Lecture 54-57 - Pharmacotherapy of Schizophrenia

Question 1

Key features that define psychotic disorders:

Answer 1

• Delusions – fixed false beliefs that are not amenable to change even with conflicting evidence
• Hallucinations – perception-like experiences that occur without an external stimulus (usually auditory, but can also be visual, tactile, or olfactory)
• Disorganized thinking and speech – switching from one topic to another, unrelated answers to questions
• Disorganized or abnormal motor behavior
• Negative symptoms

Question 2

Disease Course in Schizophrenia

Answer 2

Onset late adolescence to early adulthood
Men – late teens, early 20’s
Women – late 20’s, early 30’s

Question 3

Link to Substance Use

Answer 3

Smoking is associated with induction of 1A2, not due to nicotine, but because of hydrocarbons produced and inhaled, which decreases the serum concentration of 1A2 substrate antipsychotics (olanzapine, asenapine, clozapine, loxapine)
Marijuana, cocaine, and amphetamine use can hasten the onset of schizophrenia, exacerbate symptoms, and reduce time to relapse
Substance use treatment can be successfully achieved along with mental health treatment in patients with schizophrenia, should be undertaken at the same time

Question 4

Antipsychotic Drug Therapy Overview

Answer 4

MUST CONSIDER:
◦ Doses per day
◦ Side effects – what will the patient tolerate? What are their other disease states or risk factors?
◦ Previous drug therapy – success or failure? Do family members have this disease? What did they take?
◦ Cost of drug therapy – How will the patient pay for it? Oral or Intramuscular depot?
◦ Concomitant drug therapy
◦ Need for monitoring – labs? Weight? ECG?

Question 5

Antipsychotic Drug Selection

Answer 5

Oral antipsychotic drug therapy is generally considered first-line, unless the patient presents with reasons to consider IM depot drug therapy first

Question 6

Typical Antipsychotics

Answer 6

◦ Older agents – primarily D2 receptor antagonists
◦ Efficacy for positive symptoms is similar to atypical antipsychotics
Haloperidol, Fluphenazine, Loxapine, Chlorpromazine, perphenazine, thioridazine

Question 7

Typical Antipsychotics Clinical Pearls

Answer 7

◦ Haloperidol is most commonly used – routine and PRN
◦ More EPS with higher potency typicals
◦ Are very effective for treating the positive
symptoms, but are likely to worsen negative
and cognitive symptoms

Question 8

Atypical Antipsychotics

Answer 8

◦ D2 antagonists + 5HT2A antagonists
◦ Less EPS than typicals; more metabolic side effects
Aripiprazole, Clozapine, Olanzapine, Ziprasidone, Asenapine, Iloperidone, Paliperidone, Brexpiprazole, Lumateperone, Quetiapine, Cariprazine, Lurasidone, Risperidone

Question 9

Partial Agonists

Answer 9

◦ “Stabilize” dopamine transmission – not too much, not too little
◦ Associated with more akathisia than other antipsychotics
◦ Approved for adjunct treatment in depression so all have boxed warning for suicidal thoughts/behavior
aripiprazole, brexpiprazole, cariprazine

Question 10

Aripiprazole

Answer 10

• 2D6 and 3A4 substrate
• Moderate akathisia
• Low weight gain

Question 11

Brexpiprazole

Answer 11

• 2D6 and 3A4 substrate
• Moderate akathisia
• Low-moderate weight gain

Question 12

Cariprazine

Answer 12

• 3A4 substrate
• Moderate akathisia
• Low-moderate weight gain

Question 13

The “Pines”

Answer 13

◦ Less D2 antagonism, more 5HT2A antagonist – so significantly less EPS
◦ Higher weight gain than other agents
asenapine, clozapine, olanzapine, quetiapine

Question 14

Asenapine

Answer 14

• Sublingual and
  patch formulations
• 1A2 substrate
• QTc prolongation

Question 15

Clozapine

Answer 15

1A2 substrate
* Boxed warnings:
neutropenia, orthostasis, bradycardia, syncope, seizures, myocarditis, cardiomyopathy
* Side effects: sedation,
weight gain, constipation, hypersalivation, dry
mouth, GI hypomotility
with obstruction risk
* QTc prolongation

Question 16

Olanzapine

Answer 16

• 1A2 substrate
• Significant weight gain and sedation
• High risk metabolic syndrome
• DRESS warning

