Antipsychotic medications

ACRONYMS AND DEFINITIONS

EPS - Extrapyramidal symptoms

MDD - Major depressive disorder

NMS - Neuroleptic malignant syndrome

ODT - Orally disintegrating tablet

P = Drugs with pediatric dosing

TD - Tardive dyskinesia

SECOND GENERATION ANTIPSYCHOTICS

Dosage forms

Tablet (Abilify®)

2 mg
5 mg
10 mg

15 mg
20 mg
30 mg

Orally-disintegrating tablet (Abilify Discmelt®)

10 mg
15 mg

Tablet with IEM (Abilify MyCite®)

2 mg
5 mg
10 mg
15 mg

20 mg
30 mg
Comes in kit with 30 tablets and 7 patches

Solution (Abilify®)

1 mg/ml
Comes in 150 ml bottle

Prefilled syringe and vial (Abilify Maintena™)

300 mg
400 mg

Prefilled syringe (Aristada®)

441 mg
662 mg
882 mg
Aristada is aripiprazole lauroxil

Dosing - Abilify® (tablets / discmelt / solution)

Schizophrenia (adults)

Starting: 10 - 15 mg once daily
Maintenance: - 10 - 20 mg once daily
Max: 30 mg once daily
Increase dose at intervals of ≥ 2 weeks
Solution can be substituted for tablet on mg-to-mg basis up to 25 mg

Schizophrenia (13 - 17 years old)

Starting: 2 mg once daily for 2 days, then 5 mg once daily for 2 days, then 10 mg once daily
Maintenance: 10 mg once daily
Max: 30 mg once daily
After initial dosing, increase dose by increments of 5 mg/day
Doses > 10 mg/day have not been shown to be more efficacious

Bipolar I (adults)

Starting: 10 - 15 mg once daily
Maintenance: - 10 - 20 mg once daily
Max: 30 mg once daily
Increase dose at intervals of ≥ 2 weeks
Solution can be substituted for tablet on mg-to-mg basis up to 25 mg

Bipolar I (10 - 17 years old)

Starting: 2 mg once daily for 2 days, then 5 mg once daily for 2 days, then 10 mg once daily
Maintenance: 10 mg once daily
After initial dosing, increase dose in increments of 5 mg/day

Depression in adults (adjunctive with antidepressant)

Starting: 2 - 5 mg once daily
Maintenance: 2 - 15 mg once daily
Increase dose by up to 5 mg a day at intervals of ≥ 1 week

Irritability associated with autistic disorder (6 - 17 years)

Starting: 2 mg once daily
Maintenance: 5 - 15 mg once daily
Increase dose by up to 5 mg/day at intervals of ≥ 1 week

Tourette’s disorder (6 - 18 years)

Dosing (< 50 kg): 2 mg once daily for 2 days, then 5 mg once daily. May increase to 10 mg once daily if necessary.
Dosing (≥ 50 kg): 2 mg once daily for 2 days, then 5 mg once daily for 5 days, then 10 mg once daily
After initial dosing, increase dose at intervals of ≥ 1 week

Dosing - Abilify Maintena™

Schizophrenia/Bipolar I (adults)

Dosing: 400 mg IM once a month
Patients should demonstrate tolerability of oral Abilify® before using
After initial injection, continue oral aripiprazole for 14 days
See Abilify Maintena™ PI for guidelines on missed injections

Dosing - Aristada™

Schizophrenia (adults)

Dosing: 441 - 882 mg IM once monthly. 882 mg dose may also be given every 6 weeks.
Patients should demonstrate tolerability of oral Abilify® before using
After initial injection, continue oral aripiprazole for 21 days
Converting from oral:

10 mg/day = 441 mg/month
15 mg/day = 662 mg/month
≥ 20 mg/day = 882 mg/month

See Aristada PI sec 2.2 for guidelines on missed injections

Efficacy

Aripiprazole in resistant depression

Generic / Price

Abilify tablet - YES/$
Abilify ODT - YES/$$$$
Abilify MyCite - NO/$$$$
Abilify solution - YES/$$$-$$$$
Abilify Maintena - NO/$$$$
Aristada - NO/$$$$

Other

Tablet and discmelt

May take without regard to food
Discmelt is placed on tongue where it dissolves

Abilify MyCite®

Abilify MyCite is a system composed of a tablet with an ingestible event marker (IEM) sensor, a wearable sensor patch, a smartphone app, and a web-based portal for healthcare providers. The IEM is a 1 mm sized sensor embedded in the Abilify Mycite tablet. Upon contact with gastric fluid, magnesium and cuprous chloride within the IEM react to activate and power the device. The IEM then communicates the ingestion to the MyCite Patch. Detected ingestions can be reviewed on the app and in the portal.
The IEM sensor detects most ingestions within 30 minutes, but may take up to 2 hours
The patch is applied every 7 days to the left side of the body just above the lower edge of the rib cage. The patch should be removed for MRIs.
Swallow tablets whole; do not divide, crush, or chew

Solution

Solution can be substituted for tablet on mg-to-mg basis up to 25 mg
Once bottle is opened, good for 6 months
Store at room temperature

Abilify Maintena

For intramuscular injection in the deltoid or gluteal muscle
Store at room temperature

Aristada

For intramuscular injection in the deltoid (441 mg dose only) or gluteal muscle (all doses)
Store at room temperature

Pharmacokinetics (tablet)

Half-life (aripiprazole): 75 hours
Half-life (active metabolite): 94 hours

Mechanism of action

Dopamine D₂ receptor partial agonist
Serotonin 5-HT_1A receptor partial agonist
Serotonin 5-HT_2A receptor antagonist

FDA-approved indications

Abilify tablets/solution

Schizophrenia
Bipolar I - Acute treatment of manic and mixed episodes
Depression - adjunct with antidepressants
Tourette's disorder
Irritability associated with autistic disorder

Abilify MyCite

Schizophrenia
Bipolar I
Depression - adjunct with antidepressants

Abilify Maintena

Schizophrenia
Bipolar I - maintenance monotherapy

Aristada

Schizophrenia

Side effects

Side effect	Aripiprazole	Placebo
Headache	27%	23%
Agitation	19%	17%
Insomnia	18%	13%
Anxiety	17%	13%
Nausea	15%	11%
Skin irritation (MyCite patch)	12.4%	N/A
Somnolence	11%	6%
Constipation	11%	7%
Vomiting	11%	6%
Dizziness	10%	7%
Akathisia	10%	4%
Other Extrapyramidal symptoms - 8 to 13% of patients in trials Weight gain - up to 8% of patients Orthostatic hypotension - 1% of patients Difficulty swallowing - incidence not well-defined Hyperprolactinemia - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

CYP3A4 strong inhibitors - administer half of recommended dose
Known CYP2D6 Poor Metabolizers + CYP3A4 strong inhibitors - administer a quarter of recommended dose
CYP3A4 strong inducers - double recommended dose over 1 to 2 weeks
CYP2D6 strong inhibitors - administer half of recommended dose
CYP2D6 strong inhibitor + CYP3A4 inhibitor - administer a quarter of recommended dose
Carbamazepine - carbamazepine is a strong CYP3A4 inducer. Double aripiprazole dose when taken together.
Alpha blockers - aripiprazole can block alpha receptors. It may potentiate the effects of alpha blockers.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - aripiprazole may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Lab interactions

Urine drug screen - there have been case reports of false-positive amphetamines on urine drug screens in children exposed to aripiprazole. Subsequent confirmatory testing with gas chromatography-mass spectrometry was negative. [PMID 26527556]

Contraindications / Precautions

Poor CYP2D6 metabolizers - reduce dose by one-half and adjust as needed
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 24 weeks, aripiprazole had no significant effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 24 weeks, aripiprazole had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Impulse-control problems - cases of uncontrollable urges to gamble, binge eat, shop, and have sex have been reported in patients taking aripiprazole
Liver disease - no dose adjustment necessary
Kidney disease - no dose adjustment necessary

Asenapine | Saphris® | Secuado®

Dosage forms

Sublingual tablet (Saphris®)

5 mg
10 mg

Patch (Secuado®)

3.8 mg/24 hours
5.7 mg/24 hours
7.6 mg/24 hours
Comes in carton with 30 patches

Dosing - Tablet

Schizophrenia (adults)

Starting: 5 mg twice a day
Maintenance: 5 - 10 mg twice a day
Max: 10 mg twice a day
Increase dose at intervals of 1 week

Bipolar mania (adults)

Starting: 5 - 10 mg twice a day
Maintenance: 5 - 10 mg twice a day
Max: 10 mg twice a day

Bipolar mania (10 - 17 years old)

Starting: 2.5 mg twice a day
Maintenance: 2.5 - 10 mg twice a day
Max: 10 mg twice a day

Bipolar mania - adjunct to lithium or valproate (adults)

Starting: 5 mg twice a day
Maintenance: 5 - 10 mg twice a day
Max: 10 mg twice a day

Dosing - Patch

Schizophrenia (adults)

Starting: 3.8 mg/24 hours patch applied once daily
Maintenance: 3.8 mg - 7.6 mg/24 hours patch applied once daily
Max: 7.6 mg/24 hours patch applied once daily
Increase dose at intervals of 1 week
3.8 mg/24 hours patch corresponds to 5 mg twice daily of sublingual asenapine and 7.6 mg/24 hours corresponds to 10 mg twice daily
Apply to the upper arm, upper back, abdomen, or hip
Showering is permitted, but use during swimming or taking a bath has not been evaluated
Do not apply heat to the patch because it will increase absorption

Generic / Price

Sublingual tablet - YES/$$$$
Patch - NO/$$$$

Other

Saphris

Saphris is a sublingual tablet that dissolves under the tongue
It should not be crushed, chewed, or swallowed
Patients should not eat or drink for 10 minutes after administration

Pharmacokinetics

Tablet

Tmax: 1 hour
Half-life: 24 hours

Patch

Tmax: 12 - 24 hour
Half-life: 30 hours

Mechanism of action

Dopamine D₂ receptor antagonist
Serotonin (5-HT_2A) receptor antagonist

FDA-approved indications

Tablet

Schizophrenia
Bipolar - acute mania

Patch

Schizophrenia

Side effects

Side effect	Asenapine	Placebo
Somnolence	24%	6%
Headache	12%	11%
Dizziness	11%	3%
Akathisia	4%	2%
Other Weight gain (≥ 7% increase) - 15% after one-year of therapy Extrapyramidal symptoms - up to 10% of patients in trials Orthostatic hypotension - < 1% of patients Difficulty swallowing - incidence not well-defined Hyperprolactinemia (elevated prolactin level) - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare Local skin reactions (patch) - up to 15%

Drug interactions

Drugs that prolong the QT interval - DO NOT COMBINE
CYP1A2 inhibitors and inducers - asenapine is a CYP1A2 substrate
CYP2D6 substrates and inhibitors - asenapine is a weak CYP2D6 inhibitor
Dopamine agonists (Mirapex®, Sinemet®, etc.) - asenapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - asenapine can block alpha receptors. It may potentiate the effects of alpha blockers.
Lithium - when adding to lithium, starting dose should be 5 mg twice a day
Valproate - when adding to valproate, starting dose should be 5 mg twice a day

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Asenapine may prolong the QT interval.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, asenapine caused a slight increase in blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. See cholesterol below for ADA monitoring recommendations.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Liver disease

Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
Severe (Child-Pugh C) - DO NOT USE

Kidney disease - No dose adjustment necessary

Brexpiprazole (Rexulti®)

Dosage forms

Tablet

0.25 mg
0.5 mg
1 mg

2 mg
3 mg
4 mg

Dosing

Schizophrenia (adults)

Starting: 1 mg once daily on Days 1 to 4, increase dose to 2 mg once daily on Days 5 to 7, then to 4 mg on Day 8 if needed
Maintenance: 2 - 4 mg once daily
Max: 4 mg once daily
May take without regard to food

Schizophrenia (pediatric patients 13 to 17 years old)

Starting: 0.5 mg once daily on Days 1 to 4, increase dose to 1 mg once daily on Days 5 to 7, then to 2 mg on Day 8 if needed
Maintenance: 2 - 4 mg once daily
Max: 4 mg once daily
Weekly dose increases can be made in 1 mg increments
May take without regard to food

Depression (adjunctive with antidepressant)

Starting: 0.5 - 1 mg once daily
Maintenance: 2 mg once daily
Max: 3 mg once daily
Increase dose at weekly intervals
May take without regard to food

Liver disease

Moderate to severe (Child-Pugh B/C) - max of 2 mg/day in depression and 3 mg/day in schizophrenia

