has come for review. He complains of excessive drowsiness and dizziness and impaired short-term memory. He has gained 10kg and is more thirsty. His symptoms have been hard to control. He now takes a range of medication (see next slide). Can his complaints be explained in terms of his current treatment? Would you wish to revise his regime and if so how?

ANTIPSYCHOTIC DRUGS CLINICAL PROBLEMS Scenario Two Propranolol 80mg daily* Olanzapine 35mg daily* Risperidone 12mg daily* Procyclidine 15mg daily* Lorazepam 2mg PRN 6 hourly Temazepam 20mg nocte *All the above are in divided doses