Acronyms
- DA - Dopamine antagonists
- EPS - Extrapyramidal symptoms
- IM - Intramuscular
- MDD - Major depressive disorder
- NMS - Neuroleptic malignant syndrome
- OBS - Observational study
- ODT - Orally disintegrating tablet
- P - Drugs with pediatric dosing
- SC - Subcutaneous
- TD - Tardive dyskinesia
Open all
Aripiprazole
Abilify®, Aristada®
Abilify®, Aristada®
Dosage forms

Tablet (Abilify®)
- 2 mg
- 5 mg
- 10 mg
- 15 mg
- 20 mg
- 30 mg
ODT (Abilify Discmelt®)
- 10 mg
- 15 mg
Solution (Abilify®)
- 1 mg/ml
- Comes in 150 ml bottle
- Store at room temp
IM injection (Abilify Maintena®)
- 300 mg
- 400 mg
- Kit with vial and prefilled syringe
- Given intramuscularly
IM injection (Aristada®)
- 441 mg
- 662 mg
- 882 mg
- 1064 mg
- Given intramuscularly
- Aristada is aripiprazole lauroxil
IM injection (Aristada Initio®)
- 675 mg
- Given intramuscularly
- Aristada Initio is aripiprazole lauroxil
IM injection (Abilify Asimtufii®)
- 720 mg
- 960 mg
- Comes in prefilled syringe
- Given intramuscularly
Dosing - Abilify® oral forms

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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
- 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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
- 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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
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
- May take without regard to food
- Solution can be substituted for tablets on mg-to-mg basis up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution.
Kidney disease
- No dose adjustment necessary
Liver disease
- No dose adjustment necessary
Dosing with CYP2D6 and CYP3A4 modulators
Factor | Aripiprazole dose adjustment |
---|---|
Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors | Administer a quarter of usual dose |
Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
Strong CYP2D6 and CYP3A4 inhibitors | Administer a quarter of usual dose |
Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
Dosing - Abilify Maintena®

Schizophrenia and Bipolar I (adults)
- Starting: 400 mg IM every month (no sooner than 26 days)
- Maintenance: 300 - 400 mg IM every month
- When initiating, administer oral aripiprazole (10 mg to 20 mg) for 14 consecutive days
- Patients should demonstrate tolerability of oral Abilify® before using
- Administer in the gluteal or deltoid muscle by a healthcare provider
- See Abilify Maintena® PI for complete prescribing information
Dosing - Aristada®

Schizophrenia (adults)
- Aristada and Aristada Initio are IM injections administered by healthcare providers. Aristada Initio is only to be used for the initial dose. Aristada may be given monthly to every 2 months, depending on the dose.
- See Aristada PI and Aristada Initio PI for complete prescribing information
Dosing - Abilify Asimtufii®

Schizophrenia and Bipolar I (adults)
- Starting: 960 mg once every 2 months (56 days)
- Maintenance: 720 - 960 mg once every 2 months (56 days)
- When initiating, give oral aripiprazole (10 mg to 20 mg) for 14 consecutive days
- Administer in the gluteal muscle by a healthcare provider
- See Abilify Asimtufii PI for complete prescribing information
Efficacy / Studies

Generic / Price

- Abilify tablet - YES/$
- Abilify ODT - YES/$$$$
- Abilify solution - YES/$$$-$$$$
- Abilify Maintena - NO/$$$$
- Aristada - NO/$$$$
- Asimtufii - NO/$$$$
Pharmacokinetics

Abilify tablet
- Half-life (aripiprazole): 75 hours
- Half-life (active metabolite): 94 hours
Mechanism of action

- The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
FDA-approved indications

Abilify tablets/solution
- Schizophrenia (adults and adolescents aged 13 - 17)
- Bipolar I (adults and adolescents aged 10 - 17) - acute treatment of manic and mixed episodes
- Depression (adults) - adjunctive treatment with antidepressants
- Tourette's disorder (children and adolescents aged 6 - 18)
- Irritability associated with autistic disorder (children and adolescents aged 6 - 17)
Abilify Maintena
- Schizophrenia (adults)
- Bipolar I (adults) - maintenance monotherapy
Aristada
- Schizophrenia (adults)
Abilify Asimtufii
- Schizophrenia (adults)
- Bipolar I (adults) - maintenance monotherapy
Side effects

Adult trials | ||
---|---|---|
Side effect | Aripiprazole (N=1843) |
Placebo (N=1166) |
Headache | 27% | 23% |
Agitation | 19% | 17% |
Insomnia | 18% | 13% |
Anxiety | 17% | 13% |
Nausea | 15% | 11% |
Somnolence | 11% | 6% |
Constipation | 11% | 7% |
Vomiting | 11% | 6% |
Dizziness | 10% | 7% |
Akathisia | 10% | 4% |
Dyspepsia | 9% | 7% |
Sedation | 7% | 4% |
Fatigue | 6% | 4% |
Dry mouth | 5% | 4% |
EPS | 5% | 3% |
Tremor | 5% | 3% |
Somnolence | 5% | 3% |
Restlessness | 5% | 3% |
Other
|
Drug interactions

- CYP3A4 inhibitors and inducers - aripiprazole is a CYP3A4 sensitive substrate. See Dosing above for recommendations.
- CYP2D6 inhibitors - aripiprazole is a CYP2D6 sensitive substrate. See Dosing above for recommendations.
- Carbamazepine - carbamazepine is a strong CYP3A4 inducer, and the aripiprazole dose should be doubled when taken together
- Alpha blockers - aripiprazole can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - aripiprazole may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
Lab interactions

- Urine drug screen - there have been case reports of false-positive amphetamines on urine drug screens in children exposed to aripiprazole. 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, or olanzapine had a higher incidence of stroke and TIA. Aripiprazole is not approved for dementia-related psychosis.
- Suicide in depression - in trials involving antidepressants (SSRIs and others), 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.
- 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. In trials, the incidence of new-onset seizures in aripiprazole-treated patients was less than 1%. Use caution in susceptible patients.
- Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. In trials, the incidence of orthostatic hypotension-associated events in aripiprazole-treated patients was 1% or less. 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. Use caution in susceptible patients.
- Liver disease - no dose adjustment necessary
- Kidney disease - no dose adjustment necessary
Open all
Asenapine
Saphris®, Secuado®
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

Schizophrenia (adults)
- Tablet
- Starting: 5 mg twice daily
- Maintenance: 5 - 10 mg twice daily
- Max: 10 mg twice daily
- Increase dose at intervals of 1 week
- Patch
- 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
Bipolar mania (adults)
- Starting: 5 - 10 mg twice daily
- Maintenance: 5 - 10 mg twice daily
- Max: 10 mg twice daily
- When adding to lithium or valproate, use a starting dose of 5 mg twice daily
Bipolar mania (10 - 17 years old)
- Starting: 2.5 mg twice daily
- Maintenance: 2.5 - 10 mg twice daily
- Max: 10 mg twice daily
Kidney disease
- No dose adjustment necessary
Liver disease
- Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
- Severe (Child-Pugh C) - DO NOT USE
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-HT2A) receptor antagonist
FDA-approved indications

Tablet
- Schizophrenia
- Bipolar - acute mania
Patch
- Schizophrenia
Side effects

Adult bipolar mania trials | ||
---|---|---|
Side effect | Asenapine (N=620) |
Placebo (N=329) |
Somnolence | 23% | 5% |
Oral hypoesthesia | 10% | 1% |
EPS | 8% | 4% |
Dizziness | 8% | 4% |
Akathisia | 6% | 2% |
Bipolar disorder | 6% | 5% |
Agitation | 4% | 3% |
Dysgeusia | 4% | <1% |
Fatigue | 4% | 2% |
Increased appetite | 4% | 2% |
Other
|
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE. Asenapine may prolong the QT interval.
- CYP1A2 strong inhibitors - asenapine is a CYP1A2 substrate, and CYP1A2 strong inhibitors may increase its exposure. Depending on clinical response, asenapine dosage reductions may be necessary when combining.
- CYP2D6 substrates and inhibitors - asenapine is a weak CYP2D6 inhibitor that may alter the exposure of CYP2D6 substrates
- Paroxetine (Paxil) - asenapine may increase paroxetine exposure. Reduce paroxetine dose by half when combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - asenapine may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - asenapine can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
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, or olanzapine had a higher incidence of stroke and TIA
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Hyperprolactinemia - asenapine blocks the dopamine D2 receptor, which may cause prolactin levels to rise. In adult and pediatric trials, the incidences of adverse events related to abnormal prolactin levels were 2% or less in asenapine-treated patients. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In schizophrenia trials lasting up to 6 weeks, asenapine caused a slight increase in fasting blood sugars (1 - 4 mg/dl). 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.
- Weight gain - atypical antipsychotics have been associated with weight gain in some patients. In a 52-week trial, asenapine-treated adults had an average weight gain of 2 pounds.
- 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
Open all
Brexpiprazole
Rexulti®
Rexulti®
Dosage forms

