Antipsychotic drugs

Question 1

First-gen antipsychotics examples (3)

Answer 1

chlorpromazine, haloperidol, loxapine

Question 2

Second-gen antipsychotics examples (3)

Answer 2

Aripiprazole, clozapine, olanzapine

Question 3

Burden of SZ

Answer 3

• in top 15 leading causes of disability world-wide
• co-occurring medical conditions like heart disease, liver disease, and diabetes
• suicide risk
• co-occurring mental health

Question 4

positive symptoms of SZ

Answer 4

hallucinations, delusions, illogical disturbances in flow, order, content of thought, disorganized speech, absence of clear goal-directed behaviour

Question 5

negative symptoms of SZ

Answer 5

decrease in emotional range, poverty of speech, loss of interests and drive (anhedonia), problems with working memory, worsened attention, deteriorating IQ

• symptoms generally worsened by antipsychotics (def not improved)

Question 6

antipsychotics are often prescribed just on basis of…

Answer 6

positive symptoms
- these are the symptoms that respond well to anti-psychotics

Question 7

etiology of SZ

Answer 7

unknown
- maybe genetic but all loci found are low effect
- maybe DA transmission is fucked up (more DA in striatum of SZ patients)

Question 8

methylene blue

Answer 8

antiparasitic used to treat malaria
- helped with psychosis?

Question 9

chlorpromazine

Answer 9

Was used to try to sedate/ calm patients down
- ended up curing their positive psychotic symptoms
- chemical lobotomy

Question 10

Mech of action of antipsychotics

Answer 10

D2 receptor antagonists
- both chlorpromazine and haloperidol bind to D2R
- positive correlation between D2 affinity and clinical potency

Question 11

GSK3

Answer 11

Glycogen kinase
- linked to psychiatric diseases
- inhibition of this could be target for antipsychotics

Question 12

Typical antipsychotics ( first gen APS, neuroleptics)

• discovered via

Answer 12

identified based on their ability to antagonize dopamine-mediated behaviours in rodents (locomotor activity)

Question 13

In support of DA hypothesis of SZ (3)

Answer 13

• antipsychotics block D2Rs
• amphetamine (which pumps dopamine into synapse) induces SZ-like state in normal individuals
• PET imaging shows SZ patients release more DA in basal ganglia when given amphetamine

Question 14

Against excess DA hypothesis of SZ (5)

Answer 14

• typical anti-psychotics only treat the positive symptoms and can worsen the negative and cognitive symptoms
• amphetamine does NOT induce negative or cognitive symptoms, and can even improve in some patients
• evidence for diminished DA in cortex and hippocampus (dysregulated DA rather than too much?)
• NMDAR antagonists like phencyclidine (PCP/angel dust) cause both positive, negative, and cognitive symptoms in healthy people
• genetic links point to multiple NT systems and neuro-developmental processes

Question 15

EPS

Answer 15

extrapyramidal side Fx
- typical first gen antipsychotics can cause immobility and muscle rigidity similar to PD at their therapeutic dose
- can be overcome with addition of muscarinic antagonists

Question 16

mnemonic for muscarinic receptor antagonist side effects

Answer 16

red as a beet, dry as a bone, blind as a bat, mad as a hatter

dry mouth, mydriasis (causes blurred vision), tachycardia, hot and flushed skin, agitation, urinary retention, constipation, and delirium

Question 17

Muscarinic antagonists for PD and AP-induced PD-like symptoms

Answer 17

Benzatropine partially blocks cholinergic activity in the basal ganglia and has also been shown to increase the availability of dopamine by blocking its reuptake and storage in central sites, and as a result, increasing dopaminergic activity. It is used in the treatment of Parkinson’s disease and dystonia.

Question 18

Tardive dyskinesia

Answer 18

• occasionally occurs after longterm use of APSY
• symptoms persist even after APSY discontinued
• involuntary twitches of facial muscles also hands and legs

Question 19

Theory behind tardive dyskinesia

Answer 19

thought to reflect dopamine receptor hypersensitivity
- is also seen with L-dopa treatment in PD
- in both these conditions there are fluctuating states of high and low DA tone depending on drug PK

Question 20

Hyperprolactinemia

Answer 20

• Dopamine from hypothal prevents secretion of prolactin from pituitary
• more prolactin secreted with D2 blockage
• leads to production of milk and suppression of GnRH - causes disruption of menstrualcycle

Question 21

What theory did clozapine challenge

Answer 21

that a drug had to induce parkinsonism to be an effective antipsychotic

Question 22

Atypical antipsychotics

Answer 22

• drugs potentially more effective against depressive, negative, or cognitive symptoms
• better tolerated (fewer EPS)
• generally have greater affinity for 5HT2 receptors than D2 receptors and are antagonists at both

Question 23

examples of atypical anti-psychotics

Answer 23

risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole

Question 24

5HT2a activation by drugs like LSD and Psylocibin is asociated with

Answer 24

hallucinations

Question 25

Metabolic syndrome induced by atypical APS

Answer 25

• diabetes
• weight gain
• CV disease
• hypertension

Question 26

Side effects / adverse drug reactions to APS

Answer 26

• cause anhedonia (D2R antagonism)
• induce serious motor impairments
• cause sedation/somnolence by antagonizing H1 receptor (espesh chlorpromazine)
  -have anti-emetic properties (by blocking D2R at CNS-medulla and PNS-stomach - like D2 blocker anti-nauseant, metoclopramide for migraines)
• hyperprolactinemia
• metabolic disorders
• CV disorders
• clozapine can cause WBC loss in agranulocytosis

Question 27

Adverse effects of antipsychotics due to

Answer 27

on-target (D2 and 5HT) and off-target (H1 and M1 effects)

Question 28

Antagonism of these receptors leads to which side effect:
- 5HT2C
- 5HT1A
- H1
- D2
- M1 (muscarinic)
- M3

Answer 28

• 5HT2C - weight gain, diabetes
• 5HT1A - weight gain
• H1 - weight gain, diabetes, sedation
• D2 - EPS, weight gain, endocrine effects
• M1 (muscarinic) - anticholinergic (red as a beet, dry as a bone, blind as a bat, mad as a hatter)
• M3 - diabetes

Question 29

How is aripiprazole different from other antipsychotics?

Answer 29

partial agonist at D2 receptor instead of competitive antagonist
- will activate D2R and increase neurotransmission in areas where DAergic signalling is reduced (cortex and hippocampus)
- will decrease DA in areas where it’s excessive (striatum) by competing a more effective agonist out (DA)