Kidney disease

CrCl < 60 ml/min - max of 2 mg/day in depression and 3 mg/day in schizophrenia

Dosing with CYP2D6 and CYP3A4 modulators

See **CYP2D6** and **CYP3A4** for list of modulators
Concurrent medication	Brexpiprazole dose
Strong CYP2D6 inhibitor	Half usual dose
Strong CYP3A4 inhibitor	Half usual dose
Strong/moderate CYP2D6 inhibitor + strong/moderate CYP3A4 inhibitor	Quarter of usual dose
Strong CYP3A4 inducer	Double usual dose over 1 - 2 weeks

Dosing for CYP2D6 poor metabolizers

CYP2D6 poor metabolizer - half the usual dose
CYP2D6 poor metabolizer + strong/moderate CYP3A4 inhibitor - quarter the usual dose

Generic / Price

- NO/$$$$

Pharmacokinetics

Time to max level: within 4 hours
Half-life: 91 hours

Mechanism of action

Dopamine D₂ receptor partial agonist
Serotonin 5-HT_1A receptor partial agonist
Serotonin 5-HT_2A receptor antagonist

FDA-approved indications

Schizophrenia in adults and pediatric patients ages 13 years and older
Depression in adults (adjunctive with antidepressant)

Side effects

Side effect	Rexulti	Placebo
Increase in triglycerides	10%	6%
Akathisia	7%	5%
Extrapyramidal symptoms (excluding akathisia)	5%	4%
Somnolence	5%	3%
Tremor	3%	1%
Sedation	3%	1%
Upset stomach	3%	2%
Diarrhea	3%	2%
Increase in CPK	2%	1%
Other Weight gain - in 6 week trials, patients on brexpiprazole gained an average of 2.6 lbs (1.2 kg) while patients on placebo gained 0.4 lbs (0.2 kg) Difficulty swallowing - incidence not well-defined

Drug interactions

CYP3A4 modulators - brexpiprazole is a CYP3A4 sensitive substrate. See Dosage for recommendations on concomitant dosing.
CYP2D6 modulators - brexpiprazole is a CYP2D6 sensitive substrate. See Dosage for recommendations on concomitant dosing.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - brexpiprazole may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Contraindications / Precautions

Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Suicide thoughts and behaviors - in trials involving antidepressants (e.g. SSRIs), the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. Monitor patients with depression for worsening symptoms during treatment.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Pathological gambling and other compulsive behaviors - cases of intense and uncontrollable urges, particularly for gambling, have been reported in patients taking brexpiprazole. Other types of reported urges include sexual, shopping, and eating or binge eating.
Diabetes - atypical antipsychotics may cause blood sugars to increase in some patients. In long-term schizophrenia trials, up to 10% of brexpiprazole-treated patients with baseline normal or borderline fasting glucose experienced shifts to high fasting glucose. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics may raise lipid parameters in some patients. In long-term depression trials, shifts from normal to high lipid parameters were seen in 9% (total cholesterol), 3% (LDL cholesterol), and 17% (triglycerides) of brexpiprazole-treated patients. See cholesterol below for ADA monitoring recommendations.
Weight gain - atypical antipsychotics may cause weight gain in some patients. In long-term depression trials, the average increase in weight from baseline in brexpiprazole-treated patients was 6.4 lbs at 26 weeks and 6.8 pounds at 52 weeks.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Liver disease

Moderate to severe (Child-Pugh B/C) - max of 2 mg/day in depression and 3 mg/day in schizophrenia

Kidney disease

CrCl < 60 ml/min - max of 2 mg/day in depression and 3 mg/day in schizophrenia

Cariprazine (Vraylar®)

Dosage forms

Capsule

1.5 mg
3 mg
4.5 mg
6 mg

Dosing

Schizophrenia

Starting: 1.5 mg once daily. May increase to 3 mg once daily on Day 2.
Maintenance: 1.5 - 6 mg once daily
Max: 6 mg once daily
May take without regard to food
Cariprazine has a long half-life and changes in dose will not be fully reflected in plasma for several weeks

Bipolar I (manic or mixed episode)

Starting: 1.5 mg once daily. Increase to 3 mg once daily on Day 2.
Maintenance: 3 - 6 mg once daily
Max: 6 mg once daily
May take without regard to food
Cariprazine has a long half-life and changes in dose will not be fully reflected in plasma for several weeks

Depression (bipolar I depression or adjunctive therapy in MDD)

Dosing: 1.5 mg once daily. May increase to 3 mg once daily on Day 15.
Max: 3 mg once daily
May take without regard to food

Dosing with CYP3A4 inducers and inhibitors

Initiating a strong CYP3A4 inhibitor while on stable cariprazine dose

Reduce cariprazine dose by half
For 1.5 mg dose, give every other day

Initiating cariprazine while taking a strong CYP3A4 inhibitor

Give cariprazine 1.5 mg on Day 1 and Day 3 with no dose on Day 2
From Day 4 onward, give 1.5 mg once daily
Maximum dose is 3 mg once daily

Cariprazine with a CYP3A4 inducer

Has not been studied
Not recommended

Generic / Price

- NO/$$$$

Pharmacokinetics

Cariprazine has 2 major active metabolites - DCAR, DDCAR
Half-lives:

Cariprazine: 2 - 4 days
DDCAR: 1 - 3 weeks
DCAR: 1 - 2 days

Mechanism of action

Cariprazine is a partial agonist at dopamine D₂ and serotonin 5-HT_1A receptors
Cariprazine is an antagonist at serotonin 5-HT_2A receptors

FDA-approved indication

Treatment of schizophrenia in adults
Acute treatment of manic or mixed episodes associated with bipolar I disorder
Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults
Adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults

Side effects

Side effect	Cariprazine	Placebo
Extrapyramidal symptoms	32%	14%
Insomnia	13%	11%
Somnolence	8%	5%
Constipation	7%	5%
Nausea	7%	5%
Restlessness	6%	3%
Vomiting	5%	3%
Dizziness	5%	2%
Fatigue	3%	1%
Hypertension	3%	1%
Other Weight gain - in a 6-week trial, patients taking 4.5 - 6 mg of cariprazine gained an average of 2.2 pounds while placebo-treated patients gained an average of 0.66 pounds Difficulty swallowing - incidence not well-defined

Drug interactions

Cariprazine is primarily metabolized by CYP3A4, and to a lesser extent by CYP2D6
CYP3A4 inhibitors and inducers - cariprazine is a CYP3A4 sensitive substrate. See Dosage for recommendations on dosing with CYP3A4 modulators.
Anticholinergic medications - antipsychotics have anticholinergic activity and may potentiate the effects of other anticholinergic medications

Contraindications / Precautions

Late-occurring adverse reactions - steady-state for cariprazine and its active metabolites may not be achieved for a number of weeks. Because of this, adverse effects may not appear until weeks after the drug is initiated.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In schizophrenia trials lasting up to 6 weeks, cariprazine had no significant effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In schizophrenia trials lasting up to 6 weeks, cariprazine had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Liver disease

Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
Severe (Child-Pugh C) - DO NOT USE

Kidney disease

CrCl ≥ 30 ml/min - no dose adjustment necessary
CrCl < 30 ml/min - DO NOT USE

Clozapine | Clozaril® | Fazaclo ODT® | Versacloz®

Dosage forms

Tablet (Clozapine®)

12.5 mg
25 mg
50 mg
100 mg
200 mg

Orally disintegrating tablet (Fazaclo ODT®)

12.5 mg
25 mg
100 mg
150 mg
200 mg

Suspension (Versacloz®)

50 mg/ml
Comes in 100 ml bottle

Dosing

Schizophrenia

Starting: 12.5 mg once or twice daily
Maintenance: 300 - 450 mg a day given in divided doses
Max: 900 mg a day
Increase in increments of 25 - 50 mg daily until target dose reached. Subsequently, the dose can be increased once or twice weekly in increments of up to 100 mg.
When stopping, reduce dose gradually over a period of 1-2 weeks to avoid cholinergic rebound
If ≥ 2 days elapse since last dose, reinitiate with 12.5-mg once daily or twice daily to prevent hypotension
See lab monitoring recommendations
Providers and pharmacies must be registered in the Clozapine REMS program in order to prescribe or dispense clozapine

Generic / Price

Tablet - YES/$$
Fazaclo ODT® - YES/$$$-$$$$
Versacloz® - NO/$$$$

Other

All

May take without regard to food
The Fazaclo ODT® is an orally disintegrating tablet. It may also be chewed or swallowed

Versacloz®

Store at room temperature
Shake well for 10 seconds before use
Bottle good for 100 days after opening

Pharmacokinetics

Half-life (single dose): 8 hours
Half-life (steady state): 12 hours

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin 5-HT_2A receptor antagonist

FDA-approved indications

Treatment-resistant schizophrenia
Reduction in risk of recurrent suicidal behavior in schizophrenia and schizoaffective disorder

Side effects

NOTE: Data only available for comparison with olanzapine

Side effect	Clozapine	Olanzapine
Salivary hypersecretion	48%	6%
Somnolence	46%	25%
Weight gain (≥ 7% increase)	35%	46%
Lightheaded	27%	12%
Constipation	25%	10%
Insomnia	20%	33%
Nausea	17%	10%
Vomiting	17%	9%
Upset stomach	14%	8%
Orthostatic hypotension - incidence not well-defined Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Drugs that prolong the QT interval - DO NOT COMBINE
Anticholinergic medications - clozapine has anticholinergic effects and it may potentiate the effects of other anticholinergic medications. Use caution when combining.
Clozapine is a CYP1A2, CYP3A4, and CYP2D6 substrate
CYP1A2 strong inhibitors - use one-third of clozapine dose
CYP1A2 moderate or weak inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
CYP2D6 inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
CYP3A4 inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
CYP3A4 inducers - may be necessary to increase clozapine dose; combining clozapine with strong CYP3A4 inducers is not recommended
CYP1A2 inducers - may be necessary to increase clozapine dose
Dopamine agonists (Mirapex®, Sinemet®, etc.) - clozapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - clozapine can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

Clozapine Agranulocytosis
Prolonged QT syndrome - DO NOT USE. Clozapine may prolong the QT interval.
Eosinophilia - in trials, 1% of clozapine-treated patients developed eosinophilia, typically within the first month of therapy. In some patients, organ involvement consistent with DRESS was observed, including myocarditis, pancreatitis, hepatitis, colitis, and nephritis. If eosinophilia occurs during therapy, evaluate for systemic symptoms (e.g. rash, fever, myocarditis) and discontinue clozapine immediately if they are present. In some cases, eosinophilia without organ involvement has resolved without intervention. If eosinophilia persists, the risks and benefits of continuing therapy should be considered. Some patients with eosinophilia have discontinued clozapine and restarted it without recurrence.
Poor CYP2D6 metabolizers - may need to reduce dose
Orthostatic hypotension, bradycardia, and syncope - clozapine has been associated with hypotension, bradycardia, and syncope in some patients. The risk is highest when starting therapy. Titrate dose slowly to avoid hypotension.
Anticholinergic toxicity - clozapine has potent anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, and/or a history of paralytic ileus or related conditions. Cases of GI hypomobility resulting in intestinal obstruction, fecal impaction, megacolon, perforation, ischemia, and necrosis have occurred with clozapine. Screen patients for constipation before and during therapy and consider preventative laxatives when appropriate. Avoid use with other anticholinergic medications when possible.
Cholinergic rebound with abrupt discontinuation - if clozapine is stopped abruptly, cholinergic activity may increase suddenly, causing profuse sweating, headache, nausea, vomiting, and diarrhea.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Myocarditis, cardiomyopathy, and mitral valve incompetence - myocarditis and cardiomyopathy have been reported in patients receiving clozapine. Myocarditis typically presents within the first 2 months of treatment, but may occur at any time. Nonspecific flu-like symptoms often precede overt heart failure. Clozapine-induced cardiomyopathy may lead to mitral valve incompetence.
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, clozapine raised the average fasting blood sugar by 11 mg/dl. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, clozapine raised the average total cholesterol by 13 mg/dl. See cholesterol below for ADA monitoring recommendations.
Weight gain - atypical antipsychotics have been associated with weight gain in some patients. In trials, clozapine-treated patients had an average weight gain of 8.14 lbs over 48 weeks.
Seizure - in trials, 3.5% of clozapine-treated patients experienced one or more seizures. Use caution in susceptible patients (e.g. history of seizures, head trauma, concomitant medications that lower the seizure threshold).
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Angle-closure glaucoma - may cause pupillary dilation which can worsen angle-closure glaucoma
Fever - clozapine may cause a transient fever in some patients, typically within the first 3 weeks of treatment. The fever is usually benign and self-limited, but other etiologies, including infection and NMS, should be ruled out.
Hepatotoxicity - cases of hepatotoxicity and liver failure have been reported in patients taking clozapine. Monitor for signs of liver failure (e.g. fatigue, malaise, anorexia, nausea, jaundice) and check liver function tests periodically.
Liver disease - dose adjustment may be necessary. Manufacturer makes no specific recommendation.
Kidney disease -dose adjustment may be necessary. Manufacturer makes no specific recommendation.