Tablet
- 0.25 mg
- 0.5 mg
- 1 mg
- 2 mg
- 3 mg
- 4 mg
Dosing

Schizophrenia (adults)
- Starting:
- Days 1 to 4: 1 mg once daily
- Days 5 to 7: 2 mg once daily
- Days 8 and on: 2 - 4 mg once daily
- Target: 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:
- Days 1 to 4: 0.5 mg once daily
- Days 5 to 7: 1 mg once daily
- Days 8 and on: 2 mg once daily
- Target: 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
Adjunctive treatment for depression (adults)
- Starting: 0.5 - 1 mg once daily
- Target: 2 mg once daily
- Max: 3 mg once daily
- Increase dose at weekly intervals
- May take without regard to food
Agitation due to Alzheimer's dementia (adults)
- Starting:
- Days 1 to 7: 0.5 mg once daily
- Days 8 to 14: 1 mg once daily
- Days 15 and on: 2 mg once daily
- Target dose: 2 mg once daily
- Max: 3 mg once daily (after at least 14 days on 2 mg)
- Do not prescribe for as-needed (prn) use
- May take without regard to food
Liver disease
- Depression and agitation in Alzheimer's dementia
- Child-Pugh B and C: do not exceed 2 mg once daily
- Schizophrenia
- Child-Pugh B and C: do not exceed 3 mg once daily
Kidney disease
- Depression and agitation in Alzheimer's dementia
- CrCl < 60 ml/min: do not exceed 2 mg once daily
- Schizophrenia
- CrCl < 60 ml/min: do not exceed 3 mg once daily
Dosing with CYP2D6 and CYP3A4 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
Efficacy / Studies

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-HT1A receptor partial agonist
- Serotonin 5-HT2A receptor antagonist
FDA-approved indications

- Schizophrenia in adults and pediatric patients ages 13 years and older
- Adjunctive treatment of major depressive disorder (MDD) in adults
- Treatment of agitation associated with dementia due to Alzheimer's disease (not to be used as needed "prn")
Side effects

Adult schizophrenia trials | ||
---|---|---|
Side effect | Rexulti 4 mg/day (N=364) |
Placebo (N=368) |
Akathisia | 7% | 5% |
Weight increase | 4% | 2% |
Tremor | 3% | 1% |
Sedation | 3% | 1% |
Dyspepsia | 3% | 2% |
Diarrhea | 3% | 2% |
Increase in CPK | 2% | 1% |
Other
|
Drug interactions

- CYP3A4 modulators - brexpiprazole is a CYP3A4 sensitive substrate. See Dosing above for recommendations on combining.
- CYP2D6 modulators - brexpiprazole is a CYP2D6 sensitive substrate. See Dosing above for recommendations on combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - brexpiprazole may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
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, or olanzapine had a higher incidence of stroke and TIA
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Suicide thoughts and behaviors - in trials involving antidepressants (SSRIs and others), 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 - See Dosing above
- Kidney disease - See Dosing above
Open all
Cariprazine
Vraylar®
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
Kidney disease
- CrCl ≥ 30 ml/min - no dose adjustment necessary
- CrCl < 30 ml/min - DO NOT USE
Liver disease
- Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
- Severe (Child-Pugh C) - DO NOT USE
Dosing with CYP3A4 inducers
- Vraylar has not been studied with CYP3A4 inducers and concomitant therapy is not recommended
Dosing with CYP3A4 inhibitors
Dosage modifications for the starting dosage of Vraylar in patients taking a strong or moderate CYP3A4 inhibitor | ||
---|---|---|
Vraylar Starting Dosage | ||
Indication | When Taking a Strong CYP3A4 Inhibitor | When Taking a Moderate CYP3A4 Inhibitor |
Schizophrenia or Bipolar Mania | Start at 1.5 mg every 3 days; increase to 1.5 mg every other day, if needed | Start at 1.5 mg every other day; increase to 1.5 mg daily, if needed |
Bipolar Depression or Adjunctive therapy for treatment of MDD | 1.5 mg every 3 days | 1.5 mg every other day |
Dosage modifications when initiating a strong or moderate CYP3A4 inhibitor and while taking a stable dose of Vraylar | ||
---|---|---|
Currently on Vraylar Dosage | Vraylar Dosage When Initiating a Strong CYP3A4 Inhibitor | Vraylar Dosage When Initiating a Moderate CYP3A4 Inhibitor |
1.5 or 3 mg once daily | 1.5 mg every 3 days | 1.5 mg every other day |
4.5 or 6 mg once daily | 1.5 mg every other day | 1.5 mg once daily |
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-HT1A receptors
- Cariprazine is an antagonist at serotonin 5-HT2A 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 4.5-6 mg/day (N=575) |
Placebo (N=584) |
---|---|---|
EPS | 19% | 8% |
Insomnia | 13% | 11% |
Akathisia | 13% | 4% |
Somnolence | 8% | 5% |
Constipation | 7% | 5% |
Nausea | 7% | 5% |
Restlessness | 6% | 3% |
Vomiting | 5% | 3% |
Agitation | 5% | 4% |
Anxiety | 5% | 4% |
Dizziness | 5% | 2% |
Dyspepsia | 5% | 4% |
Diarrhea | 4% | 3% |
Fatigue | 3% | 1% |
Decreased appetite | 3% | 2% |
Hypertension | 3% | 1% |
Other
|
Drug interactions

- CYP3A4 inhibitors and inducers - cariprazine is a CYP3A4 sensitive substrate. See Dosing above for recommendations on combining.
- 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 some time, causing adverse effects to appear 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, or 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
Open all
Clozapine
Clozaril®
Clozaril®
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
- Store at room temperature
Dosing

Schizophrenia
- Starting: 12.5 mg once or twice daily
- Maintenance: 300 - 450 mg/day given in divided doses
- Max: 900 mg/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
- May take without regard to food
- See lab monitoring recommendations
- Providers and pharmacies must be registered in the Clozapine REMS program in order to prescribe or dispense clozapine
Kidney disease
- Exposure is increased. Dose adjustment may be necessary.
Liver disease
- Exposure is increased. Dose adjustment may be necessary.
Dosing with CYP3A4, CYP1A2, and CYP2D6 modulators
Co-medication | Scenarios | ||
---|---|---|---|
Initiating clozapine while taking a co-medication | Adding a co-medication while taking clozapine | Discontinuing a co-medication while continuing clozapine | |
Strong CYP1A2 Inhibitors | Use one-third of the clozapine dose | Increase clozapine dose based on clinical response | |
CYP2D6 inhibitors, CYP3A4 inhibitors, or moderate or weak CYP1A2 Inhibitors | Monitor for adverse reactions. Consider reducing the clozapine dose if necessary. | Monitor for lack of effectiveness. Consider increasing clozapine dose if necessary. | |
Strong CYP3A4 Inducers | Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the clozapine dose. Monitor for decreased effectiveness. | Reduce clozapine dose based on clinical response. | |
Moderate or weak CYP1A2 or CYP3A4 Inducers | Monitor for decreased effectiveness. Consider increasing the clozapine dose if necessary. | Monitor for adverse reactions. Consider reducing the clozapine dose if necessary. |
Generic / Price

