Psychopharmacology of Antipsychotics

Question 1

What are the names of first generation antipsychotics?

Answer 1

low potency: chlorpromazine, thioridazine

high potency: perphenazine, fluphenazine, haloperidol, pimozide

Question 2

What are the names of second generation antipsychotics?

Answer 2

clozapine
risperidone
olanzapine
quentiapine
ziprazidone
paliperidone

Question 3

What are the names of third generation antipsychotics?

Answer 3

aripiprazole

Question 4

What are first generation antipsychotics?

Answer 4

chlorpromazine: first discovered in the 1950’s by accident

subsequent antipsychotics discovered through their ability to produce “neurolepsis” in animal models (psychomotor slowing, emotional quieting, affective indifference)

Question 5

How do first generation antipsychotics affect dopamine (D2) receptors?

Answer 5

by 1970’s, antipsychotic properties were characterized by the ability of neuroleptics to block dopamine (D2) receptors

classification based on potency of binding to D2 receptors, not efficacy of medication (HIGH and LOW potency), also divided into chemical families

positive symptom reduction (psychosis) due to blockade of D2 receptors in the mesolimbic dopamine pathway

side effects of typical antipsychotics due to blockage of D2 receptors throughout the brain, not just in the mesolimbic pathway

Question 6

What is the nigro-striatal pathway?

Answer 6

movement

EPS, tardive dyskinesia

Question 7

What is the meso-limbic pathway?

Answer 7

“reward” pathway

positive symptoms of schizophrenia

Question 8

What is the meso-cortical pathway?

Answer 8

motivation and emotions

negative symptoms of schizophrenia

Question 9

What is the tubulo-infundibular pathway?

Answer 9

posterior pituitary (hypoprolactinemia)

Question 10

What are the side effects of first generation antipsychotics in the mesolimbic pathway?

Answer 10

site of nucleus accumbens, “pleasure centre” of the brain and part of normal reward pathway

stimulation –> pleasure

blockage –> apathy, anhedonia, amotivation, lack of interest in social interaction (secondary negative symptoms)

Question 11

What are the side effects of first generation antipsychotics in the meso-cortical pathway?

Answer 11

to dorsolateral prefrontal cortex (DLPFC): secondary negative symptoms, worsening of cognitive symptoms

to ventromedial prefrontal cortex (VMPFC): secondary negative symptoms, worsening of emotional (affective) symptoms

Question 12

What are the side effects of first generation antipsychotics in the nigrostriatal pathway?

Answer 12

EPS and TD

unaffected pathway in untreated schizophrenia

blockage of D2 receptors here causes basal ganglia movement disorders (drug-induced parkinsonianism) part of extrapyramidal nervous system

Question 13

What is tardive dyskinesia (TD)?

Answer 13

long-term side effect of chronic D2 receptor blockade in this pathway with tongue, facial, and limb movements abnormalities

frequently irreversible, even when antipsychotic is discontinued

TD thought to be due to D2 receptors “upregulating” and becoming hypersensitive to dopamine

those developing EPS early in treatment twice as likely to develop TD

risk of onset of TD decreases after 15 years of treatment (likely due to genetic protective factors)

Question 14

What are the side effects of first generation antipsychotics in the tuberoinfundibular dopamine pathway?

Answer 14

projects from the hypothalamus to the pituitary gland

unaffected in untreated schizophrenia

dopamine D2 blockade elevated plasma prolactin levels (hyperprolactinemia), causing galactorrhea (breast milk secretion) in men and women and amenorrhea (irregular menses) in women

Question 15

What are the side effects when antipsychotics block alpha-1 adrenergic receptors?

Answer 15

dizziness, drowsiness, postural hypotension

Question 16

What are the side effects when antipsychotics block histamine-1 receptors?

Answer 16

weight gain, drowsiness

Question 17

What are the side effects when antipsychotics block muscarinic cholinergic receptors?

Answer 17

blurred vision, dry mouth, constipation, urinary retention, cognitive dysfunction

in the nigrostriatal pathway, dopamine inhibits acetylcholine release, so when there is less dopamine, there is more acetylcholine, increasing likelihood of EPS

can block acetylcholine release with “anticholinergic” medications or give antipsychotic medications with anticholinergic effects to lessen EPS (but not reduce likelihood of TD)

Question 18

What makes an antipsychotic medication “atypical”?

Answer 18

originally used to describe lower EPS risk associated with clozapine

term expanded later to include greater efficacy in treating cognitive and negative symptoms, lack of prolactin elevation, greater efficacy for treatment-resistant patients

Question 19

What is the pharmacology of atypical medication?

Answer 19

1. rapid dissociation from D2 receptors
2. serotonin (5-hydroxytryptamine, 5-HT) dopamine antagonism: increases dopamine by disinhibiting the dopamine neuron
3. serotonin (5-hydroxytryptamine, 5-HT) 1A partial agonism
4. D2 partial agonism

Question 20

What are third generation antipsychotics aka “goldilocks drugs”?

Answer 20

stabilizes dopamine transmission between antagonism (like typicals) and full stimulation (like dopamine)

reduce D2 hyperactivity in mesolimbic neurons enough to exert antipsychotic effect without completely blocking D2 receptor but also only partially block the nigrostriatal pathway (not enough to cause EPS since a little bit of the signal still gets through)

Question 21

What are side effects of second generation antipsychotics?

Answer 21

cardiometabolic risk: not simply due to increased appetite and weight gain, can cause insulin resistance to develop

other risks: orthostatic hypotension, QTc prolongation (risk of cardiac arrhythmias), serious but rare events include diabetic ketoacidosis and neuroleptic malignant syndrome

most common side effect (CATIE study): hypersomnia/sedation, common reasons for discontinuation include weight gain, EPS, sedation

Question 22

What is clozapine?

Answer 22

unique side effect profile and monitoring requirement of frequent (up to weekly) bloodwork to monitor for agranulocytosis (low white blood cells)