Iloperidone (Fanapt®)

Dosage forms

Tablet

1 mg
2 mg
4 mg
6 mg

8 mg
10 mg
12 mg

Titration pack

2 X 1 mg
2 X 2 mg
2 X 4 mg
2 X 6 mg

Dosing

Schizophrenia

Starting: 1 mg twice a day
Maintenance: 6 - 12 mg twice a day
Max: 12 mg twice a day
Increase dose daily as tolerated. Do not increase by more than 4 mg a day.
Orthostatic hypotension may occur if dose is increased too fast
See Drug Interactions for dosing with specific medications

Generic / Price

- NO/$$$$

Other

May take without regard to food
If ≥ 3 days elapse since last dose, reinitiate at 1 mg twice a day and titrate

Pharmacokinetics

Iloperidone has 2 active metabolites - P88 and P95
Half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers are 18, 26, and 23 hours, respectively, and in poor metabolizers are 33, 37, and 31 hours, respectively

Mechanism of action

Dopamine D₂ receptor antagonist
Serotonin type 2 (5-HT₂) receptor antagonist

FDA-approved indications

- Schizophrenia

Side effects

Side effect	Fanapt	Placebo
Hyperprolactinemia (elevated prolactin level)	26%	12%
Dizziness	20%	7%
Weight gain	18%	4%
Somnolence	15%	5%
Extrapyramidal symptoms	15%	11%
Rapid heart rate	12%	1%
Nausea	10%	8%
Dry mouth	10%	1%
Other Orthostatic hypotension - up to 5% of patients Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Iloperidone is a CYP2D6 and CYP3A4 sensitive substrate
Drugs that prolong the QT interval - DO NOT COMBINE
CYP2D6 strong inhibitors - reduce iloperidone dose by one-half
CYP3A4 strong inhibitors - reduce iloperidone dose by one-half
CYP3A4 substrates - in vitro studies have shown that iloperidone is a CYP3A4 inhibitor. Iloperidone may affect CYP3A4 substrates.
Alpha blockers - iloperidone can block alpha receptors. It may potentiate the effects of alpha blockers.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - iloperidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Iloperidone may prolong the QT interval.
Poor CYP2D6 metabolizers - reduce dose by one-half
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting 4 weeks, iloperidone was shown to raise blood sugars in some patients. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting 4 weeks, iloperidone was shown to raise lipid parameters in some patients. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Liver disease - has not been studied. Not recommended.
Kidney disease - No dose adjustment necessary

Lumateperone (Caplyta®)

Dosage forms

Capsule

10.5 mg
21 mg
42 mg

Dosing

Schizophrenia and Bipolar (adults)

Dosing: 42 mg once daily
Max: 42 mg once daily
Dose titration is not required
May take without regard to food

With Strong CYP3A4 inhibitors

Dosing: 10.5 mg once daily
See CYP3A4 inhibitors

With Moderate CYP3A4 inhibitors

Dosing: 21 mg once daily
See CYP3A4 inhibitors

Liver disease

Child-Pugh A: no dose adjustment necessary
Child-Pugh B or C: 21 mg once daily

Generic / Price

- NO/$$$$

Pharmacokinetics

Half-life: 18 hours

Mechanism of action

The mechanism of action of lumateperone in the treatment of schizophrenia is unknown. However, the efficacy of lumateperone could be mediated through a combination of antagonist activity at central serotonin 5-HT_2A receptors and postsynaptic antagonist activity at central dopamine D₂ receptors.

FDA-approved indications

Schizophrenia in adults
Depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate

Side effects

Side effect	Caplyta (N=406)	Placebo (N=412)
Somnolence / Sedation	24%	10%
Nausea	9%	5%
Extrapyramidal symptoms	6.7%	6.3%
Dry mouth	6%	2%
Dizziness	5%	3%
CK increase	4%	1%
Fatigue	3%	1%
Vomiting	3%	2%
Liver function abnormal	2%	1%
Decreased appetite	2%	1%

Drug interactions

CYP3A4 moderate or strong inhibitors - lumateperone is a CYP3A4 sensitive substrate, and CYP3A4 inhibitors increase its exposure. See Dosing above for recommendations on combining.
CYP3A4 inducers - DO NOT COMBINE. Lumateperone is a sensitive CYP3A4 substrate and CYP3A4 inducers decrease exposure.
UGT inhibitors - DO NOT COMBINE. UGT inhibitors increase exposure to lumateperone. Examples of UGT inhibitors include valproic acid and probenecid.

Contraindications / Precautions

Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Suicide thoughts and behaviors - in trials involving antidepressants (e.g. SSRIs), the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. Monitor patients with depression for worsening symptoms during treatment.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics may cause blood sugars to increase in some patients. In a 1-year schizophrenia trial, 8% of lumateperone-treated patients with baseline normal fasting glucose experienced a shift to high fasting glucose. See diabetes below for ADA monitoring recommendations.
Weight gain - atypical antipsychotics have been associated with weight gain in some patients. In trials, the average change in weight was similar between lumateperone-treated patients and placebo-treated patients.
Cholesterol - atypical antipsychotics may raise lipid parameters in some patients. In a 1-year schizophrenia trial, shifts from normal to high lipid parameters were seen in 8% (total cholesterol), 4% (LDL cholesterol), and 5% (triglycerides) of lumateperone-treated patients. See cholesterol below for ADA monitoring recommendations.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Orthostatic hypotension and syncope - atypical antipsychotics can cause orthostatic hypotension and syncope in some patients. In trials, orthostatic hypotension occurred in 0.7% of lumateperone-treated patients and 0% of placebo-treated patients. The incidence of syncope was 0.2% in both groups.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Seizures - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients (e.g. dementia, cognitive impairment).
Liver disease - see Dosing above
Kidney disease - no dose adjustment recommended by manufacturer

Lurasidone (Latuda®)

Dosage forms

Tablet

20 mg
40 mg
60 mg
80 mg
120 mg

Dosing

Schizophrenia (adults)

Starting: 40 mg once daily
Maintenance: 40 - 160 mg once daily
Max: 160 mg once daily
Take with food (at least 350 calories). Food increases absorption.
See Drug Interactions for dosing with specific medications

Schizophrenia (13 - 17 years old)

Starting: 40 mg once daily
Maintenance: 40 - 80 mg once daily
Max: 80 mg once daily
Take with food (at least 350 calories). Food increases absorption.
See Drug Interactions for dosing with specific medications

Bipolar I depression (adults)

Starting: 20 mg once daily
Maintenance: 20 - 120 mg once daily
Max: 120 mg once daily
Take with food (at least 350 calories). Food increases absorption.
See Drug Interactions for dosing with specific medications

Generic / Price

- NO/$$$$

Pharmacokinetics

Half-life: 18 hours

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin type 2 (5-HT_2A) receptor antagonist

FDA-approved indications

Schizophrenia
Major depressive episodes associated with bipolar 1 as monotherapy or as adjunctive therapy with lithium or valproate

Side effects

Side effect	Lurasidone	Placebo
Extrapyramidal symptoms (80 mg dose)	26%	9%
Somnolence	22%	10%
Akathisia	15%	3%
Nausea	12%	6%
Parkinsonism	11%	5%
Weight gain (≥ 7% increase)	5.6%	4%
Other Orthostatic hypotension - 1.7% with 120 mg a day Hyperprolactinemia (elevated prolactin level ≥ 5 X ULN) - 3.6% of patients Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Lurasidone is a CYP3A4 sensitive substrate
CYP3A4 strong inhibitor - DO NOT COMBINE
CYP3A4 strong inducer - DO NOT COMBINE
CYP3A4 moderate inhibitor - dose of lurasidone should not exceed 40 mg a day
Dopamine agonists (Mirapex®, Sinemet®, etc.) - lurasidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - lurasidone can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

Poor CYP2D6 metabolizers - reduce dose by one-half
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, lurasidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, lurasidone had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Liver disease

Moderate to severe (Child-Pugh B/C) - do not exceed 40 mg a day

Kidney disease

CrCl 10 - 49 ml/min - do not exceed 40 mg/day

Olanzapine | Zyprexa® | Symbyax®

Dosage forms

Tablet (Zyprexa®)

2.5 mg
5 mg
7.5 mg
10 mg
15 mg
20 mg

Orally disintegrating tablet (Zyprexa Zydis®)

5 mg
10 mg
15 mg
20 mg

Vial (Zyprexa Relprevv®)

210 mg
300 mg
405 mg

Symbyax®

Olanzapine(mg):Fluoxetine(mg)

3 : 25
6 : 25
6 : 50
12 : 25
12 : 50

Dosing - Tablet and ODT

Schizophrenia (adults)

Starting: 5 - 10 mg once daily
Maintenance: 10 - 20 mg once daily
Max: 20 mg once daily
Increase dose by 5 mg/day at intervals of ≥ 1 week
Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)

Schizophrenia (adolescents)

Starting: 2.5 - 5 mg once daily
Maintenance: 10 mg once daily
Max: 20 mg once daily
Increase dose in increments of 2.5 - 5 mg/day

Bipolar I monotherapy (adults)

Starting: 10 - 15 mg once daily
Maintenance: 5 - 20 mg once daily
Max: 20 mg once daily
Increase dose by 5 mg/day at intervals of not less than 24 hours
Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)

Bipolar I adjunctive to lithium or valproate (adults)

Starting: 10 mg once daily
Maintenance: 5 - 20 mg once daily
Max: 20 mg once daily
Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
May take without regard to food

Bipolar I (adolescents)

Starting: 2.5 - 5 mg once daily
Maintenance: 10 mg once daily
Max: 20 mg once daily
Increase dose in increments of 2.5 - 5 mg/day

Dosing - Zyprexa Relprevv®

Schizophrenia (adults)

Dosing: 150 - 300 mg IM every 2 weeks; or 300 - 405 mg every 4 weeks
Dosing based on current oral olanzapine dose
See Relprevv® PI for dosing recommendations

Dosing - Symbyax®

Depression with Bipolar I and treatment-resistant depression (adults)

Starting: 6/25 mg once daily in the evening
Maintenance: 6/25 mg - 12/50 mg once daily
Max: 18/75 mg once daily
See fluoxetine for more

Depression with Bipolar I (10 - 17 years old)

Starting: 3/25 mg once daily in the evening
Maintenance: 6/25 mg - 12/50 mg once daily
Max: 12/50 mg once daily
See fluoxetine for more

Efficacy

Continuing vs Stopping Olanzapine in Patients with Psychotic Depression in Remission, JAMA (2019) [PubMed abstract]

Generic / Price

Zyprexa® - YES/$
Zyprexa Zydis® - YES/$
Symbyax® - YES/$$-$$$
Zyprexa Relprevv® - NO/$$$$

Other

Zyprexa®

May take without regard to food

Zydis®

Do not push tablet through foil
Rapidly disintegrates in mouth
Swallow with or without liquid

Relprevv®

Only available through restricted distribution program
To enroll, call 1-877-772-9390

Pharmacokinetics (oral)

Half-life: 21 - 54 hours

Mechanism of action

Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆, dopamine D_1-4, histamine H₁, and adrenergic α₁ receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ and muscarinic M_1-5. Olanzapine binds with low affinity to GABA_A, BZD, and β-adrenergic receptors.