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

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

- Dopamine-2 receptor antagonist
- Serotonin 5-HT2A receptor antagonist
FDA-approved indications

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

Side effect | Clozapine (N=479) |
Olanzapine (N=477) |
---|---|---|
Salivary hypersecretion | 48% | 6% |
Somnolence | 46% | 25% |
Weight gain | 31% | 56% |
Dizziness (excluding vertigo) | 27% | 12% |
Constipation | 25% | 10% |
Insomnia | 20% | 33% |
Nausea | 17% | 10% |
Vomiting | 17% | 9% |
Upset stomach | 14% | 8% |
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE. Clozapine may prolong the QT interval.
- Anticholinergic medications - clozapine has potent anticholinergic activity, and it may heighten the effects of other anticholinergic medications. Use caution when combining.
- CYP1A2 modulators - clozapine is a CYP1A2 sensitive substrate. See Dosing above for recommendations on combining.
- CYP2D6 modulators - clozapine is a CYP2D6 sensitive substrate. See Dosing above for recommendations on combining.
- CYP3A4 inhibitors - clozapine is a CYP3A4 sensitive substrate. See Dosing above for recommendations on combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - clozapine may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - clozapine can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
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 and after treatment interruptions. Initiate dosing at 12.5 mg once or twice daily and titrate slowly. Reduce dosage after therapy interruptions, even if they are brief. Use caution in susceptible patients (e.g. heart disease, dehydration, antihypertensives).
- 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, or olanzapine had a higher incidence of stroke and TIA
- Myocarditis, pericarditis, cardiomyopathy, and mitral valve incompetence - Myocarditis, pericarditis, and cardiomyopathy, sometimes fatal, can occur with clozapine use. Discontinue clozapine and obtain a cardiac evaluation if these conditions are suspected. Rechallenge is generally contraindicated in patients with a history of clozapine-associated myocarditis or cardiomyopathy. If deemed necessary, rechallenge may be considered in consultation with a cardiologist. Myocarditis and pericarditis typically manifest within the first 2 months of treatment, while cardiomyopathy usually presents after 8 weeks, though these conditions can arise at any time during therapy. Mitral valve incompetence has been reported in patients diagnosed with cardiomyopathy while taking clozapine.
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, clozapine exposure lasting a median of 42 days 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 exposure lasting a median of 45 days 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 - exposure is increased. Dose adjustment may be necessary.
- Kidney disease - exposure is increased. Dose adjustment may be necessary.
Open all
Iloperidone
Fanapt®
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 (adults)
- Day 1: 1 mg twice daily
- Day 2: 2 mg twice daily
- Day 3: 4 mg twice daily
- Day 4: 6 mg twice daily
- Day 5: 8 mg twice daily
- Day 6: 10 mg twice daily
- Day 7: 12 mg twice daily
- Maintenance: 6 - 12 mg twice daily
- Orthostatic hypotension may occur if dose is increased too fast
- May take without regard to food
- Missed doses: If ≥ 3 days have elapsed since last dose, reinitiate at 1 mg twice daily and titrate
Bipolar I manic or mixed episode (adults)
- Day 1: 1 mg twice daily
- Day 2: 3 mg twice daily
- Day 3: 6 mg twice daily
- Day 4: 9 mg twice daily
- Day 5 and on: 12 mg twice daily
- Orthostatic hypotension may occur if dose is increased too fast
- May take without regard to food
- Missed doses: If ≥ 3 days have elapsed since last dose, reinitiate at 1 mg twice daily and titrate
Kidney disease
- No dose adjustment necessary
Liver disease
- Child-Pugh A: no dose adjustment necesssary
- Child-Pugh B: dose reduction may be necessary
- Child-Pugh C: not recommended
Dosing with strong inhibitors of CYP2D6 or CYP3A4
- Reduce dose by one-half
Poor CYP2D6 metabolizers
- Schizophrenia
- Day 1: 1 mg twice daily
- Day 2: 2 mg twice daily
- Day 3: 4 mg twice daily
- Day 4: 6 mg twice daily
- Maintenance: 3 - 6 mg twice daily
- Bipolar I manic or mixed episode
- Day 1: 1 mg twice daily
- Day 2: 3 mg twice daily
- Day 3 and on: 6 mg twice daily
Generic / Price

- NO/$$$$
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

- The mechanism of action of iloperidone in schizophrenia and bipolar I disorder is unknown. However, the efficacy of iloperidone could be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism. Iloperidone forms an active metabolite, P88, that has an in vitro receptor binding profile similar to the parent drug.
FDA-approved indications

- Schizophrenia in adults
- Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults
Side effects

Adult schizophrenia trials | ||
---|---|---|
Side effect | Fanapt 20-24 mg/day (N=391) |
Placebo (N=587) |
Dizziness | 20% | 7% |
Weight gain | 18% | 4% |
Somnolence | 15% | 5% |
EPS | 15% | 11% |
Tachycardia | 12% | 1% |
Nausea | 10% | 8% |
Weight gain | 9% | 1% |
Dry mouth | 10% | 1% |
Nasal congestion | 8% | 2% |
Diarrhea | 7% | 4% |
Fatigue | 6% | 3% |
Orthostatic hypotension | 5% | 1% |
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE. Iloperidone may prolong the QT interval.
- CYP2D6 strong inhibitors - iloperidone is a CYP2D6 sensitive substrate and CYP2D6 strong inhibitors increase its exposure. Reduce iloperidone dose by one-half when combining.
- CYP3A4 strong inhibitors - iloperidone is a CYP3A4 sensitive substrate and CYP3A4 strong inhibitors increase its exposure. Reduce iloperidone dose by one-half when combining.
- CYP3A4 substrates - in vitro studies have shown that iloperidone is a CYP3A4 inhibitor and may increase the exposure of CYP3A4 substrates
- Alpha blockers - iloperidone can block alpha receptors, possibly potentiating the effects of alpha blockers. Coadministration is not recommended.
- Antihypertensives - iloperidone may potentiate the effects of antihypertensives and increase the risk of hypotension. Use caution when combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - iloperidone may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
Contraindications / Precautions

- Prolonged QT syndrome - DO NOT USE. Iloperidone may prolong the QT interval.
- Hyperprolactinemia - dopamine antagonists like iloperidone can raise prolactin levels. In 4-week schizophrenia and bipolar trials, plasma prolactin levels in iloperidone-treated patients increased by 2.6 ng/ml and 15.66 ng/ml, respectively, while levels greater than 1.15 X the ULN were observed in 26% and 35%. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Priapism - iloperidone has alpha-adrenergic blocking activity, which can cause priapism. In pre-marketing studies, 4 cases of priapism were reported. Patients should seek emergency care for erections lasting more than 4 hours.
- Intraoperative floppy iris syndrome (IFIS) - iloperidone has alpha-1 adrenergic blocking activity, which can cause IFIS, a condition that can complicate eye surgery. Stopping alpha-1 blockers prior to surgery does not appear to be beneficial. Patients requiring eye surgery should ensure their surgeon is aware they are taking iloperidone.
- Poor CYP2D6 metabolizers - see Dosing
- 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, or olanzapine had a higher incidence of stroke and TIA
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Diabetes - atypical antipsychotics have been associated with increased diabetes risk in some patients. In long-term trials, the effects of iloperidone on fasting blood sugars were mixed. See diabetes below for ADA monitoring recommendations.
- Cholesterol - atypical antipsychotics have been associated with serum lipid increases in some patients. In long-term trials, total cholesterol and triglyceride levels decreased in iloperidone-treated patients. See cholesterol below for ADA monitoring recommendations.
- Weight gain - atypical antipsychotics have been associated with weight gain in some patients. In schizophrenia trials lasting up to 6 weeks, weight gain > 7% from baseline occurred in 12% (10 - 16 mg/day) and 18% (20 - 24 mg/day) of iloperidone-treated patients compared to 4% of placebo-treated patients. In a 4-week bipolar trial, weight gain > 7% from baseline occurred in 35% (24 mg/day) of iloperidone-treated patients compared to 14% of placebo-treated 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).
- 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. In studies, orthostatic hypotension and syncope were reported in up to 5% and 0.5% of iloperidone-treated patients, respectively. Follow dosage titration recommendations and 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
- Child-Pugh A: no dose adjustment necesssary
- Child-Pugh B: dose reduction may be necessary
- Child-Pugh C: not recommended
- Kidney disease - No dose adjustment necessary
Open all
Lumateperone
Caplyta®
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
Dosing with CYP3A4 inhibitors
- Strong inhibitors
- Dosing: 10.5 mg once daily
- Moderate inhibitors
- Dosing: 21 mg once daily
- See CYP3A4 inhibitors
Kidney disease
- No dose adjustment recommended by manufacturer
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-HT2A 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