Question 17

Quetiapine

Answer 17

• 3A4 substrate
• QTc prolongation
• Weight gain and sedation
• Boxed warning for suicidal ideation

Question 18

Asenapine Transdermal Patch (Secuado®)

Answer 18

Apply one patch every 24 hours, rotate patch site to minimize application site reactions
Warnings for QTc prolongation
UGT and 1A2 substrate – reduce dose of patch if given with strong 1A2 inhibitors (e.g., fluvoxamine)

Question 19

Clozapine REMS

Answer 19

Reduces ANC to 1500/μL to initiate therapy; monitoring timelines weekly x 6 months, biweekly x 6 months, then every 4 weeks

Question 20

Olanzapine/Samidorphan (Lybalvi®)

Answer 20

◦ Samidorphan is an opioid antagonist with preferential activity at the mu opioid receptor
samidorphan added to mitigate weight gain
do not take if pt already on opioids

Question 21

The “Dones”

Answer 21

◦ D2 and 5HT2A antagonists
◦ Variable EPS and metabolic side effects
Iloperidone
lurasidone
ziprasidone

Question 22

Iloperidone

Answer 22

• High risk for orthostasis and syncope
• QTc prolongation
• 2D6 substrate

Question 23

Lurasidone

Answer 23

• 3A4 substrate
• Higherriskforakathisia
• Warning for suicidal thoughts – adjunct for bipolar depression
• Take with food (350 calories) to increase bioavailability

Question 24

Ziprasidone

Answer 24

• QTc prolongation (contraindication)
• DRESS warning
• Take with food to increase absorption and bioavailability
• 3A4 substrate (1/3) and aldehyde oxidase (2/3) (less worry for P450 interactions)

Question 25

More “Dones”

Answer 25

◦ Highest D2 blockade for atypical antipsychotics ◦ High risk EPS, moderate risk metabolic side effects
Risperidone
Paliperidone

Question 26

Risperidone

Answer 26

• 2D6 substrate (minor 3A4 substrate)
• EPS, hyperprolactinemia, weight gain,
  sedation, orthostasis

Question 27

Paliperidone

Answer 27

• Renally eliminated – dose adjustments in renal
  impairment
• Similar side effects with risperidone
• QTc prolongation

Question 28

Lumateperone (Caplyta®)

Answer 28

Low risk for weight gain or metabolic side effects
Low risk for EPS or akathisia
3A4 substrate

Question 29

Pimavanserin (Nuplazid®

Answer 29

◦ Antipsychotic medication that is FDA-approved for the treatment of hallucinations or delusions in a patient with Parkinson’s Disease
MOA: inverse agonist and antagonist at the serotonin (5HT) 2A
3A4 substrate

Question 30

Warnings for all Antipsychotics

Answer 30

◦ Boxed Warning: Increased risk of death in elderly patients treated with antipsychotics for dementia with related behaviors.
◦ Metabolic adverse effects
◦ EPS
◦ Risk of somnolence, postural hypotension, and motor and/or sensory instability increases the risk for falls/fractures.
◦ Fall risk assessment should be performed for patients taking other medications or having other disease states that also have a fall/fracture or somnolence/hypotension risk; assess when initiating antipsychotic and repeat routinely if on continuous long-term treatment

Question 31

Haloperidol decanoate

Answer 31

◦ Given every 4 weeks
◦ Load: 20 times oral dose
◦ Maintenance: 10 times oral dose ◦ If only use maintenance, may
need oral overlap
◦ Oil-based – Z-track

Question 32

Risperdal® Consta (risperidone)

Answer 32

MUST supplement with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment – I tell providers until 3rd injection (week 4)

Question 33

Perseris® (risperidone

Answer 33

◦ Abdominal subcutaneous injection - must be given in transpyloric plane
◦ 3A4 inducers – use 120 mg dose or may need oral supplementation

Question 34

Rykindo® (risperidone

Answer 34

Every 2 week IM injection
Oral dose overlap is shorter than Risperdal Consta (7 days vs 21 days)

Question 35

Uzedy® (risperidone)

Answer 35

◦ Abdominal or upper arm subcutaneous injection
* Given once montly or every 2 months

Question 36

Invega® Sustenna (paliperidone

Answer 36

Loading dose, then booster, then every 4 weeks (starting 5 weeks after loading injection)
Initial loading and booster doses must be given in deltoid to improve absorption consistency
If loading strategy followed, no need for oral overlap antipsychotic treatment
May require dose adjustment in moderate to severe renal impairment

