PSYC 11: Schizophrenia THERAPEUTICS

1. Once you start and optimize a trial of SGA or TGA, how long should you evaluate improvement for

2. How much of a reduction in symptoms accounts for “improvement”

1) 2 weeks

2) Reduction by ~22%

After 2 weeks of evaluating improvement of SGA/TGA trial and there’s NO RESPONSE, what should you do

1) Gradual switch to a trial of a different SGA or TGA

2) OR consider a long acting injectable antipsychotic

After

1) Gradual switch to a trial of a different SGA or TGA

2) OR consider a long acting injectable antipsychotic

and there’s STILL not response what should you do + what if that fails too

Consider switching to clozapine

If everything fails, do clozapine augmentation (w/ another drug)

After 2 weeks of evaluating improvement of SGA/TGA trial and there’s PARTIAL RESPONSE, what should you do

1) Optimization: Adjust Dose as Needed

2) Treat side effects

3) Treat co-existing conditions

4) Remission

5) Monitor

Lets say your patient is having a problem with increase in prolactin levels due to their medication, what should you do?

BONUS: What’s an added benefit of this

Give aripiprazole 5 mg po daily

—> Added benefit = this also helps with (-) symptoms

Why is it harder to switch from 2nd gen to 3rd gen

(+ why’s it better to start on 3rd gen and switch to 2nd if need be)

2nd gen antipsychotics cause an upregulation of D2 receptors (more made to compensate for blockade)

• This causes D2 receptors to be extra sensitive to any “dopamine”

• Switching to third gen can cause breakthrough psychosis/withdrawal dyskinesia

  • (Overstimulation: Abnormal uncontrolled movements)

    • because 3rd gen can also agonize D2 receptors, not just block (sudden increase of DA levels)

After the initial 2 week monitoring to see treatment response, let’s say the patient is either

1. Responding to the drug OR

2. Responding to the drug you switched them too

What’s the recommended time to wait to evaluate treatment response (beyond initial)

6-8 weeks

Which side effects from meds are transient / pass over time ; THEREFORE DONT SWITCH RIGHT AWAY EVEN IF PATIENTS COMPLAIN

Sedation

Postural hypotension

1) D2 Antagonism in nucleus accumbens for treating psychosis had the potential to ____ negative symptoms associated with psychosis

2) D2 antagonism in striatum (EPS) has the potential to ______ negative symptoms associated with EPS

1) Treat

2) Worsen/Cause

5HT2A antagonism in prefrontal cortex has potential to treat ______ symptoms

Primary AND secondary negative symptoms5

5HT2A antagonism in the striatum has the potential to what

Treat secondary negative symptoms associated with EPS

—> more DA = less EPS = less bad mood from EPS side effects

1) What does 5HT-1A partial agonism do for EPS

1) Reduces EPS independent of dopamine activity

Cariprazine (TGA) ____ ____ the _____ autoreceptors on the _____ dopamine neurons, leading to an increase in dopamine, therefore helps with both primary and secondary negative symptoms

Partially agonizes

D3

Mesocorticol

Which medication has the potential to treat primary negative symptoms (+ what class)

Cariprazine , third generation antipsychotic

—> bc of partial d3 agonism

Cariprazine, which receptor does it have greater affinity for? How does this relate to the K1

More affinity for D3 compared to D2

Lower k1 for D3 compared to D2

**INVERSELY RELATED

What is more likely for long acting injectable (LAI)

Less likely to have rehospitalization and tx failure

Why is exercise important to consider if a patient is on LAI antipsychotics (PD/PK)

More exercise = more blood flow = absorb the drug much faster

—> May need injection q3w compared to q4w

Which drugs have LAIs available (3)

Risperidone

Paliperidone

Aripiprazole

What side effect is exercise associated with in LAIs

Increase in extrapyramidal side effects (EPS)

How long do you have to trial 2 separate antipsychotics for before trying clozapine

6-8 weeks each

D2 antagonists can cause patients to develop ____ due to _____ of D2 receptors. If left untreated / dose not adjusted, this can cause _____

Tolerance

Upregulation

Refractory psychosis

Why do you have to titrate clozapine SLOWLY

Very alpha-1 blockade

Antihistaminergic

Sedating (fall risk)

How should clozapine be dosed

Once daily at bedtime (bc of sedation)

• BID IF > 500 mg

What is the main metabolizer of clozapine & olanzapine

CYP 1A2

What are factors that increase clozapine / olanzapine plasma concentrations (reduced CYP1A2 activity)

• Which sex

• Life stages (2)

• What ancestry

• What lifestyle choices

• What 2 drugs

• Female sex

• Pregnancy

• Geriatric age

• Asian ancestry

• Obesity

• Fluvoxamine

• Valproic Acid

ALSO:

• Rapid titration

• Infection/inflammation

What’s the connection between smoking and clozapine

Aeromatic Hydrocarbon from SMOKE (not nicotine) increases/induces CYP 1A2

• CYP 1A2 metabolizes clozapine / olanzapine

• Drug gets metabolized faster; less [] in the body

• Patient needs more clozapine dose to avoid psychosis

Clozapine Augmentation

1) Adequate trial should be employed for ____ - ____ MONTHS
2) What should you rule out (4)