Adult schizophrenia trials | ||
---|---|---|
Side effect | Caplyta (N=406) |
Placebo (N=412) |
Somnolence / Sedation | 24% | 10% |
Nausea | 9% | 5% |
EPS | 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 (SSRIs and others), 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, or 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
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B or C: 21 mg once daily
- Kidney disease - no dose adjustment recommended by manufacturer
Open all
Lurasidone
Latuda®
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/day
- Max: 160 mg/day
- Take with food (at least 350 calories). Food increases absorption.
Schizophrenia (13 - 17 years old)
- Starting: 40 mg once daily
- Maintenance: 40 - 80 mg/day
- Max: 80 mg/day
- Take with food (at least 350 calories). Food increases absorption.
Bipolar I depression (adults)
- Starting: 20 mg once daily
- Maintenance: 20 - 120 mg/day
- Max: 120 mg/day
- In a monotherapy study, doses of 80 mg to 120 mg/day did not provide additional efficacy compared to 20 to 60 mg/day
- Take with food (at least 350 calories). Food increases absorption.
Bipolar I depression (10 - 17 years old)
- Starting: 20 mg once daily
- Maintenance: 20 - 80 mg/day
- Max: 80 mg/day
- Increase dose after one week based on response
- Take with food (at least 350 calories). Food increases absorption.
Kidney disease
- CrCl < 50 ml/min: starting dose is 20 mg once daily. Do not exceed 80 mg/day.
Liver disease
- Child-Pugh B: starting dose is 20 mg once daily. Do not exceed 80 mg/day.
- Child-Pugh C: starting dose is 20 mg once daily. Do not exceed 40 mg/day.
Dosing with CYP3A4 modulators
- CYP3A4 inhibitors
- Strong CYP3A4 inhibitors: DO NOT COMBINE
- Moderate CYP3A4 inhibitors:
- If a moderate CYP3A4 inhibitor is added to lurasidone therapy, reduce the lurasidone dose by one-half
- If lurasidone is added to a moderate CYP3A4 inhibitor, starting dose should be 20 mg once daily, and the maximum dose is 80 mg/day
- Strong CYP3A4 inducers: DO NOT COMBINE
- Moderate CYP3A4 inducers: it may be necessary to increase the lurasidone dose after 7 or more days of therapy
- See CYP3A4 modulators
Generic / Price

- YES/$
Pharmacokinetics

- Half-life: 18 hours
Mechanism of action

- Dopamine-2 receptor antagonist
- Serotonin type 2 (5-HT2A) receptor antagonist
FDA-approved indications

- Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia
- Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression)
- Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression)
Side effects

Adult bipolar studies | ||
---|---|---|
Side effect | Lurasidone 80-120 mg/day (N=167) |
Placebo (N=168) |
Nausea | 17% | 8% |
Somnolence | 14% | 7% |
Akathisia | 11% | 2% |
EPS | 9% | 2% |
Vomiting | 6% | 2% |
Anxiety | 5% | 1% |
Nasopharyngitis | 4% | 1% |
Other
|
Drug interactions

- CYP3A4 modulators - lurasidone is a CYP3A4 sensitive substrate, and CYP3A4 modulators affect its exposure. See Dosing above for recommendations on combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - lurasidone may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - lurasidone can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
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, or olanzapine had a higher incidence of stroke and TIA
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Hyperprolactinemia - dopamine antagonists like lurasidone can raise prolactin levels. In short-term adult trials, median plasma prolactin levels increased by 0.4 ng/ml in lurasidone-treated patients and decreased by 1.9 ng/ml in placebo-treated patients. Prolactin levels ≥ 5 X ULN occurred in 2.8% and 1%, respectively. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Suicide in depression - in trials involving antidepressants (SSRIs and others), 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.
- 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.
- Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients (e.g. dementia, cognitive impairment).
- Parkinson's disease or Lewy body dementia - patients with Parkinson's disease or Lewy body dementia may be sensitive to the effects of antipsychotics, increasing the risk of side effects, including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome.
- Liver disease
- Child-Pugh B: starting dose is 20 mg once daily. Do not exceed 80 mg/day.
- Child-Pugh C: starting dose is 20 mg once daily. Do not exceed 40 mg/day.
- Kidney disease
- CrCl < 50 ml/min: starting dose is 20 mg once daily. Do not exceed 80 mg/day.
Open all
Olanzapine
Zyprexa®
Zyprexa®
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
Kidney disease
- No dose adjustment necessary
Liver disease
- Child-Pugh A or B: no dose adjustment necessary
- Child-Pugh C: - use caution
Efficacy / Studies

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 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds with low affinity to GABAA, 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

Adult trials | ||
---|---|---|
Side effect | Olanzapine (N=532) |
Placebo (N=294) |
Somnolence | 29% | 13% |
Insomnia | 12% | 11% |
Accidental injury | 12% | 8% |
Dizziness | 11% | 4% |
Asthenia | 10% | 9% |
Dry mouth | 9% | 5% |
Constipation | 9% | 4% |
Dyspepsia | 7% | 5% |
Rhinitis | 7% | 6% |
Cough increased | 6% | 3% |
Fever | 6% | 2% |
Abnormal gait | 6% | 1% |
Back pain | 5% | 2% |
Weight gain | 5% | 3% |
Ecchymosis | 5% | 3% |
Extremity pain (other than joint) | 5% | 3% |
Joint pain | 5% | 3% |
Tremor | 4% | 3% |
Vomiting | 4% | 3% |
Pharyngitis | 4% | 3% |
Amblyopia | 3% | 2% |
Chest pain | 3% | 1% |
Postural hypotension | 3% | 1% |
Tachycardia | 3% | 1% |
Increased appetite | 3% | 2% |
Peripheral edema | 3% | 1% |
Akathisia | 3% | 2% |
Hypertonia | 3% | 2% |
Hypertension | 2% | 1% |
Articulation impairment | 2% | 1% |
Drug interactions

- CYP1A2 strong inhibitors - olanzapine is a CYP1A2 sensitive substrate, and CYP1A2 strong inhibitors increase its exposure. Consider decreasing the olanzapine dose when combining.
- CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate, and CYP1A2 strong inducers may decrease its exposure. Consider increasing the olanzapine dose when combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - olanzapine may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - olanzapine can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
- Antihypertensive medications - olanzapine may potentiate 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 effects of other anticholinergic medications. Use caution when combining.
- CNS depressants - CNS depressants, including diazepam and alcohol, may increase 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, or 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 - In premarketing trials, seizures were reported in 0.9% (22/2500) of olanzapine-treated patients, though confounding factors were present in many cases. Exercise caution when using olanzapine in patients with a history of seizures or conditions that lower the seizure threshold, such as Alzheimer's disease.
- 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. 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. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- 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
Open all
Olanzapine + samidorphan
Lybalvi®
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
Kidney disease
- CrCl ≥ 15 ml/min: no dose adjustment necessary
- CrCl < 15 ml/min: not recommended
Liver disease
- Mild to moderate (Child-Pugh A or B): no dose adjustment necessary
- Severe (Child-Pugh C): has not been studied
Efficacy / Studies

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 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds with low affinity to GABAA, 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

4-week schizophrenia trial | ||
---|---|---|
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% |
|
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, and CYP1A2 strong inhibitors may increase its exposure. Consider decreasing olanzapine dose when combining.
- CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate, and CYP1A2 strong inducers may decrease its exposure. Consider increasing olanzapine dose 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 effects of dopamine agonists used in Parkinson's disease, RLS, and others
- Alpha blockers - olanzapine can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
- Antihypertensive medications - olanzapine may potentiate 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 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
Lab interactions

