Lecture 54-57 - Pharmacotherapy of Schizophrenia Flashcards
Key features that define psychotic disorders:
- 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
Disease Course in Schizophrenia
Onset late adolescence to early adulthood
Men – late teens, early 20’s
Women – late 20’s, early 30’s
Link to Substance Use
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
Antipsychotic Drug Therapy Overview
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?
Antipsychotic Drug Selection
Oral antipsychotic drug therapy is generally considered first-line, unless the patient presents with reasons to consider IM depot drug therapy first
Typical Antipsychotics
◦ Older agents – primarily D2 receptor antagonists
◦ Efficacy for positive symptoms is similar to atypical antipsychotics
Haloperidol, Fluphenazine, Loxapine, Chlorpromazine, perphenazine, thioridazine
Typical Antipsychotics Clinical Pearls
◦ 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
Atypical Antipsychotics
◦ 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
Partial Agonists
◦ “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
Aripiprazole
- 2D6 and 3A4 substrate
- Moderate akathisia
- Low weight gain
Brexpiprazole
- 2D6 and 3A4 substrate
- Moderate akathisia
- Low-moderate weight gain
Cariprazine
- 3A4 substrate
- Moderate akathisia
- Low-moderate weight gain
The “Pines”
◦ Less D2 antagonism, more 5HT2A antagonist – so significantly less EPS
◦ Higher weight gain than other agents
asenapine, clozapine, olanzapine, quetiapine
Asenapine
- Sublingual and
patch formulations - 1A2 substrate
- QTc prolongation
Clozapine
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
Olanzapine
- 1A2 substrate
- Significant weight gain and sedation
- High risk metabolic syndrome
- DRESS warning
Quetiapine
- 3A4 substrate
- QTc prolongation
- Weight gain and sedation
- Boxed warning for suicidal ideation
Asenapine Transdermal Patch (Secuado®)
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)
Clozapine REMS
Reduces ANC to 1500/μL to initiate therapy; monitoring timelines weekly x 6 months, biweekly x 6 months, then every 4 weeks
Olanzapine/Samidorphan (Lybalvi®)
◦ 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
The “Dones”
◦ D2 and 5HT2A antagonists
◦ Variable EPS and metabolic side effects
Iloperidone
lurasidone
ziprasidone
Iloperidone
- High risk for orthostasis and syncope
- QTc prolongation
- 2D6 substrate
Lurasidone
- 3A4 substrate
- Higherriskforakathisia
- Warning for suicidal thoughts – adjunct for bipolar depression
- Take with food (350 calories) to increase bioavailability
Ziprasidone
- 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)
More “Dones”
◦ Highest D2 blockade for atypical antipsychotics ◦ High risk EPS, moderate risk metabolic side effects
Risperidone
Paliperidone
Risperidone
- 2D6 substrate (minor 3A4 substrate)
- EPS, hyperprolactinemia, weight gain,
sedation, orthostasis
Paliperidone
- Renally eliminated – dose adjustments in renal
impairment - Similar side effects with risperidone
- QTc prolongation
Lumateperone (Caplyta®)
Low risk for weight gain or metabolic side effects
Low risk for EPS or akathisia
3A4 substrate
Pimavanserin (Nuplazid®
◦ 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
Warnings for all Antipsychotics
◦ 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
Haloperidol decanoate
◦ 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
Risperdal® Consta (risperidone)
MUST supplement with oral risperidone (or another oral antipsychotic) for the first few weeks of treatment – I tell providers until 3rd injection (week 4)
Perseris® (risperidone
◦ Abdominal subcutaneous injection - must be given in transpyloric plane
◦ 3A4 inducers – use 120 mg dose or may need oral supplementation
Rykindo® (risperidone
Every 2 week IM injection
Oral dose overlap is shorter than Risperdal Consta (7 days vs 21 days)
Uzedy® (risperidone)
◦ Abdominal or upper arm subcutaneous injection
* Given once montly or every 2 months
Invega® Sustenna (paliperidone
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
Invega® Trinza (paliperidone q3mo)
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
Invega® Hafyera (paliperidone q6mo)
◦ May be initiated after stable Invega Sustenna for 4 months or stable Invega Trinza after one 3- month dose
* Gluteal injection only
Zyprexa® Relprevv (olanzapine)
PDSS – post-dose delirium sedation syndrome
Abilify® Maintena (aripiprazole)
◦ MUST overlap with oral aripiprazole (or another oral antipsychotic) for at least 14 days after first injection
◦ Deltoid or gluteal injection
Abilify® Maintena – Dose Adjustments for P450 Interactions
If taking 2D6 or 3A4 inhibitors or 3A4 inducers for more than 14 days as concomitant therapy, must look at dosing table
Abilify® Asimtufii (aripiprazole)
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
Aristada® (aripiprazole lauroxil)
Overlap with oral aripiprazole for 3 weeks after first injection
Aristada Initio®
- 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
Immediate Release Antipsychotic Injections/ Psychiatric Emergencies
- 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®)
Clinical Treatment Strategies for EPS
acute dystonia
drug-induced parkinson’s
akathisia
tardive dyskinesia
Acute dystonia
Not life-threatening, but very frightening
* IM anticholinergic NOW dose (benztropine 2mg, diphenhydramine 50mg)
Drug-induced parkinson’s
longer-term side effect – months into antipsychotic treatment
* Oral anticholinergic (benztropine, trihexyphenidyl, diphenhydramine)
Akathisia
subjective feeling of restlessness; increases risk for suicidal thinking/behaviors
Beta-blocker: propranolol preferred for 1st line
Benzodiazepine: usually lorazepam
Tardive dyskinesia
lower dose of antipsychotic if possible, or switch to antipsychotic with less risk
VMAT inhibitors
VMAT Inhibitors
◦ Inhibit the vesicular monoamine transporter to decrease storage/increase release of dopamine, serotonin, norepinephrine
tetrabenazine, valbenazine, deutetrabenazine
Valbenazine
2D6/3A4 substrate
QTc prolongation
Deutetrabenazine
2D6 substrate
QTc prolongation
Neuroleptic Malignant Syndrome
- 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
Metabolic Adverse Effects
◦ Hyperglycemia, hyperlipidemia, hypertension
greastest risk in clozapine and olanzapine
least risk in ziprasidone, luradisone, aripiprazole
Metabolic monitoring: FPG/HgbA1c
baseline
12 weeks
yearly
