PSYC 10.5: Schizophrenia PHARMACOLOGY

First Generation Antipsychotics

1) What receptors do these medications target + what do they do

2) Out of the receptors

1. Which produce the action we want

2. Which produce side effects

3) MOST COMMON side effect of FGA (more common than in SGA) (2)

4) What is the cause of the most common side effect from Q3

1) D2, H1, Alpha-1, M1 (ANTAGONIZE / Block all of these)

2) Action = D2, Side effects = H1, alpha-1, M1

3) Extrapyramidal symptom (muscle), NMS

4) FGA likely occupy/block >80% DA receptors

Antagonizing Histamine-1 Side effects

Weight gain

Sedation

Antagonizing Alpha-1 side effects

Orthostasis

HYPOtension (decreased blood pressure)

Priapism / sexual dysfunction

Dizziness

Drowziness

Antagonizing Muscarinic M1 receptors side effects

Dry mouth

Urinary retention

Blurred vision

Constipation

(ANTICHOLINERGIC)

Primary vs secondary symptoms (especially negative)

Primary symptoms = From the disease itself

Secondary symptoms = Because of the medications

1st Gen Antipsychotics: LOW POTENCY

1) Essentially ~____s of mgs

2) Give an example

3) Side effect profile more likely to be related to what receptor(s) antagonism

4) List common side effects

5) WHY ARE 1st GEN ANTIPSYCHOTICS NOT OFTEN USED

1) 100s of mgs

2) Chlorpromazine

3) H1, A1, M1

4) SE:

• Sedation

• Weight gain

• Orthostatic HYPOtension

• Urinary retention

5) Tardive dyskinesia risk

1st Gen Antipsychotics: HIGH POTENCY

1) Essentially ~____s of mgs

2) Give an example

3) Side effect profile more likely to be related to what receptor(s) antagonism

4) List common side effects

5) WHY ARE 1st GEN ANTIPSYCHOTICS NOT OFTEN USED

1) Like 5mg

2) Haloperidol, pimozide, perphenazine

3) D2 receptor antagonism

4) Extrapyramidal side effects

5) Tardive dyskinesia risk

Second Generation Antipsychotics

1) Antagonize what receptor(s)

2) Some 2nd gen antipsychotics are PARTIAL AGONISTS for what receptor(s)

3) Compared to 1st gen antipsychotics, whats one common type of side effect associated with SAG

1) D2, H1, A1, M1, AND 5HT2A

2) Partial agonist = 5HT-1A (only some)

3) Metabolic effects (Weight gain, hyperglycemia, dyslipidemia)

What is the metabolite of risperidone

Paliperidone

2nd Gen Antipsychotics

1) What SEs do we consider when we say “metabolic effects”

2) Most common with which SAGs?

3) Mneumonic to remember this

1) Weight gain, hyperglycemia, dyslipidemia

2) Olanzapine, Clozapine

3) “A FAT aPINE tree”

Clozapine

1) Side effects (5)

2) What’s special about this

3) What line therapy is it

4) When do we use this

5) What does this increase your likelihood of

6) Are side effects reversible?

7) What do you need to monitor

1) SE:

1. Bone marrow toxicity

2. Agranulocytosis

3. Neutropenia

4. Seizures

5. Myocarditis

2) Strongest antipsychotic; most side effects

3) 3rd/4th line

4) Use in treatment resistant schizophrenia

5) Makes you more highly susceptible to infections

6) Reversible once drug is stopped!

7) WBC count, neutrophil count

Which 2nd Gen medications are MOST likely to cause metabolic symptoms + weight gain

Olanzapine and Clozapine

Which 2nd Gen medications are LESS likely to cause weight gain and metabolic syndrome

Aripiprazole

Ziprasidone

Which 2nd Gen medication is MOST likely to cause hyperprolactinemia (increase prolactin) and endocrine issues

Risperidone + Paliperidone

Which 2nd Gen medication is LEAST sedating but highest risk for akathesia AND HIGH RISK FOR IMPULSIVITY

Aripiprazole

Which 2nd Gen is MOST sedating

Quetiapine

Which 2nd gen medication has the strongest anti-muscarinic effects (dry mouth, constipation, etc)

Clozapine

Serotonin: 5HT-2A ANTAGONISM

1) What is the 5HT-2A receptor

2) What does the 5HT-2A receptor sit on

3) What happens when serotonin hits (agonizes) 5HT-2A receptor

4) What happens when we block/antagonize 5HT-2A receptor with a medication

5) Which pathway(s) benefit from 5HT-2A antagonism

6) Which pathway(s) don’t really have any effect from 5HT-2A despite ____ in dopamine

1) An autoreceptor

2) Sits on dopamine neuron

3) Reduce/inhibit release of dopamine

4) Block 5HT-2A = can’t inhibit release of dopamine = increase dopamine release

5) Pathways: (bc of increased dopamine)