FDA-approved indications

Zyprexa®

Schizophrenia
Bipolar - manic or mixed episodes

Zyprexa Relprevv®

Schizophrenia

Symbyax®

Treatment resistant depression
Bipolar I depression

Side effects

Side effect	Zyprexa	Placebo
Somnolence	29%	13%
Extrapyramidal symptoms	25%	16%
Weight gain (≥ 7% increase)	22%	3%
Insomnia	12%	11%
Dizziness	11%	4%
Fatigue	10%	9%
Constipation	9%	4%
Dry mouth	6%	1%
Orthostatic hypotension	5%	2%
Hyperprolactinemia	30%	11%
Other Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

CYP1A2 strong inhibitors - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inhibitors may increase olanzapine exposure. Consider decreasing olanzapine dosage when combining.
CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inducers may decrease olanzapine exposure. Consider increasing olanzapine dosage when combining.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - olanzapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.. Concomitant use is not recommended.
Alpha blockers - olanzapine blocks alpha₁ receptors, and therefore, it may potentiate the blood pressure-lowering effects of alpha blockers, particularly doxazosin, prazosin, and terazosin. Use caution when combining.
Antihypertensive medications - olanzapine may enhance the effects of antihypertensives. Monitor blood pressure when combining and reduce antihypertensive dosage when necessary.
Medications with anticholinergic activity - olanzapine has anticholinergic activity, and it may potentiate the anticholinergic effects of other anticholinergic medications. Use caution when combining.
CNS depressants - CNS depressants, including diazepam and alcohol, may potentiate the orthostatic hypotensive effects of olanzapine. Use caution when combining.
OCT2 substrates - olanzapine is an OCT2 inhibitor, and it may increase exposure to OCT2 substrates
Omeprazole (Prilosec®) - omeprazole may increase olanzapine clearance
Rifampin - rifampin may increase olanzapine clearance

Contraindications / Precautions

Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In trials, incidence of death in elderly patients with dementia-related psychosis was 3.5% in olanzapine-treated patients and 1.5% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Suicide - patients with schizophrenia and bipolar disorder are at increased risk for suicide. Consider the risk of intentional overdose when prescribing and limit quantity when necessary.
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Serious skin reactions - serious skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported. Signs of DRESS include fever, rash, swollen lymph glands, facial swelling, and systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Patients who experience these symptoms should stop olanzapine and seek immediate medical care.
Increase in blood sugar - atypical antipsychotics have been associated with increased blood sugars in some patients. In trials lasting at least 48 weeks, olanzapine-treated patients had an average increase in fasting blood sugar of 4.2 mg/dl. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Weight gain - olanzapine can cause weight gain in some patients. In trials lasting a median of 6 weeks, olanzapine-treated patients gained an average of 5.7 lbs (2.6 kg) compared to a loss of 0.6 lbs (0.3 kg) in placebo-treated patients.
Dyslipidemia - atypical antipsychotics have been associated with increased cholesterol in some patients. In trials lasting at least 48 weeks, fasting triglyceride increases ≥ 50 mg/dl and LDL increases ≥ 30 mg/dl occurred in 61% and 40% of olanzapine-treated patients, respectively. See cholesterol below for ADA monitoring recommendations.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. An analysis of the vital sign data from 41 studies (N=6030) in which adult patients were treated with oral olanzapine found that orthostatic hypotension was recorded in ≥ 20% of patients. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients (e.g. dementia, cognitive impairment).
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Anticholinergic effects - olanzapine has anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post-marketing surveillance, the risk for severe adverse reactions (including fatalities) was increased when olanzapine was taken with other anticholinergic medications.
Hyperprolactinemia - olanzapine blocks the dopamine D₂ receptor which may cause prolactin levels to rise. Elevated prolactin levels can impair gonadal steroidogenesis in females and males leading to infertility. Galactorrhea, amenorrhea, gynecomastia, and impotence have also been reported. Long-standing hyperprolactinemia may lead to decreased bone density in female and male subjects. One-third of human breast cancers are prolactin-dependent in vitro. Theoretically, this could increase the risk of breast cancer in some patients; although, studies performed to date have not found an association between chronic administration of antipsychotics and cancer risk. In trials lasting up to 12 weeks, prolactin shifts from normal to high occurred in 30% of olanzapine-treated patients and 10.5% of placebo-treated patients.
Infertility - olanzapine may increase prolactin levels which may cause a reversible reduction in fertility among female patients of childbearing age
Liver disease

Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
Severe (Child-Pugh C) - use caution

Kidney disease - no dose adjustment necessary

Olanzapine + Samidorphan (Lybalvi®)

Dosage forms

Tablet

Olanzapine(mg):Samidorphan(mg)

5 : 10
10 : 10
15 : 10
20 : 10

Dosing

Schizophrenia (adults)

Starting: 5/10 - 10/10 mg once daily
Maintenance: 10/10 - 20/10 mg once daily
Max: 20/10 mg once daily
Increase olanzapine dose by 5 mg/day at intervals of ≥ 1 week
Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
May take without regard to food

Bipolar I monotherapy (adults)

Starting: 10/10 - 15/10 mg once daily
Maintenance: 5/10 - 20/10 mg once daily
Max: 20/10 mg once daily
Increase olanzapine dose by 5 mg/day at intervals of not less than 24 hours
Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
May take without regard to food

Bipolar I adjunctive to lithium or valproate (adults)

Starting: 10/10 once daily
Maintenance: 10/10 - 20/10 mg once daily
Max: 20/10 mg once daily
Increase olanzapine dose by 5 mg/day at intervals of ≥ 1 week
Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
May take without regard to food

Efficacy

Lybalvi vs Olanzapine vs Placebo in Acute Schizophrenia Exacerbation, J Clin Psychiatry (2020) [PubMed abstract]

Generic / Price

- NO/$$$$

Pharmacokinetics

Half-life (olanzapine): 35 - 52 hours
Half-life (samidorphan): 7 - 11 hours

Mechanism of action

Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆, dopamine D_1-4, histamine H₁, and adrenergic α₁ receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃ and muscarinic M_1-5. Olanzapine binds with low affinity to GABA_A, BZD, and β-adrenergic receptors.
Samidorphan binds to the mu-, kappa-, and delta-opioid receptors. Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at kappa- and delta-opioid receptors. Samidorphan is included to help reduce the weight gain that occurs with olanzapine therapy. Opiate antagonists suppress appetite through an unknown mechanism.

FDA-approved indications

Schizophrenia in adults
Bipolar I disorder in adults

Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
Maintenance monotherapy treatment

Side effects

NOTE: Data is from a 4-week schizophrenia trial. Only side effects that occurred at an incidence ≥ 2% overall, and more than placebo are listed.

Side effect	Lybalvi (N=134)	Placebo (N=134)
Weight gain^✝	19%	3%
Somnolence	9%	2%
Dry mouth	7%	1%
Headache	6%	3%
Blood insulin increase	3%	1%
Sedation	2%	0%
Dizziness	2%	1%
Neutrophil count decrease	2%	0%
^✝Lybalvi contains samidorphan which is included to help suppress the weight gain that occurs with olanzapine. In a 24-week trial, Lybalvi-treated patients had an average weight gain of 4.2% compared to 6.6% in olanzapine-treated patients.

Drug interactions

Opiate medications - samidorphan is an opiate antagonist, and it should not be given to patients on opiate therapy or those undergoing acute opioid withdrawal. Prior to initiating Lybalvi, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations that require opioid therapy, Lybalvi should be discontinued, and the patient should be monitored closely. In non-emergency situations, discontinue Lybalvi at least 5 days before opioids are required and use olanzapine.
CYP1A2 strong inhibitors - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inhibitors may increase olanzapine exposure. Consider decreasing olanzapine dosage when combining.
CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inducers may decrease olanzapine exposure. Consider increasing olanzapine dosage when combining.
CYP3A4 strong inducers - DO NOT COMBINE. Samidorphan is a CYP3A4 sensitive substrate, and strong CYP3A4 inducers may decrease its exposure.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - olanzapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.. Concomitant use is not recommended.
Alpha blockers - olanzapine blocks alpha₁ receptors, and therefore, it may potentiate the blood pressure-lowering effects of alpha blockers, particularly doxazosin, prazosin, and terazosin. Use caution when combining.
Antihypertensive medications - olanzapine may enhance the effects of antihypertensives. Monitor blood pressure when combining and reduce antihypertensive dosage when necessary.
Medications with anticholinergic activity - olanzapine has anticholinergic activity, and it may potentiate the anticholinergic effects of other anticholinergic medications. Use caution when combining.
CNS depressants - CNS depressants, including diazepam and alcohol, may potentiate the orthostatic hypotensive effects of olanzapine. Use caution when combining.
OCT2 substrates - olanzapine is an OCT2 inhibitor, and it may increase exposure to OCT2 substrates
Omeprazole (Prilosec®) - omeprazole may increase olanzapine clearance
Rifampin - rifampin may increase olanzapine clearance

Contraindications / Precautions

Patients receiving opiate medications - samidorphan is an opiate antagonist, and it should not be given to patients on opiate therapy or those undergoing acute opioid withdrawal. Prior to initiating Lybalvi, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations that require opioid therapy, Lybalvi should be discontinued, and the patient should be monitored closely. In non-emergency situations, discontinue Lybalvi at least 5 days before opioids are required and use olanzapine.
Surgery / Procedures - samidorphan is an opiate antagonist, and it can block the analgesic effect of opioid medications. Lybalvi should be stopped at least 5 days before a procedure or surgery requiring opioid analgesics. Olanzapine may be continued by itself. Before restarting Lybalvi, patients should be off short-acting opioids for at least 7 days and long-acting opioids for at least 14 days.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In trials, the incidence of death in elderly patients with dementia-related psychosis was 3.5% in olanzapine-treated patients and 1.5% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Serious skin reactions - serious skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported. Signs of DRESS include fever, rash, swollen lymph glands, facial swelling, and systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Patients who experience these symptoms should stop olanzapine and seek immediate medical care.
Increase in blood sugar - atypical antipsychotics have been associated with increased blood sugars in some patients. In a 24-week trial that compared Lybalvi to olanzapine, 42% of Lybalvi-treated patients had an increase in HgA1C from <5.7% to 5.7 - 6.5% compared to 35% of olanzapine-treated patients. See diabetes below for ADA monitoring recommendations.
Weight gain - Lybalvi contains samidorphan which is included to help suppress the weight gain that occurs with olanzapine. In a 24-week trial, Lybalvi-treated patients had an average weight gain of 4.2% compared to 6.6% in olanzapine-treated patients.
Dyslipidemia - atypical antipsychotics have been associated with increased cholesterol in some patients. In a 4-week trial, fasting triglycerides shifted from normal to high in 14% of Lybalvi-treated patients and 4% of placebo-treated patients. See cholesterol below for ADA monitoring recommendations.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. In a 24-week study, rates of orthostatic hypotension were 3.7% in Lybalvi-treated patients and 0.4% in olanzapine-treated patients. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients (e.g. dementia, cognitive impairment).
Seizures - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Anticholinergic effects - olanzapine has anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post-marketing surveillance, the risk for severe adverse reactions (including fatalities) was increased when olanzapine was taken with other anticholinergic medications.
Hyperprolactinemia - olanzapine blocks the dopamine D₂ receptor, which may cause prolactin levels to rise. Elevated prolactin levels can impair gonadal steroidogenesis in females and males, leading to infertility. Galactorrhea, amenorrhea, gynecomastia, and impotence have also been reported. Long-standing hyperprolactinemia may lead to decreased bone density in female and male subjects. One-third of human breast cancers are prolactin-dependent in vitro. Theoretically, this could increase the risk of breast cancer in some patients; although, studies performed to date have not found an association between chronic administration of antipsychotics and cancer risk. In a 24-week trial, prolactin shifts from normal to high occurred in 32.9% of females and 22.5% of males treated with Lybalvi compared to 41.7% of females and 28.5% of males treated with olanzapine.
Infertility - olanzapine may increase prolactin levels which may cause a reversible reduction in fertility among female patients of childbearing age
Liver disease

Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
Severe (Child-Pugh C): has not been studied

Kidney disease

CrCl ≥ 15 ml/min: no dose adjustment necessary
CrCl < 15 ml/min: not recommended

Paliperidone | Invega® | Invega Sustenna® | Invega Trinza® | Invega Hafyera®

Dosage forms

Extended-release tablet (Invega®)

1.5 mg
3 mg
6 mg
9 mg

Prefilled syringe (Invega Sustenna®)

39 mg
78 mg
117 mg
156 mg
234 mg

Prefilled syringe (Invega Trinza®)

273 mg
410 mg
546 mg
819 mg

Prefilled syringe (Invega Hafyera®)

1092 mg
1560 mg

Dosing - Tablet

Schizophrenia / Schizoaffective disorder (adults)

Starting: 6 mg once daily
Maintenance: 3 - 12 mg once daily
Max: 12 mg once daily
Increase dose by 3 mg/day at intervals of ≥ 5 days
May take without regard to food. Do not crush, chew, or divide tablet.
Insoluble tablet may be seen in stool. This is normal.