- Opioid immunoassays - samidorphan, an opioid antagonist, can cause false-positive opioid results on urine immunoassays. Positive results should be confirmed with another method (e.g., gas or liquid chromatography).
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, or 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 - 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. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- 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
Open all
Paliperidone
Invega®
Invega®
Dosage forms

Extended-release tablet (Invega®)
- 1.5 mg
- 3 mg
- 6 mg
- 9 mg
IM injection (Invega Sustenna®)
- 39 mg/0.25 ml
- 78 mg/0.50 ml
- 117 mg/0.75 ml
- 156 mg/1 ml
- 234 mg/1.5 ml
- Comes in prefilled syringe
IM injection (Invega Trinza®)
- 273 mg/0.88 ml
- 410 mg/1.32 ml
- 546 mg/1.75 ml
- 819 mg/2.63 ml
- Comes in prefilled syringe
IM injection (Invega Hafyera®)
- 1092 mg/3.5 ml
- 1560 mg/5 ml
- Comes in prefilled syringe
IM injection (Erzofri®)
- 39 mg/0.25 ml
- 78 mg/0.50 ml
- 117 mg/0.75 ml
- 156 mg/1 ml
- 234 mg/1.5 ml
- 351 mg/2.25 ml
- Comes in prefilled syringe
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
Liver disease
- Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
- Severe (Child-Pugh C): has not been studied
Dosing - IM forms

Invega Sustenna (schizophrenia and schizoaffective disorder in 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
- See Invega Sustenna PI for complete prescribing information
Invega Trinza (schizophrenia in 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
- See Invega Trinza PI for complete prescribing information
Monthly Invega Sustenna dose | Starting Invega Trinza dose |
---|---|
78 mg | 273 mg |
117 mg | 410 mg |
156 mg | 546 mg |
234 mg | 819 mg |
Invega Hafyera (schizophrenia in 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
- See Invega Hafyera PI for complete prescribing information
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 |
Erzofri (schizophrenia and schizoaffective disorder in adults)
- Establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment
- Schizophrenia: 351 mg IM in the deltoid muscle on Day 1, then 39 - 234 mg IM monthly in the deltoid or gluteal muscle starting 4 weeks after the first injection. The maximum monthly dosage is 234 mg.
- Schizoaffective disorder: 351 mg IM in the deltoid muscle on Day 1, then 78 - 234 mg IM monthly in the deltoid or gluteal muscle starting 4 weeks after the first injection. The maximum monthly dosage is 234 mg.
- Patients may be given the injection up to 7 days before or after the monthly time point
- See Erzofri PI for complete prescribing information
Generic / Price

- Invega tablet: YES/$-$$
- Invega Sustenna: NO/$$$$
- Invega Trinza: NO/$$$$
- Invega Hafyera: NO/$$$$
- Erzofri: NO/$$$$
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
Erzofri®
- Half-life: 27 days
Mechanism of action

- Dopamine-2 receptor antagonist
- Serotonin type 2 (5-HT2A) 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
Erzofri
- Schizophrenia in adults
- Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants
Side effects

Adult schizophrenia trials | ||
---|---|---|
Side effect | Paliperidone 12 mg (N=242) |
Placebo (N=355) |
EPS | 18% | 8% |
Tachycardia | 14% | 7% |
Headache | 14% | 12% |
Somnolence | 11% | 7% |
Akithisia | 10% | 4% |
Dizziness | 5% | 4% |
Orthostatic hypotension | 4% | 1% |
Salivary hypersecretion | 4% | <1% |
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 effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - paliperidone can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution 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.
- Hyperprolactinemia - dopamine antagonists like paliperidone can raise prolactin levels. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Priapism - priapism, which may be caused by paliperidone's alpha-adrenergic blocking activity, has been reported in postmarketing surveillance. Patients should seek emergency care for erections lasting more than 4 hours.
- 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, or 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 sensitive to the effects of antipsychotics, increasing the risk of side effects, including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome.
- 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
Open all
Quetiapine
Seroquel®, Seroquel XR®
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
- May take without regard to food
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
- May take without regard to food
Bipolar mania (adults)
- Starting: 100 mg/day
- Maintenance: 400 - 800 mg/day
- Max: 800 mg/day
- Give 2 divided doses
- May take without regard to food
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
- May take without regard to food
Kidney disease
- No dose adjustment necessary
Liver disease
- Clearance is decreased. Start with 25 mg/day and increase in daily increments of 25 - 50 mg/day.
Dosing with CYP3A4 modulators
- Strong CYP3A4 inhibitors
- Reduce quetiapine dose to one-sixth of original dose. If CYP3A4 strong inhibitor is discontinued, increase quetiapine dose 6-fold.
- Strong CYP3A4 inducers
- Increase quetiapine dose up to 5-fold of the original dose when combining with a strong CYP3A4 inducer for more than 7 - 14 days. If CYP3A4 strong inducer is discontinued, reduce quetiapine dose to the original dose over 7 - 14 days.
- See CYP3A4 inducers and inhibitors
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
- Do not crush, chew, or divide tablet
- Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
Schizophrenia (13 - 17 years old)
- Starting: 50 mg once daily
- Maintenance: 400 - 800 mg once daily
- Max: 800 mg once daily
- Do not crush, chew, or divide tablet
- Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
Bipolar mania (adults)
- Starting: 300 mg once daily
- Maintenance: 400 - 800 mg once daily
- Max: 800 mg once daily
- Do not crush, chew, or divide tablet
- Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
Bipolar mania (10 - 17 years old)
- Starting: 50 mg once daily
- Maintenance: 400 - 600 mg once daily
- Max: 600 mg once daily
- Do not crush, chew, or divide tablet
- Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
Kidney disease
- No dose adjustment necessary
Liver disease
- Clearance is decreased. Start with 50 mg/day and increase in daily increments of 50 mg/day.
Dosing with CYP3A4 modulators
- Strong CYP3A4 inhibitors
- Reduce quetiapine dose to one-sixth of the original dose. If CYP3A4 strong inhibitor is discontinued, increase quetiapine dose 6-fold.
- Strong CYP3A4 inducers
- Increase quetiapine dose up to 5-fold of the original dose when combining with a strong CYP3A4 inducer for more than 7 - 14 days. If CYP3A4 strong inducer is discontinued, reduce quetiapine dose to the original dose over 7 - 14 days.
- See CYP3A4 inducers and inhibitors
Efficacy / Studies

Treatment-resistant depression
Generic / Price

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

Adult bipolar trials | ||
---|---|---|
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% |
Orthostatic hypotension | 4% | 3% |
Akathisia | 4% | 1% |
Palpitations | 4% | 1% |
Blurred vision | 4% | 2% |
Weight increase | 4% | 1% |
Other
|
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE
- CYP3A4 strong inhibitors and inducers - see Dosing above
- Medications with anticholinergic activity - norquetiapine, an active metabolite of quetiapine, has moderate to strong anticholinergic activity and may potentiate the anticholinergic effect of other medications.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - quetiapine may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - quetiapine can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
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, or olanzapine had a higher incidence of stroke and TIA
- Hyperprolactinemia - dopamine antagonists like quetiapine can raise prolactin levels. In adult trials, clinically significant prolactin elevations occurred in 3.6% of quetiapine-treated patients and 2.6% of placebo-treated patients. In pediatric trials, the incidences were 13.4% and 4% in males and 8.7% and 0% in females, respectively. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Hypothyroidism (low thyroid) - in adult trials, total and free T4 levels were reduced by 20% in patients treated with quetiapine at the higher end of dosing. The peak effect occurred within 6 weeks of initiation and was maintained thereafter. Levels returned to normal upon discontinuation in almost all cases. In all quetiapine trials, increases in TSH levels > 5 mIU/L occurred in 5% of quetiapine-treated patients. Measure TSH and free T4 levels before and during therapy and provide replacement therapy when necessary.
- Suicide in depression - in trials involving antidepressants (SSRIs and others), 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.
- 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 lasting 3 - 6 weeks, the incidence of increases in systolic blood pressure ≥ 20 mmHg was 15.2% for quetiapine-treated patients and 5.5% for placebo-treated patients. The incidence of increases 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
Open all
Risperidone
Risperdal®, Rykindo®, Risvan®, Perseris®, Uzedy®
Risperdal®, Rykindo®, Risvan®, Perseris®, Uzedy®
Dosage forms