3) What should you consider doing

1) 3-6 months

2) Rule out:

• Nonadherence

• Substance abuse

• Untreated depression

• Inadequate dosing (smoking)

3) Draw clozapine levels to confirm adherence / adequate dosing

What should you add on with clozapine-refractory positive symptoms

• (Positive symptoms not going away despite clozapine treatment)

What drug might be able to help with clozapine’s D2 upregulation problem

Aripiprazole (helps down regulate due to partial agonism)

What should you do for clozapine refractory negative symptoms (negative symptoms despite clozapine treatment)

• Antidepressant

• Mood stabilizer

• ECT

What should you add for clozapine refractory aggression

Mood stabilizer

Antipsychotic

Which drugs DO need to be monitored for lipids (All of them at baseline) BUT WITH SPECIAL PRECAUTION

• Clozapine

• Olanzapine

• Quetiapine

Which drugs (beyond baseline) should u take special monitoring considerations for Qtc prolongation (ECG)

Haloperidol

Ziprasidone

** If other risk factors are present

Acute dystonia

1) What is it

2) When does it usually occur

3) Laryngeal dystonia can cause _____

4) Treatment drug class + 2 examples

1) Involuntary contraction of muscles (painful + frightening)

• Uncontrollable

• Repetitive

• Twisting

  • Neck

  • Eyes

  • Jaw

  • Tongue

  • Back

2) Within hours/minutes of starting an antipsychotic

3) Airway obstruction

4) ANTI MUSCARINIC AGENTS

• Diphenhydramine

• Benztropine

Pseudo-Parkinsonism

1) Resembles Parkinson’s disease when ______

2) Occurs within _____ after antipsychotic started/dose increased

3) What drugs SHOULD NOT be prescribed at night in patients who experience pseudo parkinsonism

4) Treatment

1) >80% D2 receptor blockade

2) Days to weeks

3) Anticholinergics NO at night

4) Treatment:

• Reduce dose of antipsychotic (BEST)

• Change antipsychotic

• Treat with oral anticholinergic benztropine or trihexphenidyl

  • (not the best b/c anticholinergics mess w cognition)

When it comes to wanting to reduce EPS symptoms, why is is that we DONT want to block D2 receptors (antagonize)

1. Block D2 receptors on cholinergic neuron

2. Increase ACh release

3. Increase ACh = more ACh binding to M1 receptors

4. Bind to M1 = EPS side effects

THEREFORE, to decrease EPS sx, we want to BLOCK M1 receptors (decrease Ach by increasing DA)

• Dopamine INHIBITS ACh

• Low ACh = No m1 binding = no EPS

Akathisia

1) What is it

2) What does #1 cause ^

3) Is it reversible or irreversible

4) Occurs within ______

5) Treatment (+ why one of the options isn’t good)

6) Which meds are the worst offenders

1) Movement disorder characterized by an inner restlessness and a strong urge to be in constant motion

2) Anxiety

3) Reversible

4) Days to weeks

5) Treatments:

• Reduce dose of antipsychotic

• Propranolol (beta blocker)

• Mirtazapine (best choice!!)

• Benzodiazepines

  • Not choice bc it likely works indirectly rather than treating underlying cause

6) FGA then Aripiprazole are WORST offenders!!

Tardive Dyskinesia (sometimes irreversible)

1) What is it

2) Why does this potentially happen

3) What medications should you ABSOLUTELY STOP

4) Treatment

1) Involuntary movements + repetitive purposeless

2) Potentially bc of upregulation of D2 receptors

3) STOP ANTICHOLINERGICS

4) Treatments:

• Switch to clozapine or TGA

• Amantadine

• Vitamin B6

  • VMAT-2 inhibitors (only in USA)

Why do VMAT inhibitors in schizophrenia lead to depression

VMAT usually stores dopamine

If it gets inhibited, can’t store dopamine = less dopamine = depression

Treatment add on options for hyperprolactinemia

Aripiprazole

Bromocriptine

Cabergoline (Dopamine agonist)

Treatment add on options for weight gain

Metformin 750-2250

Topiramate (has cognitive SE though)

Patient on clozapine has Sx of myocarditis/cardiomyopathy

1) When is the greatest risk of myocarditis

2) When is the greatest risk of cardiomyopathy

3) What should you do

4) What might the patient present with

1) First 6-8 weeks

2) May occur at any time

3) CEASE clozapine ASAP. Admit to hospital

4) Flu-like symptoms

Clozapine: What should u use for sialorrhea (increased salivation)

Atropine eye drops, benzotropine, OR CHANGE CLOZAPINE TO BID DOSING

1) Clozapine seizures, which med should u consider

2) Clozapine: What should u use for constipation

1) Prophylactic valproate

1) PEG or stimulant laxative; usually persists