Schizophrenia (12 - 17 years)

Starting: 3 mg once daily
Maintenance: 3 - 12 mg once daily
Max: 12 mg once daily
Increase dose by 3 mg/day at intervals of > 5 days
Doses above 6 mg/day for patients weighing < 51 kg and 12 mg/day for patients weighing > 51 kg have not been shown to be more efficacious
May take without regard to food. Do not crush, chew, or divide tablet.
Insoluble tablet may be seen in stool. This is normal.

Dosing in kidney disease

CrCl 50 - 79 ml/min

Starting: 3 mg once daily
Max: 6 mg once daily

CrCl 10 - 49 ml/min

Starting: 1.5 mg once daily
Max: 3 mg once daily

CrCl < 10 ml/min

Do not use

Dosing - Invega Sustenna®

Schizophrenia / Schizoaffective disorder (adults)

Tolerability of oral Invega or risperidone should be established before using Invega Sustenna
Starting: 234 mg IM on Day 1, and 156 mg IM on Day 8
Maintenance: 39 - 234 mg IM once a month. Administer first maintenance dose 5 weeks after first injection.
The recommended maintenance dose for schizophrenia is 117 mg
Give initial 2 doses in deltoid muscle. Following doses may be given in deltoid or gluteal muscle.
Maintenance doses may be given up to 7 days before or after the scheduled monthly dose. If more than 1 month and 7 days have elapsed since the last dose, see Sustenna PI® [sec 2.3] for missed dose recommendations.

Dosing in kidney disease

CrCl 50 - 79 ml/min

Dosing: Start with 156 mg on Day 1 and 117 mg on Day 8. Administer both doses in the deltoid muscle. Follow with monthly injections of 78 mg in either the deltoid or gluteal muscle. Adjust monthly dose between 39 mg and 156 mg, depending on efficacy and tolerability. Do not exceed 156 mg.

CrCl < 50 ml/min

Not recommended

Dosing - Invega Trinza®

Schizophrenia (adults)

Invega Trinza is given once every 3 months as an IM injection in the deltoid or gluteal muscles
Invega Trinza should only be used after at least 4 months of Invega Sustenna therapy
Recommended initial dosing based on Invega Sustenna dosing is provided in the table below. The first dose of Invega Trinza should be given when the next dose of Invega Sustenna is scheduled. Invega Trinza may be administered up to 1 week before or 1 week after the next scheduled dose of Invega Sustenna.
Dosage adjustments between 237 mg and 819 mg can be made every 3 months. Patient response to dose adjustments may not be apparent for several months.
Doses may be given up to 2 weeks before or after the scheduled 3-month dose. If more than 3 months and 2 weeks have elapsed since the last dose, see Invega Trinza PI [sec 2.3] for missed dose recommendations
For recommendations on switching from Invega Trinza to Invega Sustenna or paliperidone tablets, see Invega Trinza PI [sec 2.6 and 2.7]

Monthly Invega Sustenna dose	Starting Invega Trinza dose
78 mg	273 mg
117 mg	410 mg
156 mg	546 mg
234 mg	819 mg

Dosing in kidney disease

CrCl 50 - 79 ml/min

Dosing: Dosing based on the previous dose of Invega Sustenna that the patient was stabilized on prior to initiation of Invega Trinza

CrCl < 50 ml/min

Not recommended

Dosing - Invega Hafyera®

Schizophrenia (adults)

Invega Hafyera is administered as a gluteal IM injection once every 6 months
Invega Hafyera should only be initiated in patients who are receiving adequate treatment with Invega Sustenna or Invega Trinza
Recommended initial dosing based on Sustenna/Trinza dosing is provided in the table below. The first dose of Invega Hafyera should be given when the next dose of Sustenna or Trinza is scheduled. Invega Hafyera may be administered up to 1 week before or 1 week after the next scheduled Sustenna dose and up to 2 weeks before or 2 weeks after the next scheduled Trinza dose.
Dosage adjustments between 1092 mg and 1560 mg can be made every 6 months. Patient response to dose adjustments may not be apparent for several months.
Doses may be given up to 2 weeks before and 3 weeks after the scheduled 6-month dose. If more than 6 months and 3 weeks have elapsed since the last dose, see Invega Hafyera PI [sec 2.3] for missed dose recommendations.

Equivalent dosing for other strengths of Sustenna/Trinza has not been studied
Monthly Invega Sustenna dose	Starting Invega Hafyera dose
156 mg	1092 mg
234 mg	1560 mg
Monthly Invega Trinza dose	Starting Invega Hafyera dose
546 mg	1092 mg
819 mg	1560 mg

Generic / Price

Invega tablet - YES/$$-$$$
Invega Sustenna - NO/$$$$
Invega Trinza - NO/$$$$
Invega Hafyera - NO/$$$$

Pharmacokinetics

Invega®

Half-life: 23 hours

Invega Sustenna®

Half-life: 25 - 49 days

Invega Trinza®

Half-life: 84 - 95 days

Invega Hafyera®

Half-life: 148 - 159 days

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin type 2 (5-HT_2A) receptor antagonist

FDA-approved indications

Invega

Schizophrenia in adults and adolescents 12 - 17 years old
Schizoaffective disorder in adults

Invega Sustenna

Schizophrenia in adults
Schizoaffective disorder in adults

Invega Trinza / Invega Hafyera

Schizophrenia in adults

Side effects

Side effect	Paliperidone	Placebo
Extrapyramidal symptoms	20%	8%
Rapid heart rate	12%	7%
Headache	14%	12%
Somnolence	10%	7%
Weight gain (≥ 7% increase)	9%	5%
Akathisia	8%	4%
Orthostatic hypotension	2%	1%
Other Hyperprolactinemia - similar to risperidone which is up to 87% of patients (13 - 17 years old) in some studies Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Drugs that prolong the QT interval - DO NOT COMBINE. Paliperidone can prolong the QT interval and should not be combined with other QT-prolonging drugs.
Centrally-acting drugs - paliperidone may interact with other centrally-acting drugs and increase the risk for adverse events. Use caution when combining.
Carbamazepine (Tegretol®) - carbamazepine is a strong inducer of CYP3A4 and P-gp. In studies, carbamazepine at a dose of 200 mg twice daily decreased the average steady-state concentration of paliperidone by 37%. Consider increasing the paliperidone dose when initiating carbamazepine and decreasing it when stopping carbamazepine.
Divalproex sodium (Depakote®) - in a single dose study, divalproex sodium 1000 mg caused an increase of 50% in the Cmax and area under the curve of paliperidone (single 12 mg dose). Consider reducing the dose of paliperidone when prescribing with divalproex.
CYP2D6 inhibitors and inducers - paliperidone is metabolized to a limited extent by CYP2D6. CYP2D6 inhibitors and inducers may affect paliperidone levels.
CYP3A4 strong inducers (Invega Trinza and Invega Sustenna) - strong inducers of CYP3A4 may reduce Invega Trinza and Invega Sustenna exposure, and they should not be given together. If concomitant therapy is necessary, consider using paliperidone tablets.
P-glycoprotein (P-gp) inhibitors and inducers - Paliperidone is a P-gp substrate. P-gp inhibitors and inducers may affect paliperidone levels. Strong inducers of P-gp should not be given with Invega Trinza or Invega Sustenna; if concomitant therapy is necessary, consider using paliperidone tablets.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - paliperidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - paliperidone can block alpha receptors; this may potentiate the effects of alpha blockers and increase the risk of orthostatic hypotension and syncope. Monitor orthostatic vital signs in susceptible patients when combining.

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Paliperidone may prolong the QT interval.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Potential for GI obstruction - paliperidone comes in a non-deformable extended-release tablet. Do not use in patients who are susceptible to obstruction (e.g. esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum)
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, paliperidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Hyperprolactinemia - paliperidone-induced hyperprolactinemia may suppress GnRH secretion leading to galactorrhea, amenorrhea, gynecomastia, impotence and impaired gonadal steroidogenesis in both females and males
Breast cancer - up to one-third of breast cancers have been shown to be prolactin-dependent in vitro. Because paliperidone raises prolactin levels, caution should be used in patients with a history of breast cancer.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting 6 weeks, paliperidone did not have an adverse effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Parkinson's disease or Lewy body dementia - patients with Parkinson's disease or Lewy body dementia may be especially sensitive to the effects of paliperidone. Side effects including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome may occur.
Liver disease

Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
Severe (Child-Pugh C) - has not been studied

Kidney disease -see Dosing

Quetiapine | Seroquel® | Seroquel XR®

Dosage forms

Tablet (Seroquel®)

25 mg
50 mg
100 mg

200 mg
300 mg
400 mg

Extended-release tablet (Seroquel XR®)

50 mg
150 mg
200 mg

300 mg
400 mg

Dosing - Seroquel®

NOTE: Dosing below is general ranges. See the Seroquel® PI [sec 2] for specific recommendations.

Schizophrenia (adults)

Starting: 25 mg twice a day
Maintenance: 150 - 750 mg/day
Max: 800 mg/day
Give in 2 - 3 divided doses
Increase in increments of 50 - 100 mg/day at intervals ≥ 2 days

Schizophrenia (13 - 17 years old)

Starting: 25 mg twice a day
Maintenance: 400 - 800 mg/day
Max: 800 mg/day
Give in 2 - 3 divided doses

Bipolar mania (adults)

Starting: 100 mg/day
Maintenance: 400 - 800 mg/day
Max: 800 mg/day
Give 2 divided doses

Bipolar mania (10 - 17 years old)

Starting: 50 mg/day
Maintenance: 400 - 600 mg/day
Max: 600 mg/day
Give in 2 - 3 divided doses

Dosing - Seroquel XR®

NOTE: Dosing below is general ranges. See the Seroquel XR® PI [sec 2] for specific recommendations.

Schizophrenia (adults)

Starting: 300 mg once daily
Maintenance: 400 - 800 mg once daily
Max: 800 mg once daily
Increase in increments of 300 mg/day at intervals ≥ 1 day

Schizophrenia (13 - 17 years old)

Starting: 50 mg once daily
Maintenance: 400 - 800 mg once daily
Max: 800 mg once daily

Bipolar mania (adults)

Starting: 300 mg once daily
Maintenance: 400 - 800 mg once daily
Max: 800 mg once daily

Bipolar mania (10 - 17 years old)

Starting: 50 mg once daily
Maintenance: 400 - 600 mg once daily
Max: 600 mg once daily

Generic / Price

Seroquel® - YES/$
Seroquel XR® - YES/$

Other

Seroquel®

May take without regard to food

Seroquel XR®

Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
Do not crush, chew, or divide tablet

Pharmacokinetics

Quetiapine has an active metabolite, norquetiapine
Half-life (quetiapine): 7 hours
Half-life (norquetiapine): 12 hours

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin type 2 (5-HT₂) receptor antagonist

FDA-approved indications

Schizophrenia
Bipolar disorder - mania

Side effects

NOTE: Only side effects that occurred at an overall incidence ≥ 5% are shown. Data is from an 8-week trial in bipolar patients who were treated with 300 - 600 mg/day

Side effect	Quetiapine (N=698)	Placebo (N=347)
Somnolence	57%	15%
Dry Mouth	44%	13%
Dizziness	18%	7%
Constipation	10%	4%
Fatigue	10%	8%
Dyspepsia	7%	4%
Vomiting	5%	4%
Increased Appetite	5%	3%
Lethargy	5%	2%
Nasal Congestion	5%	3%
Other Extrapyramidal symptoms - incidence is low, similar to placebo in some studies Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Quetiapine is a CYP3A4 sensitive substrate
Drugs that prolong the QT interval - DO NOT COMBINE
CYP3A4 strong inhibitors - quetiapine dose should be reduced to one-sixth of the original dose when taken with a CYP3A4 strong inhibitor. If the CYP3A4 strong inhibitor is discontinued, the quetiapine dose should be increased by 6-fold.
CYP3A4 strong inducers - quetiapine dose should be increased up to five-fold of the original dose when used in combination with a strong CYP3A4 inducer during chronic treatment (greater than 7-14 days). When the CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7 - 14 days.
Medications with anticholinergic activity - norquetiapine, an active metabolite of quetiapine, has moderate to strong anticholinergic activity, and it may potentiate the anticholinergic effect of other medications.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - quetiapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - quetiapine can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Quetiapine may prolong the QT interval.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Hypothyroidism (low thyroid) - quetiapine may cause low thyroid in some patients (3 - 5% of patients)
Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Anticholinergic effects - norquetiapine, an active metabolite of quetiapine, has moderate to strong anticholinergic activity. Use caution in patients with urinary retention, constipation, bowel motility issues, or increased intraocular pressure, and in those who are taking other medications with anticholinergic activity. Intestinal obstruction, including fatal cases, has been reported in patients taking quetiapine with other anticholinergic drugs.
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, quetiapine caused mild to no elevation of blood sugars when compared to placebo. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, more patients on quetiapine saw increases in their total cholesterol and triglycerides when compared to placebo. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Weight gain - quetiapine may cause weight gain. In bipolar trials lasting up to 12 weeks, 21% of quetiapine-treated patients gained ≥ 7% of their body weight compared to 7% of placebo-treated patients.
Increases in blood pressure (children and adolescents) - quetiapine may raise blood pressure in children and adolescents. In trials with children and adolescents lasting 3 - 6 weeks, the incidence of increases at any time in systolic blood pressure (≥ 20 mmHg) was 15.2% for quetiapine-treated patients and 5.5% for placebo-treated patients. The incidence of increases at any time in diastolic blood pressure (≥ 10 mmHg) was 40.6% and 24.5%, respectively.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Serious skin reactions - serious skin reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking quetiapine
Liver disease