Tablet (Risperdal®)
- 0.25 mg
- 0.5 mg
- 1 mg
- 2 mg
- 3 mg
- 4 mg
ODT (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
- Store at room temperature
IM injection (Risperdal Consta®)
- 12.5 mg
- 25 mg
- 37.5 mg
- 50 mg
- Kit with vial and prefilled syringe
- Given intramuscularly
IM injection (Rykindo®)
- 12.5 mg
- 25 mg
- 37.5 mg
- 50 mg
- Kit with vial and prefilled syringe
- Given intramuscularly
IM injection (Risvan®)
- 75 mg
- 100 mg
- Kit with vial and prefilled syringe
- Given intramuscularly
SC injection (Perseris®)
- 90 mg
- 120 mg
- Comes in 2 syringes that are mixed
- Given subcutaneously
SC injection (Uzedy®)
- 50 mg/0.14 ml
- 75 mg/0.21 ml
- 100 mg/0.28 ml
- 125 mg/0.35 ml
- 150 mg/0.42 ml
- 200 mg/0.56 ml
- 250 mg/0.7 ml
- Given subcutaneously
- Comes in prefilled syringe
Dosing - Oral forms

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
- May take without regard to food
Schizophrenia (13 - 17 years old)
- 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
- May take without regard to food
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
- May take without regard to food
Bipolar mania (10 - 17 years old)
- 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
- May take without regard to food
Irritability in autistic disorder (5 - 17 years old)
- Weight < 20 kg (44 lbs)
- 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 (44 lbs)
- 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
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.
Liver disease
- 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.
Dosing - IM forms

Risperdal Consta® (schizophrenia and bipolar I in adults)
- Starting: 25 mg IM every 2 weeks
- Maintenance: 25 - 50 mg IM every 2 weeks
- Max: 50 mg IM every 2 weeks
- Oral risperidone should be continued for 3 weeks after initial injection, then discontinued
- Increase dose at intervals of no less than 4 weeks
- Administer in the gluteal or deltoid muscle by a healthcare provider
- See Risperdal Consta PI for complete prescribing information
Rykindo® (schizophrenia and bipolar I in adults)
- Starting: 25 mg IM every 2 weeks
- Maintenance: 25 - 50 mg IM every 2 weeks
- Max: 50 mg IM every 2 weeks
- Administer the first dose along with 7 days of oral risperidone
- Increase dose at intervals of no less than 4 weeks
- Administer in the gluteal muscle by a healthcare provider
- See Rykindo PI for complete prescribing information
Risvan® (schizophrenia in adults)
- Initiate Risvan at a dose of 75 mg or 100 mg once monthly by deltoid or gluteal intramuscular injection. Do not administer more than one dose (75 mg or 100 mg total) per month.
- For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating Risvan.
- For patients switching from oral risperidone:
- 3 mg of oral risperidone per day, administer a 75 mg Risvan dose one day after the last oral risperidone dose
- 4 mg of oral risperidone per day, administer a 100 mg Risvan dose one day after the last oral risperidone dose
- Patients who are on stable oral risperidone doses lower than 3 mg per day or higher than 4 mg per day may not be candidates for Risvan
- Neither a loading dose nor supplemental oral risperidone is recommended. Administer subsequent Risvan doses once monthly as a deltoid or gluteal intramuscular injection.
- When a dose of Risvan is missed, administer the next Risvan dose as soon as possible. Do not administer more than one Risvan dose per month.
- See Risvan PI for complete prescribing information
Dosing - SC forms

Perseris® (schizophrenia in adults)
- Dosing: 90 - 120 mg by subcutaneous injection once monthly
- Patients should have established tolerability to oral risperidone
- 90 mg of Perseris corresponds to 3 mg/day of oral risperidone, and 120 mg corresponds to 4 mg/day of oral risperidone
- Administer subcutaneously in the abdomen or back of the upper arm by a healthcare provider
- See Perseris PI for complete prescribing information
Uzedy® (schizophrenia in adults)
- Dosing provided in the table below
- Administer subcutaneously in the abdomen or upper arm by a healthcare provider
- Patients should have established tolerability to oral risperidone
- Uzedy may be given once monthly or once every 2 months
- See Uzedy PI for complete prescribing information
Prior oral risperidone therapy | Uzedy once monthly dose | Uzedy every 2 months dose |
---|---|---|
2 mg per day | 50 mg | 100 mg |
3 mg per day | 75 mg | 150 mg |
4 mg per day | 100 mg | 200 mg |
5 mg per day | 125 mg | 250 mg |
Generic / Price

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

- The mechanism of action of risperidone in schizophrenia is unclear. The drug's therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone (paliperidone). Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of risperidone.
FDA-approved indications

Risperdal (oral)
- Schizophrenia (adults and adolescents aged 13 - 17)
- Bipolar mania as monotherapy and adjunctive therapy (adults and adolescents aged 10 - 17)
- Irritability associated with autistic disorder (children and adolescents aged 5 to 17)
Risperdal Consta and Rykindo
- Schizophrenia (adults)
- Bipolar mania as monotherapy and adjunctive therapy (adults)
Perseris, Uzedy, and Risvan
- Schizophrenia (adults)
Side effects

Adult schizophrenia trials | ||
---|---|---|
Side effect | Risperidone 2-8 mg/day (N=366) |
Placebo (N=225) |
Insomnia | 32% | 27% |
Anxiety | 16% | 11% |
Parkinsonism | 14% | 8% |
Akathisia | 10% | 3% |
Sedation | 10% | 2% |
Nausea | 9% | 4% |
Constipation | 8% | 6% |
Dyspepsia | 8% | 5% |
Dizziness | 7% | 2% |
Dry mouth | 4% | 1% |
Back pain | 4% | 1% |
Nasal congestion | 4% | 2% |
Other
|
Drug interactions

- Alpha blockers - risperidone can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
- 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 its exposure. 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 its exposure. 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 block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Drugs with hypotensive effects - risperidone may potentiate the hypotensive effects of other drugs that can lower blood pressure. 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 its exposure. 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

- Hyperprolactinemia - dopamine antagonists like risperidone can raise prolactin levels. In adolescent trials, up to 87% of risperidone-treated patients had elevated prolactin levels. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- 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, or olanzapine had a higher incidence of stroke and TIA
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- Weight gain - atypical antipsychotics may cause weight gain in some patients. In 3- to 8-week adult trials, risperidone-treated patients (8-16 mg/day) gained an average of 4.84 pounds, and 21% had a ≥ 7% increase in body weight from baseline.
- 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.
- Priapism - priapism, which may be caused by risperidone's alpha-adrenergic blocking activity, has been reported in postmarketing surveillance. Patients should seek emergency care for erections lasting more than 4 hours.
- 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 sensitive to the effects of antipsychotics, increasing the risk of side effects, including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome.
- 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.
- 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.
Open all
Ziprasidone
Geodon®
Geodon®
Dosage forms

Capsule
- 20 mg
- 40 mg
- 60 mg
- 80 mg
Dosing

Schizophrenia (adults)
- Starting: 20 mg twice daily
- Maintenance: 20 - 80 mg twice daily
- Max: 80 mg twice daily
- Increase dose at intervals of ≥ 2 days
- Take with food. Food increases absorption. Do not open or crush capsules.
Bipolar I (adults)
- Starting: 40 mg twice daily
- Maintenance: 40 - 80 mg twice daily
- Max: 80 mg twice daily
- Take with food. Food increases absorption. Do not open or crush capsules.
Kidney disease
- No dose adjustment necessary
Liver disease
- Exposure is increased. Use caution. In a study of patients with Child-Pugh B, AUC increased by 34% compared to control.
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 in adults
- Bipolar I disorder in adults - acute mixed or manic episodes and maintenance treatment as an adjunct to lithium or valproate
Side effects

