Antipsychotics

Question 1

_____ is the prototypical antipsychotic, and other drugs are compared to it in assessing potency/ effectiveness

Answer 1

Chlorpromazine

Question 2

What differentiates typical vs atypical antipsychotic drugs?

Answer 2

typical: dopamine receptor antagonists
atypical: dopamine and serotonin receptor antagonists

Question 3

List evidence for the dopamine hypothesis of psychosis

Answer 3

1. D2 receptor blockade correlates with therapeutic potency of antipsychotic drugs
2. Drugs that increase DA activity aggravate psychotic symptoms
3. PET scans and post mortem analysis of brains from psychotic patients show increased DA receptor density
4. Successful treatment decreases levels of DA metabolites in CSF, plasma, urine

Question 4

List evidence for the hypothesis that excess serotonin activity causes psychosis

Answer 4

1. 5-HT2A partial agonists are hallucinogens that produce perceptual and cognitive changes resembling the positive symptoms of psychosis
2. Atypical antipsychotic agents are inverse agonists at 5-HT2A receptors
3. 5-HT2A receptors modulate DA release in cortex, limbic areas, and striatum

Question 5

List evidence for the glutamate hypofunction hypothesis of psychosis

Answer 5

1. Noncompetitive NMDA antagonists induce positive, negative, and cognitive symptoms in healthy individuals and exacerbate symptoms in patients
2. Increased glycine (which promotes glutamate binding to NMDA receptors) improves negative and cognitive symptoms
3. 5-HT2A partial agonists inhibit NMDA-mediated transmission in cortex

Question 6

All effective antipsychotic drugs reduce ___ mediated neurotransmission

Answer 6

D2

Question 7

List some extrapyramidal symptoms that were common to earlier antipsychotic drugs

Answer 7

Acute dystonia
Akathisia- uncontrollable urge to be in motion
Parkinsonism
Perioral tremor
Tardive dyskinesia

Question 8

List signs of neuroleptic malignant syndrome

Answer 8

Mental changes- delirium, stupor, disorientation, incoherent speech
Lead pipe rigidity 
Hyperthermia
Autonomic instability
Tx with danrolene and bromocriptine

Question 9

List common general adverse effects of antipsychotic drugs

Answer 9

Anticholinergic effects
Orthostatic hypotension due to a1 blockade
Sedation due to H1 blockade
Hyperprolactinemia via D2 receptor blockade in pituitary
Seizures (< 1%, but clozapine 3-5%)
Sexual dysfunction
Dermatoses, photosensitivity
Cardiac dysrhythmias, QTc prolongation (except haloperidol)
Metabolic effects- more characteristic of atypical agents
Agranulocytosis: clozapine

Question 10

Describe the mechanism of action of chlorpromazine

Answer 10

D2 receptor antagonist with strong anticholinergic and a1 receptor blocking effects

Question 11

List some precautions for chlorpromazine or haloperidol use

Answer 11

CNS depression, coma, encephalopathy, head trauma, intoxication
Labor
Heart disease
Hepatic disease, jaundice
Parkinson's disease

Question 12

Describe the mechanism of action of haloperidol

Answer 12

D2 receptor antagonist with weak anticholinergic and a1 receptor blocking effects (contrast with chlorpromazine)

Question 13

Describe the mechanism of action of aripiprazole

Answer 13

Binds to D2 D3, D4, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, a1, and H1 receptors; partial agonist at D2 and 5-HT1A sites

Question 14

Describe the mechanism of action of quetiapine

Answer 14

Antagonist at D2, 5-HT1A, 5-HT2A, M1, a1, H1 receptors

Improves both positive and negative symptoms
Large and frequent doses

Question 15

Describe precautions for quetiapine use

Answer 15

Hepatic insufficiency may require dosage adjustment
Diabetes
Parkinson’s disease
Conditions that may be aggravated by anticholinergic activity (prostatic hypertrophy, ileus, glaucoma)

Question 16

Describe the mechanism of action of olanzapine

Answer 16

Multireceptor activity: olanzapine is a potent antagonist at D1-D4 receptors, 5-HT2A and 5-HT2C receptors, M1-M5 receptors, a1 receptors, and H1 receptors; olanzapine is ~ 8X more potent at 5-HT2A receptors than D2 receptors

Smaller doses, only once daily (contrast with quetiapine)

Question 17

Describe the mechanism of action of resperidone

Answer 17

Antagonist at D2, D4, 5-HT1A, 5-HT2A, 5-HT2C, a1, H1 receptors; low antimuscarinic activity

Improves both positive and negative symptoms

Question 18

Describe the pros and cons of clozapine

Answer 18

Greater risk of seizures and agranulocytosis but useful for refractory schizophrenia

Question 19

List other conditions that can be treated with antipsychotic agents

Answer 19

Delirium and dementia with psychotic features
Disruptive behaviors associated with autism or mental retardation
Emesis
Acute mania
Intractable hiccups
Tourette’s syndrome, tics
As adjuncts to uptake inhibitors for anxiety or major depression