Seroquel® - clearance is decreased; start with 25 mg/day and increase by 25 - 50 mg/day; use caution
Seroquel XR® - clearance is decreased; start with 50 mg/day and increase by 50 mg/day; use caution

Kidney disease - no dose adjustment necessary

Risperidone | Risperdal® | Risperdal Consta® | Perseris®

Dosage forms

Tablet (Risperdal®)

0.25 mg
0.5 mg
1 mg

2 mg
3 mg
4 mg

Orally disintegrating tablet (Risperdal M-Tab®)

0.25 mg
0.5 mg
1 mg

2 mg
3 mg
4 mg

Solution (Risperdal®)

1 mg/ml
Comes in 30 ml bottle

Vial (Risperdal Consta®)

12.5 mg
25 mg
37.5 mg
50 mg

Prefilled syringe (Perseris®)

90 mg
120 mg

Dosing - Risperdal®

Schizophrenia (adults)

Starting: 2 mg/day
Maintenance: 4 - 8 mg/day
Max: 16 mg/day
May be given in one or two divided doses
Increase dose in increments of 1 - 2 mg/day at intervals of ≥ 24 hours
Start low and go slow in patients at risk for orthostatic hypotension

Schizophrenia (adolescents)

Starting: 0.5 mg once daily
Maintenance: 3 mg/day
Max: 6 mg/day
May be given in one or two divided doses
Increase dose in increments of 0.5 - 1 mg/day at intervals of ≥ 24 hours

Bipolar mania (adults)

Starting: 2 - 3 mg/day
Maintenance: 1 - 6 mg/day
Max: 6 mg/day
May be given in one or two divided doses
Increase dose in increments of 1 mg per day at intervals of ≥ 24 hours
Start low and go slow in patients at risk for orthostatic hypotension

Bipolar mania (children and adolescents)

Starting: 0.5 mg once daily
Maintenance: 1 - 2.5 mg/day
Max: 6 mg/day
May be given in one or two divided doses
Increase dose in increments of 0.5 - 1 mg/day at intervals of ≥ 24 hours

Irritability in autistic disorder (children and adolescents)

Weight < 20 kg

Starting: 0.25 mg once daily for 4 days, then 0.5 mg/day
Maintenance: 0.5 - 3 mg/day
Max: 3 mg/day
May be given in one or two divided doses
Increase dose in increments of 0.25 mg/day at intervals of ≥ 14 days
No data is available for children weighing < 15 kg

Weight ≥ 20 kg

Starting: 0.5 mg once daily for 4 days, then 1 mg/day
Maintenance: 0.5 - 3 mg/day
Max: 3 mg/day
May be given in one or two divided doses
Increase dose in increments of 0.5 mg/day at intervals of ≥ 14 days

Dosing - Risperdal Consta®

Schizophrenia (adults)

Starting: 25 mg IM every 2 weeks
Maintenance: 25 - 50 mg IM every 2 weeks
Max: 50 mg IM every 2 weeks
Increase dose at intervals ≥ 4 weeks
Oral risperidone should be continued for 3 weeks after initial injection, then discontinued

Bipolar mania (adults)

Starting: 25 mg IM every 2 weeks
Maintenance: 25 - 50 mg IM every 2 weeks
Max: 50 mg IM every 2 weeks
Increase dose at intervals ≥ 4 weeks
Oral risperidone should be continued for 3 weeks after initial injection, then discontinued

Dosing - Perseris®

Schizophrenia (adults)

Dosing: 90 - 120 mg by subcutaneous injection once monthly
Administer in the abdomen only
Comes in package with 2 syringes. Drug must be mixed before injecting.
Must be given by healthcare professional
90 mg of Perseris corresponds to 3 mg/day of oral risperidone and 120 mg corresponds to 4 mg/day of oral risperidone

Generic / Price

Risperdal® tablet - YES/$
Risperdal® M-tab - YES/$
Risperdal® solution - YES (60 ml)/$
Risperdal® Consta® - NO/$$$$
Perseris® - NO/$$$$

Other

Risperdal®

May take without regard to food
Store solution at room temperature

Orally disintegrating tablet

Once tablet is removed from blister packet, it cannot be stored. Take immediately.
Tablet disintegrates in mouth within seconds and can be swallowed with or without liquid
Do not attempt to chew or split tablet

Consta®

See Consta® PI for instructions on how to mix and inject

Pharmacokinetics

Risperidone has one, major active metabolite called 9-hydroxyrisperidone
The apparent half-life of risperidone is 3 hours in CYP2D6 extensive metabolizers and 20 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone is about 21 hours in extensive metabolizers and 30 hours in poor metabolizers.

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin type 2 (5-HT₂) receptor antagonist

FDA-approved indications

Schizophrenia
Bipolar mania
Irritability associated with autistic disorder

Side effects

Side effect	Risperidone	Placebo
Insomnia	32%	27%
Extrapyramidal symptoms (10 mg/day)	21%	13%
Weight gain (≥ 7% increase)	21%	3%
Anxiety	16%	11%
Sedation	10%	2%
Nausea	9%	4%
Constipation	8%	6%
Dizziness	7%	2%
Other Hyperprolactinemia - up to 87% of patients (13 - 17 years old) in some studies Orthostatic hypotension - 1 - 2% of patients Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Alpha blockers - risperidone can block alpha receptors. This may potentiate the effects of alpha blockers and increase the risk of hypotension.
Centrally-acting drugs and alcohol - use caution when combining risperidone with other centrally-acting drugs and alcohol. The risk for adverse neurologic effects may be increased.
Clozapine (Clozaril®) - chronic administration of clozapine with risperidone may decrease the clearance of risperidone
CYP2D6 strong inhibitors - risperidone is a CYP2D6 sensitive substrate and CYP2D6 strong inhibitors (e.g. fluoxetine, paroxetine) may increase risperidone levels. Risperidone doses should not exceed 8 mg/day when taken together.
CYP3A4 inducers - risperidone is a CYP3A4 sensitive substrate and CYP3A4 inducers (e.g. carbamazepine) may decrease risperidone levels. Risperidone doses may need to be increased when taken with CYP3A4 inducers, but they should not exceed twice the patient's usual dose.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - risperidone may inhibit the effects of dopamine agonists
Drugs with hypotensive effects - risperidone may potentiate the hypotensive effects of other drugs that can cause hypotension. Use caution.
Methylphenidate - combined use of methylphenidate with risperidone may increase the risk of extrapyramidal symptoms (EPS), particularly when the dose of either drug is adjusted. Monitor for EPS symptoms when combining.
P-glycoprotein - risperidone is a P-glycoprotein substrate and P-glycoprotein inducers may decrease risperidone levels. Risperidone doses may need to be increased when taken with P-glycoprotein inducers, but they should not exceed twice the patient's usual dose.

Contraindications / Precautions

Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, risperidone had mixed effects on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, risperidone had an adverse effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients, particularly during initiation and dose increases. In trials, syncope was reported in 0.2% of risperidone-treated patients. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment. Use caution in susceptible patients (e.g. heart disease, dehydration, elderly patients with renal or hepatic impairment).
Infertility - risperidone-induced increases in serum prolactin may cause a reduction in female fertility that is reversible upon discontinuation
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Phenylketonuria - risperidone orally disintegrating tab contains phenylalanine
Parkinson's disease or Lewy body dementia - patients with Parkinson's disease or Lewy body dementia may be especially sensitive to the effects of risperidone. Side effects including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome may occur.
Liver disease (Risperdal®)

Severe (Child-Pugh C) - initial dose should be 0.5 mg twice a day. Increase dose in increments of 0.5 mg or less. For doses > 1.5 mg twice daily, increase in intervals of 1 week or more.

Liver disease (Risperdal Consta®)

Titrate dose with oral risperidone first. If a total daily dose of ≥ 2 mg of oral risperidone is well tolerated, an injection of 25 mg Risperdal Consta® can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection. Alternatively, a starting dose of Risperdal Consta® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been established.

Kidney disease

CrCl < 30 ml/min - initial dose should be 0.5 mg twice a day. Increase dose in increments of 0.5 mg or less. For doses > 1.5 mg twice daily, increase in intervals of 1 week or more.

Kidney disease (Risperdal Consta®)

Titrate dose with oral risperidone first. If a total daily dose of ≥ 2 mg of oral risperidone is well tolerated, an injection of 25 mg Risperdal Consta® can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection. Alternatively, a starting dose of Risperdal Consta® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been established.

Ziprasidone (Geodon®)

Dosage forms

Capsule

20 mg
40 mg
60 mg
80 mg

Dosing

Schizophrenia (adults)

Starting: 20 mg twice a day
Maintenance: 20 - 80 mg twice a day
Max: 80 mg twice a day
Increase dose at intervals of ≥ 2 days
Take with food. Food increases absorption.

Bipolar I (adults)

Starting: 40 mg twice a day
Maintenance: 40 - 80 mg twice a day
Max: 80 mg twice a day
Take with food. Food increases absorption.

Generic / Price

- YES/$

Pharmacokinetics (oral)

Half-life: 7 hours

Mechanism of action

Dopamine-2 receptor antagonist
Serotonin type 2 (5-HT₂) receptor antagonist

FDA-approved indications

Schizophrenia
Bipolar I disorder
Agitation in schizophrenia

Side effects

Side effect	Ziprasidone	Placebo
Weight gain (≥ 7% increase)	16%	4%
Somnolence	14%	7%
Extrapyramidal symptoms	14%	8%
Nausea	10%	7%
Other Rash - ziprasidone causes a rash in 5% of patients. Stop therapy if rash occurs. Orthostatic hypotension - up to 1% of patients Hyperprolactinemia - incidence not well-defined Difficulty swallowing - incidence not well-defined Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Drugs that prolong the QT interval - DO NOT COMBINE
CYP3A4 strong inhibitors and inducers - ziprasidone undergoes a small amount of metabolism by CYP3A4. Strong CYP3A4 inhibitors and inducers may affect levels.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - ziprasidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Alpha blockers - ziprasidone can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Ziprasidone may prolong the QT interval.
Recent Heart attack - DO NOT USE. Ziprasidone may prolong the QT interval.
Uncompensated heart failure - DO NOT USE. Ziprasidone may prolong the QT interval.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, ziprasidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 6 weeks, ziprasidone had a mixed effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
DRESS syndrome - severe skin reactions including DRESS syndrome have occurred in some users. DRESS syndrome is a rare, but serious skin reaction marked by rash, fever, and swollen lymph nodes.
Liver disease - clearance is decreased; manufacturer makes no dose adjustment recommendation
Kidney disease - no dose adjustment necessary

FIRST GENERATION ANTIPSYCHOTICS

Chlorpromazine (Thorazine®)

Dosage forms

Tablet

10 mg
25 mg
50 mg
100 mg
200 mg

Oral concentrate

30 mg/ml | 120 ml bottle
100 mg/ml | 240 ml bottle

Dosing

Schizophrenia and manic states (adults)

Starting: 10 - 25 mg three times a day
Increase daily dose every 3 - 4 days by 10 to 50 mg
Effective maintenance dose is usually around 400 mg/day

Intractable hiccups (adults)

Dosing: 25 - 50 mg three to four times a day

Nausea and vomiting (adults)

Dosing: 10 - 25 mg every 4 - 6 hours as needed

Presurgical apprehension (adults)

Dosing: 25 - 50 mg two to three hours before surgery

Acute Intermittent Porphyria (adults)

Dosing: 25 - 50 mg three to four times a day

Generic / Price

- YES/$ (all forms)

Mechanism of action

Chlorpromazine is a dopamine receptor antagonist

FDA-approved indications

Psychotic/manic disorders
Nausea and vomiting
Intractable hiccups
Surgical anxiety
Acute intermittent porphyria

Side effects

NOTE: Incidence of side effects is not well-defined.