Question 37

Invega® Trinza (paliperidone q3mo)

Answer 37

May be initiated for a patient who has been on a stable monthly (every 4 week) IM injection of Invega Sustenna (only way that it should be used), at least FOUR stable Invega Sustenna doses
Recommended to be given deltoid; gluteal administration results in a lower Cmax
Not recommended if CrCl < 50 mL/min

Question 38

Invega® Hafyera (paliperidone q6mo)

Answer 38

◦ May be initiated after stable Invega Sustenna for 4 months or stable Invega Trinza after one 3- month dose
* Gluteal injection only

Question 39

Zyprexa® Relprevv (olanzapine)

Answer 39

PDSS – post-dose delirium sedation syndrome

Question 40

Abilify® Maintena (aripiprazole)

Answer 40

◦ MUST overlap with oral aripiprazole (or another oral antipsychotic) for at least 14 days after first injection
◦ Deltoid or gluteal injection

Question 41

Abilify® Maintena – Dose Adjustments for P450 Interactions

Answer 41

If taking 2D6 or 3A4 inhibitors or 3A4 inducers for more than 14 days as concomitant therapy, must look at dosing table

Question 42

Abilify® Asimtufii (aripiprazole)

Answer 42

Every 2 month dosing
Gluteal injection only
Must establish tolerability to aripiprazole with oral dosing up to 2 weeks to assess; after tolerability is established, continue oral aripiprazole for 2 weeks after first injection

Question 43

Aristada® (aripiprazole lauroxil)

Answer 43

Overlap with oral aripiprazole for 3 weeks after first injection

Question 44

Aristada Initio®

Answer 44

• Developed to avoid need for 21-day oral overlap of antipsychotic
• Avoid in patients who are 2D6 poor metabolizers or with strong 3A4 or 2D6 inhibitors

Question 45

Immediate Release Antipsychotic Injections/ Psychiatric Emergencies

Answer 45

• Haloperidol, chlorpromazine, fluphenazine are used, haloperidol most commonly
  ◦ Olanzapine immediate release IM – CANNOT be given at the same time as a benzodiazepine immediate release injection – boxed warning for respiratory depression
  ◦ Loxapine for inhalation (Adasuve®)

Question 46

Clinical Treatment Strategies for EPS

Answer 46

acute dystonia
drug-induced parkinson’s
akathisia
tardive dyskinesia

Question 47

Acute dystonia

Answer 47

Not life-threatening, but very frightening
* IM anticholinergic NOW dose (benztropine 2mg, diphenhydramine 50mg)

Question 48

Drug-induced parkinson’s

Answer 48

longer-term side effect – months into antipsychotic treatment
* Oral anticholinergic (benztropine, trihexyphenidyl, diphenhydramine)

Question 49

Akathisia

Answer 49

subjective feeling of restlessness; increases risk for suicidal thinking/behaviors
Beta-blocker: propranolol preferred for 1st line
Benzodiazepine: usually lorazepam

Question 50

Tardive dyskinesia

Answer 50

lower dose of antipsychotic if possible, or switch to antipsychotic with less risk
VMAT inhibitors

Question 51

VMAT Inhibitors

Answer 51

◦ Inhibit the vesicular monoamine transporter to decrease storage/increase release of dopamine, serotonin, norepinephrine
tetrabenazine, valbenazine, deutetrabenazine

Question 52

Valbenazine

Answer 52

2D6/3A4 substrate
QTc prolongation

Question 53

Deutetrabenazine

Answer 53

2D6 substrate
QTc prolongation

Question 54

Neuroleptic Malignant Syndrome

Answer 54

• Life threatening - IS a medical emergency
  ◦ Hyperpyrexia, tachycardia, labile blood pressure
  ◦ Muscle rigidity – elevated (significantly) CK, myoglobinuria
  ◦ Treatment is supportive – discontinue antipsychotics, consider dopamine agonists
  ◦ Future antipsychotic use is NOT contraindicated

Question 55

Metabolic Adverse Effects

Answer 55

◦ Hyperglycemia, hyperlipidemia, hypertension
greastest risk in clozapine and olanzapine
least risk in ziprasidone, luradisone, aripiprazole

Question 56

Metabolic monitoring: FPG/HgbA1c

Answer 56

baseline
12 weeks
yearly