Adult schizophrenia trials | ||
---|---|---|
Side effect | Ziprasidone (N=702) |
Placebo (N=273) |
Somnolence | 14% | 7% |
EPS | 14% | 8% |
Nausea | 10% | 7% |
Constipation | 9% | 8% |
Akathisia | 8% | 7% |
Dizziness | 8% | 6% |
Dyspepsia | 8% | 7% |
Respiratory tract infection | 8% | 3% |
Asthenia | 5% | 3% |
Diarrhea | 5% | 4% |
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE. Ziprasidone can prolong the QT interval.
- Monoamine oxidase (MAO) inhibitors - DO NOT COMBINE. Concomitant use increases the risk of serotonin syndrome. MAO inhibitors and ziprasidone should not be taken within 14 days of each other. Examples of MAO inhibitors include selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue.
- CYP3A4 strong inhibitors and inducers - ziprasidone is a CYP3A4 substrate, and strong CYP3A4 inhibitors and inducers may affect its exposure. Consider dose adjustments when combining.
- Dopamine agonists (Mirapex®, Sinemet®, etc.) - ziprasidone may block the effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Alpha blockers - ziprasidone can block alpha receptors, possibly potentiating the effects of alpha blockers. Use caution when combining.
- Serotonergic drugs - ziprasidone has serotonergic activity and may increase the risk of serotonin syndrome when coadministered with other serotonergic drugs (e.g., SSRIs, SNRIs, lithium, buspirone)
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.
- Serotonin syndrome - ziprasidone can precipitate serotonin syndrome, a rare but potentially fatal condition. Symptoms of serotonin syndrome include agitation, confusion, tachycardia, labile blood pressure, flushing, sweating, fever, tremor, rigidity, seizures, and diarrhea. The risk is increased when ziprasidone is coadministered with other serotonergic agents (e.g., SSRIs, SNRIs, lithium, buspirone).
- Rash - in trials, about 5% of ziprasidone-treated patients developed a dose-related rash and/or urticaria. Several patients also had concomitant systemic symptoms (e.g., elevated WBCs). Most cases improved with antihistamines, steroids, and/or ziprasidone discontinuation. If a rash develops for which there is no alternative etiology, ziprasidone should be discontinued.
- Weight gain - atypical antipsychotics can cause weight gain in some patients. In adult trials lasting up to 6 weeks, 4.4% of ziprasidone-treated patients (60 - 80 mg BID) had a ≥ 7% weight increase from baseline compared to 1.8% of placebo-treated patients.
- Hyperprolactinemia - dopamine antagonists like ziprasidone can raise prolactin levels. Monitor for signs of hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea) and consider dose reductions or discontinuation if necessary. Hyperprolactinemia can suppress hypothalamic gonadotropin-releasing hormone, reducing pituitary gonadotropin secretion and potentially impairing gonadal steroidogenesis in both males and females, leading to reproductive dysfunction. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia with hypogonadism may decrease bone density in both sexes. Approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor to consider if prescribing these drugs to patients with previously detected breast cancer. Increased pituitary, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) were observed in animal studies. Epidemiologic studies on the association between hyperprolactinemia and breast cancer have yielded inconsistent results.
- Priapism - ziprasidone has alpha-adrenergic blocking activity, which can cause priapism. In pre-marketing studies, one case of priapism was reported. Patients should seek emergency care for erections lasting more than 4 hours.
- 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, or 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.
- 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 ziprasidone and seek immediate medical care.
- Liver disease - exposure is increased. Use caution. In a study of patients with Child-Pugh B, AUC increased by 34% compared to control.
- Kidney disease - no dose adjustment necessary
Open all
Chlorpromazine
Thorazine®
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
Kidney disease
- Exposure may be increased. Use caution.
Liver disease
- Exposure may be increased. Use caution.
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

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 effects of dopamine agonists used in Parkinson's disease, RLS, and others.
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. Use caution.
- Kidney disease - exposure may be increased. Use caution.
Open all
Haloperidol
Haldol®
Haldol®
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
Kidney disease
- Has not been studied. Use caution.
Liver disease
- Has not been studied. Haloperidol is primarily metabolized by the liver, so exposure may be increased. Use caution.
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 / Studies

Generic / Price

- YES/$ (all forms)
Mechanism of action

- Dopamine receptor antagonist
FDA-approved indications

- Psychotic disorders
- Tourette's syndrome - control of tics
Side effects

Incidence of side effects is not well defined
- Extrapyramidal symptoms - common
- Sedation - common
- Weight gain
- Hyperprolactinemia (elevated prolactin level)
- Priapism (erection lasting longer than 4 hours) - rare
Drug interactions

- Drugs that prolong the QT interval - DO NOT COMBINE. Cases of QT porlongation have been reported with haloperidol.
- CYP3A4 inducers and inhibitors - haloperidol is a CYP3A4 substrate, and CYP3A4 inducers and inhibitors may alter its exposure
- CYP2D6 inducers and inhibitors - haloperidol is a CYP2D6 substrate, and CYP2D6 inducers and inhibitors may alter its exposure
- CYP2D6 substrates - haloperidol is a CYP2D6 inhibitor and substrate, and it may affect the exposure of 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 effects of dopamine agonists used in Parkinson's disease, RLS, and others.
- Epinephrine - haloperidol may block the vasopressor effects of epinephrine, and an alternative vasopressor should be used
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, as haloperidol may prolong the QT interval and increase the risk of arrhythmias
- Cerebrovascular disease - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, or olanzapine had a higher incidence of stroke and TIA
- 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 - has not been studied. Haloperidol is primarily metabolized by the liver, so exposure may be increased. Use caution.
- Kidney disease - has not been studied. Use caution.
Open all
Prochlorperazine
Compazine®
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
Kidney disease
- Exposure may be increased. Use caution
Liver disease
- Exposure may be increased. Use caution
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

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 effects of dopamine agonists used in Parkinson's disease, RLS, and others.
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 placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, or olanzapine had a higher incidence of stroke and TIA
- 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. Use caution.
- Kidney disease - exposure may be increased. Use caution.
Open all
Xanomeline + trospium chloride
Cobenfy®
Cobenfy®
Dosage forms

Capsule
- Xanomeline / Trospium chloride
- 50 mg/20 mg
- 100 mg/20 mg
- 125 mg/30 mg
- Starter pak: 50 mg/20 mg X 4, 100 mg/20 mg X 52
Dosing

Schizophrenia (adults)
- The recommended starting dosage is one 50/20 mg capsule orally twice daily for at least two days
- Increase the dosage to one 100/20 mg capsule orally twice daily for at least five days
- The dosage may be increased to one 125/30 mg capsule orally twice daily based on patient tolerability and response
- The maximum recommended dose is 125/30 mg orally twice daily
- Take at least one hour before a meal or at least two hours after a meal. Trospium absorption is greatly reduced (up to 90%) when taken with food. Do not open the capsules.
- Geriatric patients: The recommended starting dose is 50/20 mg twice daily. Consider a slower titration. The maximum recommended dose is 100/20 mg twice daily.
- Before therapy: Check liver enzymes and bilirubin. Assess heart rate.
Kidney disease dosing
- eGFR ≥ 60 ml/min: No dose adjustment necessary
- eGFR < 60 ml/min: Use is not recommended
Liver disease dosing
- Child-Pugh A: Use is not recommended
- Child-Pugh B or C: Do not use. Contraindicated.
Lab monitoring

- Check liver enzymes and bilirubin prior to initiating therapy and as clinically indicated during treatment
Efficacy / Studies

Generic / Price

- NO/$$$$
Mechanism of action

- The mechanism of action of xanomeline in the treatment of schizophrenia is unclear; however, its efficacy is thought to be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system.
- Trospium chloride is a muscarinic antagonist. Trospium chloride antagonizes the muscarinic receptors primarily in the peripheral tissues.
FDA-approved indications