Extrapyramidal symptoms
Drowsiness
Dizziness
Skin reactions
Hypotension

Drug interactions

Lithium - a syndrome similar to neuroleptic malignant syndrome (NMS) has been reported in patients taking lithium with antipsychotics, particularly haloperidol. Symptoms include weakness, lethargy, fever, tremor, confusion, extrapyramidal symptoms, leukocytosis, and elevated liver enzymes. In some cases, the syndrome was followed by irreversible brain damage. Use caution in patients receiving concomitant lithium, and stop treatment if signs of neurologic toxicity occur.
CNS depressants - antipsychotics may potentiate the effects of CNS depressants (e.g. alcohol, benzodiazepines). Use caution when combining.
Alpha blockers - chlorpromazine can block alpha receptors and potentiate the effects of alpha blockers. This may increase the risk of alpha blocker-induced orthostatic hypotension.
Propranolol - chlorpromazine may increase propranolol exposure and vice versa
Phenytoin - chlorpromazine may interfere with phenytoin metabolism and increase its exposure
Anticholinergic medications - antipsychotics have anticholinergic activity and may potentiate the effects of other anticholinergic medications
Dopamine agonists (Mirapex®, Sinemet®, etc.) - chlorpromazine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Lab interactions

Phenylketonuria (PKU) test - chlorpromazine may cause false-positive PKU results

Contraindications / Precautions

Hypersensitivity to phenothiazines - DO NOT USE. Chlorpromazine is a phenothiazine. Examples of phenothiazines include promethazine, prochlorperazine, and thioridazine.
Comatose state or CNS depression - DO NOT USE
Parkinson's disease - DO NOT USE. Chlorpromazine may block the antiparkinson effects of levodopa and other dopamine agonists.
Hepatotoxicity - cases of cholestatic jaundice have occurred in patients receiving chlorpromazine. Most cases have occurred between the second and fourth weeks of therapy, and symptoms typically resolve with drug discontinuation. If signs of liver disease develop, chlorpromazine should be stopped, and an appropriate workup should be initiated.
Hematologic disorders - cases of agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura, and pancytopenia have been reported in patients treated with chlorpromazine. Most cases have occurred between the fourth and tenth weeks of therapy. Monitor CBC closely in susceptible patients and stop chlorpromazine if toxicity occurs.
Skin reactions - skin reactions, including urticaria and photosensitivity, have been reported. More severe reactions, including exfoliative dermatitis and toxic epidermal necrolysis (TEN), have also occurred in rare cases.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Cerebrovascular disease - In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known.
Tardive dyskinesia
Neuroleptic malignant syndrome (NMS)
Skin pigmentation - skin pigmentation changes (e.g. darkening, gray color) have occurred in chronic therapy. These changes have mostly been seen in females treated with high doses for more than 3 years and may be worsened by sun exposure. Pigmentation may fade with drug discontinuation.
Ocular changes - ocular changes, including deposition of fine particulate matter in the lens and cornea, have been reported with chronic therapy (more than 2 years). Cases of epithelial keratopathy and pigmentary retinopathy have also occurred. Lesions may regress with treatment discontinuation. Patients receiving long-term therapy at moderate-to-high doses should have periodic eye exams.
Cough reflex - phenothiazines like chlorpromazine may suppress the cough reflex and increase the risk of aspiration pneumonia
Sudden discontinuation - sudden discontinuation of chlorpromazine after chronic use may cause nausea, vomiting, dizziness, and tremulousness
Reye’s syndrome or other encephalopathies - Reye’s syndrome or other encephalopathies may cause signs and symptoms similar to chlorpromazine-induced EPS. Do not use in children and adolescents who may have Reye’s syndrome.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Hyperprolactinemia - antipsychotics can raise prolactin levels. If symptoms of hyperprolactinemia develop (e.g. gynecomastia, amenorrhea, galactorrhea), consider the risks and benefits of continued use.
Angle-closure glaucoma - chlorpromazine may cause pupillary dilation, which can worsen angle-closure glaucoma
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability, which can lead to falls. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Liver disease - exposure may be increased. Manufacturer makes no recommendation.
Kidney disease - exposure may be increased. Manufacturer makes no recommendation.

Haloperidol | Haldol® | Haldol® Decanoate

Dosage forms

Tablet

0.5 mg
1 mg
2 mg

5 mg
10 mg
20 mg

Solution

2 mg/ml
Comes in 15 ml and 120 ml bottle

Vial (Haldol® decanoate)

50 mg
100 mg

Dosing - Oral

Psychosis (adults)

Starting (moderate symptoms): 0.5 - 2 mg two to three times a day
Starting (severe symptoms): 3 - 5 mg two to three times a day
Maintenance: titrate to effect
Max: 100 mg/day

Psychotic disorders (3 - 12 years weighing 15 - 40 kg)

Dosing: 0.05 mg/kg/day to 0.15 mg/kg/day
Daily dose may be given in 2 or 3 divided doses
Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days

Non-psychotic behavior disorders (3 - 12 years weighing 15 - 40 kg)

Dosing: 0.05 mg/kg/day to 0.075 mg/kg/day
Daily dose may be given in 2 or 3 divided doses
Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days

Tourette's disorder (3 - 12 years weighing 15 - 40 kg)

Dosing: 0.05 mg/kg/day to 0.075 mg/kg/day
Daily dose may be given in 2 or 3 divided doses
Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days

Dosing - Haldol® Decanoate

Psychosis (adults)

Dose: 10 - 20 X the daily oral dose of haloperidol
Frequency: IM injection every 4 weeks
Max: 450 mg

Efficacy

Haloperidol vs Placebo for Delirium in ICU Patients, NEJM (2022) [PubMed abstract]

Generic / Price

- YES/$ (all forms)

Mechanism of action

Dopamine receptor antagonist

FDA-approved indications

Psychotic disorders
Tourette's syndrome - control of tics

Side effects

NOTE: Incidence of side effects not well-defined

Extrapyramidal symptoms - common
Sedation - common
Weight gain
Hyperprolactinemia (elevated prolactin level)
Priapism (erection lasting longer than 4 hours) - rare

Drug interactions

Haloperidol is a CYP3A4 and CYP2D6 substrate
Drugs that prolong the QT interval - DO NOT COMBINE
CYP3A4 inducers and inhibitors - haloperidol is a CYP3A4 substrate. CYP3A4 inducers and inhibitors may affect levels
CYP2D6 inducers and inhibitors - haloperidol is a CYP2D6 substrate. CYP2D6 inducers and inhibitors may affect haloperidol levels.
CYP2D6 substrates - haloperidol is a CYP2D6 inhibitor and substrate. Haloperidol may affect other CYP2D6 substrates.
Anticholinergic medications - antipsychotics have anticholinergic activity and may potentiate the effects of other anticholinergic medications
CNS depressants - antipsychotics may potentiate the effects of CNS depressants (e.g. alcohol, benzodiazepines). Use caution when combining.
Lithium - a syndrome similar to neuroleptic malignant syndrome (NMS) has been reported in patients taking lithium with antipsychotics, particularly haloperidol. Symptoms include weakness, lethargy, fever, tremor, confusion, extrapyramidal symptoms, leukocytosis, and elevated liver enzymes. In some cases, the syndrome was followed by irreversible brain damage. Use caution in patients receiving concomitant lithium, and stop treatment if signs of neurologic toxicity occur.
Alpha blockers - haloperidol can block alpha-1 receptors and potentiate the effects of alpha blockers. This may increase the risk of alpha blocker-induced orthostatic hypotension.
Dopamine agonists (Mirapex®, Sinemet®, etc.) - haloperidol may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
Epinephrine - haloperidol may block the vasopressor effects of epinephrine. An alternative vasopressor should be used in patients receiving haloperidol.

Contraindications / Precautions

Prolonged QT syndrome - DO NOT USE. Haloperidol may prolong the QT interval.
Comatose state or CNS depression - DO NOT USE
Parkinson's disease - DO NOT USE. Haloperidol may block the antiparkinson effects of levodopa and other dopamine agonists.
Dementia with Lewy bodies - DO NOT USE. Patients with Lewy body dementia may have an increased risk of adverse effects from haloperidol including severe extrapyramidal symptoms, confusion, sedation, and falls.
Cardiovascular disease - use with caution. Haloperidol may prolong the QT interval and increase the risk of arrhythmia.
Cerebrovascular disease - In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Hyperprolactinemia - antipsychotics can raise prolactin levels. If symptoms of hyperprolactinemia develop (e.g. gynecomastia, amenorrhea, galactorrhea), consider the risks and benefits of continued use.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Liver disease - manufacturer does not make recommendation
Kidney disease - manufacturer does not make recommendation

Prochlorperazine (Compazine®)

Dosage forms

Tablet

5 mg
10 mg

Suppository

25 mg
Comes in box of 12

Dosing

Severe nausea and vomiting (adults)

Tablets

Dosing: 5 - 10 mg three to four times daily
Max: 40 mg/day

Suppository

Dosing: 25 mg twice daily as needed

Severe nausea and vomiting (children ≥ 2 years and weighing ≥ 20 lbs)

20 - 29 lbs: 2.5 mg one or two times a day. Do not exceed 7.5 mg/day.
30 - 39 lbs: 2.5 mg two or three times a day. Do not exceed 10 mg/day.
40 - 85 lbs: 2.5 mg three times a day or 5 mg two times a day. Do not exceed 15 mg/day.
Do not use in pediatric surgery

Non-psychotic anxiety (adults)

Dosing: 5 mg three or four times daily
Do not administer in doses of more than 20 mg/day or for longer than 12 weeks

Psychotic disorders (adults)

Starting: 5 - 10 mg three or four times daily
Maintenance: 50 - 150 mg/day
Increase dose in small increments every 2 - 3 days

Schizophrenia (children 2 - 12 years old)

Starting: 2.5 mg two or three times daily
Max (2 - 5 years old): 20 mg/day
Max (6 - 12 years old): 25 mg/day

Generic / Price

- YES/$ (all forms)

Mechanism of action

Prochlorperazine is a dopamine receptor antagonist

FDA-approved indications

Tablets

Severe nausea and vomiting (adults and children)
Schizophrenia (adults and children)
Generalized non-psychotic anxiety (adults)

Suppository

Severe nausea and vomiting in adults

Side effects

NOTE: Incidence of side effects is not well-defined.

Extrapyramidal symptoms
Drowsiness
Dizziness
Blurred vision
Skin reactions
Hypotension

Drug interactions

Lithium - a syndrome similar to neuroleptic malignant syndrome (NMS) has been reported in patients taking lithium with antipsychotics, particularly haloperidol. Symptoms include weakness, lethargy, fever, tremor, confusion, extrapyramidal symptoms, leukocytosis, and elevated liver enzymes. In some cases, the syndrome was followed by irreversible brain damage. Use caution in patients receiving concomitant lithium, and stop treatment if signs of neurologic toxicity occur.
CNS depressants - antipsychotics may potentiate the effects of CNS depressants (e.g. alcohol, benzodiazepines). Use caution when combining.
Alpha blockers - prochlorperazine can block alpha receptors and potentiate the effects of alpha blockers. This may increase the risk of alpha blocker-induced orthostatic hypotension.
Propranolol - prochlorperazine may increase propranolol exposure and vice versa
Phenytoin - prochlorperazine may interfere with phenytoin metabolism and increase its exposure
Anticholinergic medications - antipsychotics have anticholinergic activity and may potentiate the effects of other anticholinergic medications
Dopamine agonists (Mirapex®, Sinemet®, etc.) - prochlorperazine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Lab interactions

Phenylketonuria (PKU) test - prochlorperazine may cause false-positive PKU results

Contraindications / Precautions

Hypersensitivity to phenothiazines - DO NOT USE. Prochlorperazine is a phenothiazine. Examples of phenothiazines include promethazine, chlorpromazine, and thioridazine.
Comatose state or CNS depression - DO NOT USE
Pediatric surgery - DO NOT USE
Parkinson's disease - DO NOT USE. Prochlorperazine may block the antiparkinson effects of levodopa and other dopamine agonists.
Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
Cerebrovascular disease - In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known.
Hepatotoxicity - cases of cholestatic jaundice and fatty liver disease have occurred in patients receiving prochlorperazine. If signs of liver disease develop, prochlorperazine should be considered a possible cause.
Leukopenia - antipsychotics have been associated with a decrease in white blood cells (WBC) in some patients. Patients with risk factors for leukopenia (e.g. pre-existing low WBC, history of drug-induced leukopenia) should have frequent CBCs during therapy initiation, and antipsychotics should be stopped if leukopenia occurs.
Neuroleptic malignant syndrome (NMS)
Tardive dyskinesia
Sudden discontinuation - sudden discontinuation of prochlorperazine after chronic use may cause nausea, vomiting, dizziness, and tremulousness
Reye’s syndrome or other encephalopathies - Reye’s syndrome or other encephalopathies may cause signs and symptoms similar to prochlorperazine-induced EPS. Do not use in children and adolescents who may have Reye’s syndrome.
Cough reflex - phenothiazines like prochlorperazine may suppress the cough reflex and increase the risk of aspiration pneumonia
Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
Hyperprolactinemia - antipsychotics can raise prolactin levels. If symptoms of hyperprolactinemia develop (e.g. gynecomastia, amenorrhea, galactorrhea), consider the risks and benefits of continued use.
Angle-closure glaucoma - prochlorperazine may cause pupillary dilation, which can worsen angle-closure glaucoma
Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability, which can lead to falls. Use caution in susceptible patients.
Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
Liver disease - exposure may be increased. Manufacturer makes no recommendation.
Kidney disease - exposure may be increased. Manufacturer makes no recommendation.