• Mesocortical pathway (helps w/ (-) symptoms)

• Nigrostriatal pathways (helps w/ Parkinsons symptoms; bc now more dopamine = <80% receptor occupation)

• Tuberoinfundibular Pathway (Increase dopamine = Decrease prolactin)

6) Mesolimbic doesn’t rlly get affected despite the INCREASE in dopamine

INCREASE In prolactin release can result from:

1) SIGNIFICANT D2 Antagonism (blocking DA) [1st gen, some 2nd (risperidone/paliperidone)

2) 5HT-2A AGONISM (via SSRI/Serotonin)

because:

2A activation = less dopamine

Less dopamine = more prolactin

DECREASE in prolactin release can result from

1) D2 agonism (dopamine, 3rd gen antipsychotics)

• This promotes more dopamine increase

2) 5HT-2A antagonism (2nd gen antipsychotics, 3rd gen antipsychotics)

Block 2A = increase dopamine release = less prolactin

What are the 3rd gen antipsychotics

Aripiprazole

Brexpiprazole

Cariprazine

3rd Gen Antipsychotics:

1) These medications also antagonize/block H1, M1, A1, 5HT-2A ….. compared to 2nd gen… what are these medications NOT blocking/antagonizing

2) 3rd gen antipsychotics are PARTIAL AGONISTS for which receptors (3)

3

1) D2

2) D2, D3, 5HT-1A

1st + 2nd generation antipsychotics:

1) The intrinsic activity of the antagonist is ___%

2) This means what

3) Their clinical effect is dependent on what

1) 0%

2) These medications produce no effect and/or PREVENT ANY EFFECT OF THAT RECEPTOR

3) Affinity for the receptor

3rd Generation Antipsychotics:

1) The intrinsic activity of a PARTIAL AGONIST (D2) is what

2) What happens when there’s too much dopamine floating around

3) What happens when there’s too little dopamine floating around

4) Clinical effect is dependent on what

1) Between 0 and 1

2) 3rdGA will compete w/ dopamine for receptors and lowers receptor signals without completely blocking it (since it’s effect is ~18%, lower than dopamine’s 100%)

3) 3rdGA can step in and give a small boost (since it produces more than 0 effect compared to an antagonist)

4) Intrinsic activity (3rdGA are basically antagonists; low intrinsic activity)

Which 3rd gen antipsychotic has MORE intrinsic activity

• (increase dopamine more)

• (out of the 3, acts most like an agonist than an antagonist)

Aripiprazole

Which 3rd gen antipsychotic has the LEAST intrinsic activity

• (more dopamine antagonist activity > agonist)

• (more like 1st gen antipsychotic)

Cariprazine

What’s the most effective medication for treatment of REFRACTORY PSYCHOSIS

Clozapine is the best treatment

Negative symptoms are best treated by which generations (in order of best to worst)

1. Third gen

2. Second gen

3. First gen

Why do we NOT want to agonize D3 receptors

Side effects of craving, gambling addiction

Why do we like agonizing 5HT-1A receptors in schizophrenia

Antidepressant, anxiolytic, reduces EPS

1) Therapeutic effects from BLOCKING/Antagonizing 5HT-2A

2) Side effects from AGONIZING 5HT-2A

1) Therapeutic effects from blocking:

• Reduces EPS

• Improves negative symptoms

2) SIDE EFFECTS FROM AGONIZING:

• Agitation, Anxiety

• Sexual Dysfunction

• EPS

• Insomnia

• Cognitive dulling

• Akathisia

THERAPEUTIC benefits of blocking/antagonizing M1 (muscarinic)

Reduces EPS

THERAPEUTIC benefits of blocking H1 (histamine)

Anxiolytic

FGA + SGA: D2 Antagonism

1) Blocking ___% results in (+) symptom improvement

2) Blocking ___% results in increased prolactin

3) Blocking ___% results in EPS (Parkinsonism)

4) Blocking ___% leads to dysphoria (explains why some ppl resort to drugs to feel better)

5) Does D2 receptor upregulation occur? If so, why is this a concern

1) 60-75%

2) 72%

3) 80%

4) 60%

5) Yes, brain grows more receptors to compensate (bc it thinks theres none). If the medication is stopped suddently, can result in rebound effect due to major increase in dopamine levels

3rd GEN ANTIPSYCHOTIC:

1) Occupying ____% of D2 receptors leads to (+) symptom improvement

2) What also may occur at this point

3) ____ and ____ doesn’t really get affected, therefore patients with these problem should be switched to a third generation antipsychotic

4) Is there D2 receptor upregulation? If so, why is this a concern?

1) 80-95%

2) Akathisia

3) Prolactin effects and dysphoria

4) No upregulation