- Schizophrenia in adults
Side effects

Side effects in two 5-week schizophrenia trials | ||
---|---|---|
Side effect | Cobenfy (N=251) |
Placebo (N=253) |
Nausea | 19% | 4% |
Dyspepsia | 18% | 5% |
Constipation | 17% | 7% |
Vomiting | 15% | 1% |
Hypertension | 11% | 2% |
Abdominal Pain | 8% | 4% |
Diarrhea | 6% | 2% |
Tachycardia | 5% | 2% |
Dizziness | 5% | 2% |
Gastroesophageal reflux disease | 5% | <1% |
Dry mouth | 4% | 2% |
Somnolence | 3% | 2% |
Vision blurred | 3% | 0% |
Salivary hypersecretion | 2% | 0% |
Orthostatic hypotension | 2% | 1% |
Cough | 2% | 1% |
Extrapyramidal symptoms (EPS), non-akathisia | 2% | <1% |
Drug interactions

- Strong CYP2D6 inhibitors - xanomeline is a CYP2D6 sensitive substrate, and strong CYP2D6 inhibitors may increase its exposure, raising the risk of adverse events. Use caution and monitor patients for increased frequency and/or severity of adverse reactions when taking Cobenfy with strong CYP2D6 inhibitors.
- Drugs Eliminated by Active Tubular Secretion - Concomitant use of Cobenfy with drugs that are eliminated by active tubular secretion may increase exposure of trospium and/or the competing drug, raising the risk of adverse events. Use caution and monitor patients for increased frequency and/or severity of adverse reactions when combining.
- Oral CYP3A4 sensitive substrates - Xanomeline transiently inhibits CYP3A4 locally in the gut but not systemically. Increased exposure of concomitant oral CYP3A4 sensitive substrates may occur, raising the risk of adverse events. Use caution and monitor patients for increased frequency and/or severity of adverse reactions when combining.
- Oral P-glycoprotein substrates - Xanomeline transiently inhibits P-glycoprotein locally in the gut but not systemically. Increased exposure of concomitant oral P-glycoprotein substrates may occur, raising the risk of adverse events. Use caution and monitor patients for increased frequency and/or severity of adverse reactions when combining.
- Anticholinergic / Antimuscarinic medications - Concomitant use of Cobenfy with other anticholinergic medications may increase the risk of anticholinergic side effects (e.g., dry mouth, constipation). Use caution and monitor patients for increased frequency and/or severity of adverse reactions when combining.
- Effects on absorption of drugs - Cobenfy slows gastrointestinal motility, possibly altering the absorption of concomitantly administered drugs. Dosage adjustment of concomitant medications may be necessary based on clinical response and tolerability.
Contraindications / Precautions

Contraindications
- Urinary retention
- Moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment
- Gastric retention
- History of hypersensitivity to Cobenfy or trospium chloride. Angioedema has been reported with Cobenfy and trospium chloride
- Untreated narrow-angle glaucoma
Precautions
- Risk of Urinary Retention - Cobenfy can cause urinary retention, especially in geriatric patients and those with bladder outlet obstruction. In 5-week placebo-controlled studies, urinary retention was reported in 0.8% of Cobenfy-treated patients and 0.4% on placebo. In long-term, open-label studies, it was reported in 3.5% of Cobenfy-treated patients. Monitor for symptoms like hesitancy, weak stream, and dysuria. Consider reducing the dose, discontinuing Cobenfy, or urologic evaluation if symptoms occur.
- Risk of use in patients with hepatic impairment - Patients with hepatic impairment have higher systemic exposures of xanomeline, which may increase adverse reactions. In 5-week, placebo-controlled schizophrenia studies, ALT or AST elevations of ≥3 times the upper limit of normal were seen in 2.8% of Cobenfy patients and 0.4% of placebo patients. Assess liver enzymes prior to initiating Cobenfy and as clinically indicated during treatment.
- Risk of use in patients with biliary disease - In clinical studies with Cobenfy, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage. Assess liver enzymes and bilirubin prior to initiating Cobenfy and as clinically indicated during treatment. Monitor for symptoms like dyspepsia, nausea, and abdominal pain, and assess for gallbladder disease when indicated. Discontinue Cobenfy if signs of substantial liver injury occur.
- Decreased gastrointestinal motility - Cobenfy may decrease gastrointestinal motility. Use with caution in patients with gastrointestinal obstructive disorders or conditions like ulcerative colitis, intestinal atony, and myasthenia gravis.
- Risk of angioedema - Angioedema, sometimes occurring after the first dose, has been reported with Cobenfy and trospium chloride. Discontinue Cobenfy and initiate appropriate therapy if angioedema occurs.
- Risk of use in patients with narrow-angle glaucoma - Cobenfy's anticholinergic effects may trigger an acute angle closure attack in patients with narrow angles. Use with caution in susceptible patients.
- Increases in heart rate - Cobenfy can increase heart rate. In a dedicated 8-week clinical study, there was a mean change in 24-hour heart rate of 9.8 bpm from baseline to Week 8. Assess heart rate at baseline and during treatment.
- Anticholinergic adverse reactions in patients with renal impairment - Cobenfy is not recommended in patients with moderate or severe renal impairment because trospium elimination is decreased, increasing the risk of anticholinergic adverse reactions.
- Central Nervous System Effects - Cobenfy can cause anticholinergic CNS effects, including dizziness, confusion, hallucinations, and somnolence. Monitor for these effects and advise patients not to drive or operate heavy machinery, particularly after initiation or with dosage increases, until they know how Cobenfy affects them.
- Kidney disease
- eGFR ≥ 60 ml/min: No dose adjustment necessary
- eGFR < 60 ml/min: Use is not recommended
- Liver disease
- Child-Pugh A: Use is not recommended
- Child-Pugh B or C: Do not use. Contraindicated.
EXTRAPYRAMIDAL SYMPTOMS (EPS)
- Overview
- The extrapyramidal motor system is a tract of motor nerve fibers originating in the brain stem and ending in the spinal cord. It plays a role in modulating involuntary muscle control, including muscle tone, reflexes, balance, and posture. The pyramidal motor tract controls voluntary muscle movement.
- Dopamine receptor-blocking drugs like antipsychotics can disrupt the extrapyramidal motor system and cause extrapyramidal symptoms (EPS), a constellation of movement disorders described below. Severe EPS can lead to tardive dyskinesia.
- EPS can occur with any antipsychotic drug but are more common with first-generation antipsychotics, where they are seen in up to 62% of patients. Rates of EPS vary among second-generation antipsychotics, with risperidone having the highest (21% at 10 mg/day) and clozapine the lowest.
- EPS can be treated with anticholinergic medications (e.g. benztropine, trihexyphenidyl), dosage reductions, and drug discontinuation. EPS from first-generation antipsychotics may resolve if the patient is switched to a second-generation antipsychotic.
- 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. It typically occurs within 4 weeks of antipsychotic initiation or dosage increases.
- Parkinsonism - parkinsonism symptoms include 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 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. TD risk factors 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 and older. [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 with 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 is more common with first-generation antipsychotics, particularly haloperidol and chlorpromazine. NMS risk factors 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 antipsychotic drug initiation; 67% of cases occur within 1 week and 96% within 30 days.
- Pathology
- The exact mechanism behind NMS is not entirely 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) D2 blockade in the hypothalamus raises the body temperature set point and impairs heat dissipation (e.g. sweating and cutaneous vasodilation), (2) D2 blockade 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 secondary to 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, diabetes, and lipid increases in some patients. The mechanism of these effects is not completely understood, and some drugs carry a greater risk than others. In 2004, the ADA issued the recommendations below 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 collectively called granulocytes. Clozapine has been shown to cause agranulocytosis, particularly neutropenia (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. To prevent adverse events, the FDA requires that providers, patients, and pharmacies enroll in the Clozapine REMS program to prescribe, receive, and dispense clozapine.
- During therapy, white blood cell counts (CBC) must be monitored frequently, with treatment adjustments based on those results. See clozapine agranulocytosis guidelines [sec 5.1] for recommendations on adjusting therapy.
- Recommendations for CBC monitoring in patients with normal counts 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
OBS
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.
OBS
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.
OBS
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.
OBS
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
RCT
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.
RCT
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
- $ = 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