EXTRAPYRAMIDAL SYMPTOMS (EPS)

Overview

The extrapyramidal motor system is a tract of motor nerve fibers that originates in the brain stem and ends in the spinal cord. It plays a role in modulating involuntary muscle control which includes muscle tone, reflexes, balance, and posture. This is in contrast to the pyramidal motor tract which controls voluntary muscle movement.
Drugs like antipsychotics that block dopamine receptors can disrupt the extrapyramidal motor system and cause what are called "extrapyramidal symptoms" or "extrapyramidal side effects." Extrapyramidal symptoms are a constellation of movement disorders described below. Severe EPS can lead to tardive dyskinesia.
EPS can occur with any antipsychotic drug, but they are more common with first generation antipsychotics, affecting up to 62% of treated patients. Rates of EPS vary among second generation antipsychotics with risperidone having the highest (21% at 10 mg/day) and clozapine having the lowest.
EPS can be treated with anticholinergic medications (e.g. benztropine, trihexyphenidyl), dosage reductions, and drug discontinuation. If EPS are from a first-generation antipsychotic, switching to a second generation antipsychotic may be tried.

Extrapyramidal symptoms include the following:

Akathisia - akathisia is a sense of inner restlessness that causes an urge to move and/or an inability to sit still. Akathisias typically occur within 4 weeks of antipsychotic initiation or dosage increases.
Parkinsonism - parkinsonism symptoms includes tremor, mask-like facies (expressionless), rigid body movements, slow body movements, stooped posture, shuffling gait, and difficulty rising from a seated position
Dystonias - dystonias are involuntary, sustained muscle contractions that result in abnormal posture or repetitive movements. Ninety percent of dystonias occur within 5 days of drug initiation or dosage increases, and 50% occur within 48 hours. [5]

TARDIVE DYSKINESIA (TD)

TD is an extreme form of extrapyramidal symptoms that can be caused by antipsychotic medications. TD is marked by intermittent, involuntary, jerky movements of the face, tongue, jaw, trunk, or limbs. TD symptoms can take years to resolve after the offending medication is stopped, and in some cases, the condition is permanent. Risk factors for TD include first generation antipsychotics, chronic antipsychotic use, high-dose antipsychotics, and advanced age.
The annual incidence of TD with first generation antipsychotics is about 5% in adults and as high as 25 - 30% in elderly patients. The annual incidence of TD with second generation antipsychotics is around 1% in adults and 5.3% in patients ≥ 54 years [3]
Patients who develop TD should discontinue their antipsychotic. If discontinuation is not possible, the dose should be reduced or the drug should be changed to another antipsychotic that has a lower incidence of EPS. In 2017, the FDA approved the first drug to treat TD, a vesicular monoamine transporter 2 (VMAT2) inhibitor called Ingrezza® (valbenazine). [Ingrezza PI] Another VMAT2 inhibitor called Austedo® (deutetrabenazine) was subsequently approved. [Austedo PI]

NEUROLEPTIC MALIGNANT SYNDROME (NMS)

Epidemiology and risk factors

The incidence of NMS among patients taking antipsychotics ranges from 0.07% - 2.2%, depending on the study. NMS can occur with any antipsychotic, but it is more common with first generation antipsychotics, particularly haloperidol and chlorpromazine. Risk factors for NMS include high-dose antipsychotics, rapid antipsychotic titration, injectable antipsychotics, male sex, dehydration, concomitant litium, history of electoconvulsive therapy, and family history of NMS. NMS typically occurs between 1 and 44 days after the initiation of an antipsychotic drug; 67% of cases occur within 1 week and 96% within 30 days.

Pathology

NMS is a rare condition caused by antipsychotic medications that can be fatal. The exact mechanism behind NMS is not completely understood, but it is believed to occur through dopamine-2 (D2) receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord. Blockade in these regions may cause the following reactions: (1) blockade of D2 receptors in the hypothalamus causes an elevation in the body temperature set point and impairment of heat dissipation (e.g. sweating and cutaneous vasodilation), (2) blockade of D2 receptors in the nigrostriatal pathways causes muscle rigidity, (3) D2 blockade removes tonic inhibition from the sympathetic nervous system, (4) D2 blockade increases contractility in peripheral muscles.
Sequelae of NMS include dehydration from decreased oral intake, rhabdomyolysis leading to renal failure, venous thromboembolism from rigidity and immobilization, seizures, arrhythmias, and aspiration pneumonia from dysphagia.

Symptoms

Fever
Muscle rigidity
Mental status changes
Elevated blood pressure
Rapid heart beat
Excessive sweating
Elevated creatine phosphokinase (CK)
Rhabdomyolysis
Elevated white count

Treatment

Treatment of NMS is supportive and includes discontinuing antipsychotic therapy, body temperature lowering (e.g. cooled IV fluids, antipyretics, ice packs), IV fluids, and management of hypoxemia. The use of dantrolene and dopamine agonists (e.g. bromocriptine) is controversial. [2,6]

DIABETES/CHOLESTEROL SCREENING

Overview

Second-generation antipsychotics may cause weight gain and diabetes in some patients. They may also have a negative effect on lipid parameters. The mechanism of this effect is not completely understood, and some antipsychotics carry a greater risk than others. In 2004, the ADA issued diabetes and cholesterol screening guidelines for patients taking second-generation antipsychotics.

ADA screening recommendations for patients starting second generation antipsychotics

Fasting blood sugar at baseline, 12 weeks, and annually thereafter
Fasting lipid profile at baseline, 12 weeks, and every 5 years thereafter [4]

CLOZAPINE AGRANULOCYTOSIS

Overview

Neutrophils, eosinophils, and basophils are white blood cells that are collectively called granulocytes. Clozapine has been shown to cause agranulocytosis, a decrease in granulocytes, particularly neutrophils (see neutropenia). Agranulocytosis is a serious condition that can lead to fatal infections, and approximately 1.3% of clozapine-treated patients are affected after a year of use. Because of this, the FDA requires providers and patients to enroll in the Clozapine REMS program.
During therapy, white blood cell counts (CBC) must be monitored frequently, with treatment changes based on those results. See clozapine agranulocytosis guidelines [sec 5.1] for recommendations on adjusting therapy.
Recommendations for CBC monitoring in patients with normal lab values are presented below

CBC frequency for patients with normal WBC counts:

Initiation of therapy - check CBC weekly for 6 months
6 - 12 months of therapy - every 2 weeks for 6 months
12 months of therapy and on - check CBC monthly indefinitely
NOTE: Normal CBC defined as WBC ≥ 3500/mm³ and ANC ≥ 2000/mm³

STUDIES

Pregnancy safety studies

Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine, Am J Psychiatry (2018) [PubMed abstract]

Design: Prospective registry cohort study (N=357) among pregnant women 18 - 45 years old
Exposure: First-trimester exposure to quetiapine
Primary outcome: Major congenital malformation
Results:

Primary outcome: Quetiapine-exposed - 1.3%, Control - 1.4% (OR 0.90, 95%CI [0.15 - 5.46])

Findings: These data regarding the safety of fetal exposure to quetiapine in a small sample of well-characterized participants are reassuring given that the confidence interval does not exceed a fivefold increased risk of major malformations relative to psychiatric control subjects. Future analyses based on ongoing data collection will produce more precise estimates.

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations, JAMA Psychiatry (2016) [PubMed abstract]

Design: Cohort registry study (N=1,341,715) among women enrolled in Medicaid with a live-born infant
Exposure: Use of antipsychotics during the first trimester
Primary outcome: Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery
Results:

Congenital malformations: Not exposed - 32.7/1000 births, Atypical antipsychotic exposure - 44.5/1000 births, Typical antipsychotic exposure - 38.2/1000 births

Findings: Evidence from this large study suggests that use of antipsychotics early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

Reproductive Safety of Second-Generation Antipsychotics, American Journal of Psychiatry (2015) [PubMed abstract]

Design: Cohort registry study (N=303) among pregnant women 18 - 45 years old
Exposure: Use of antipsychotics during the first trimester
Primary outcome: Major congenital malformations
Results:

Primary outcome: Exposed infants - 1.4%, Unexposed infants - 1.1% (OR 1.25, 95%CI [0.13 - 12.19])

Findings: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety.

Antipsychotic drug use in pregnancy: high dimensional, propensity matched, population based cohort study, BMJ (2015) [PubMed abstract]

Design: Propensity matched cohort study (N=2042)
Exposure: Use of antipsychotics during the first or second trimester
Primary outcome: The main maternal medical outcomes were gestational diabetes, hypertensive disorders of pregnancy, and venous thromboembolism. The main perinatal outcomes were preterm birth (<37 weeks), and a birth weight <3rd or >97th centile.
Findings: Antipsychotic drug use in pregnancy had minimal evident impact on important maternal medical and short term perinatal outcomes. However, the rate of adverse outcomes is high enough to warrant careful assessment of maternal and fetal wellbeing among women prescribed an antipsychotic drug in pregnancy.

Aripiprazole in resistant depression

Switch to Bupropion vs Add Bupropion vs Add Antipsychotic in Resistant MDD, JAMA (2017) [PubMed abstract]

Design: Randomized, controlled trial (N=1522, length = 12 weeks) in patients with MDD who were failing SSRI, SNRI, or mirtazapine therapy
Treatment: Switch to Bupropion 300 - 400 mg/day vs Add Bupropion 300 - 400 mg/day vs Add aripiprazole 5 - 15 mg/day
Primary outcome: Remission during the acute treatment phase of 12 weeks
Results:

Primary outcome: Switch to Bupropion - 22%, Add Bupropion - 27%, Add Aripiprazole - 29%

Findings: Among a predominantly male population with MDD unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

Addition of Aripiprazole vs Placebo to MDD resistant to Venlafaxine (Lancet 2015) [PubMed abstract]

Design: Randomized, controlled trial (N=468, length = 12 weeks) in adults older than 60 with MDD who were failing venlafaxine 150 - 300 mg/day
Treatment: Aripiprazole (target dose 10 mg/day) vs Placebo
Primary outcome: Remission (defined as an MADRS score of ≤ 10 and at least 2 points below the score at the start of the randomized phase) at both of the final two consecutive visits
Results:

Primary outcome: Aripiprazole - 44%, Placebo - 29% (p=0.03)

Findings: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.

PRICE ($) INFO

Pricing legend

$ = 0 - $50
$$ = $51 - $100
$$$ = $101 - $150
$$$$ = > $151

Pricing based on one month of therapy at standard dosing in an adult
Pricing based on information from GoodRX.com®
Pricing may vary by region and availability

BIBLIOGRAPHY

1 - Manufacturer's Package Insert for each drug listed
2 - PMID 10928001
3 - PMID 14992963
4 - PMID 14747245
5 - D'Souza RS, Hooten WM. Extrapyramidal Symptoms. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. [PubMed link]
6 - Neuroleptic Malignant Syndrome, Medscape

ANTIPSYCHOTICS

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Dosing - Aristada™

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