Johns Hopkins Psychiatry Guide

Second-Generation Neuroleptics

Paul M. Kim, M.D., Ph.D., Sujin Lee Weinstein, Pharm.D., BCPP

DRUG CLASS

  • Neuroleptics (antipsychotics)

INDICATIONS

FDA

NON-FDA APPROVED USES

MECHANISM

  • The first-generation antipsychotics (“typical” or “traditional” antipsychotics) and second-generation antipsychotics (“atypicals”) block post-synaptic D2 dopamine receptors in the mesolimbic system, which has been correlated with antipsychotic effect.
  • The first-generation antipsychotics have minimal antagonism of serotonin receptors, whereas the second-generation antipsychotics have greater antagonism of serotonin receptors.
  • Side effects of both first- and second-generation antipsychotics are due to antagonism at histamine, muscarinic, and alpha-adrenergic receptors. Second-generation antipsychotics are not as strongly associated with neuromotor side effects compared to first-generation antipsychotics. However, second-generation antipsychotics are associated with the metabolic syndrome.

Some atypical antipsychotics such as clozapine may activate glutamate pathways to improve negative symptoms [1].

FORMS

brand name

preparation

manufacturer

route

form

dosage

cost*

Abilify

Aripiprazole

Otsuka

PO

IM

Tablet

ODT

Liquid

IM, acute

IM, depot

PO: 5-30 mg daily

IM, acute:

  • Recommended dose: 9.75 mg
  • Range: 5.25-15 mg
  • May repeat in > 2-hour intervals
  • Maximum dose: 30 mg/day


IM, depot:

  • Standard dose: 300-400 mg once monthly (doses should be separated by ≥ 26 days)
  • More conservative doses are recommended when used with potent CYP 2D6 and/or 3A4 inhibitors

Tablet:

2 mg (30): $931.56

5 mg (30): $931.56

10 mg (30): $931.56

15 mg (30): $931.56

20 mg (30): $1317.34

30 mg (30):

$1317.34

ODT:

10 mg (30): $1108.75

15 mg (30):

$1108.75

Liquid (1 mg/mL), 150-mL bottle: $1025.12

IM, acute (9.75 mg/1.3 mL):

$29.08

IM, depot:

300 mg: $1384.48

400 mg: $1845.97

Saphris

Asenapine

Merck

SL

SL tablet

SL: 5-20 mg daily

SL tablet:

5 mg (10): $151.59

10 mg (10): $151.59

Clozaril

Clozapine

Multiple generic companies

PO

Tablet

ODT

Liquid

300-600 mg daily for most patients

FDA maximum of 900 mg/day given BID-TID

Tablet (brand):

25 mg (100): $504.22

100 mg (100): $1306.45

Tablet (generic):

25 mg (100): $129.43

50 mg (100): $165.00

100 mg (100): $335.80

200 mg (100): $632.32

ODT (brand):

12.5 mg (100): $284.63

25 mg (48): $183.85

100 mg (48): $735.41

150 mg (48): $885.65

200 mg (48): $1180.84

ODT (generic):

12.5 mg (100): $222.75

25 mg (48): $143.89

100 mg (48): $392.40

Liquid (50 mg/mL), 100-mL bottle (brand only): $880.97

Fanapt

Iloperidone

Novartis

PO

Tablet

2-24 mg dosed BID

Tablet:

1 mg (60): $919.04

2 mg (60): $919.04

4 mg (60): $919.04

6 mg (60): $919.04

8 mg (60): $919.04

10 mg (60): $919.04

12 mg (60): $919.04

Latuda

Lurasidone

Sunovion

PO

Tablet

20-160 mg daily

Tablet:

20 mg (30): $840.24

40 mg (30): $840.24

60 mg (30): $840.24

80 mg (30): $840.24

120 mg (30): $1254.24

Zyprexa

Olanzapine

Eli Lilly

Multiple generic companies

PO

IM

Tablet

ODT

IM, acute

IM, depot

PO: 2.5-20 mg daily

IM, acute:

  • 10 mg for the first dose
  • May repeat 10 mg in 2- to 4-hour intervals
  • Maximum of 30 mg/day

IM, depot:

  • 10 mg PO daily conversion:
    • Initial: 210 mg q 2 weeks x 4 doses OR 405 mg q 4 weeks x 2 doses
    • Maintenance: 150 mg q2 weeks OR 300 mg q4 weeks
  • 15 mg PO daily conversion:
    • Initial: 300mg q 2 weeks x 4 doses
    • Maintenance: 210 mg q 2 weeks or 405 mg q 4 weeks
  • 20 mg PO daily conversion: 300 mg q 2 weeks (both initial and maintenance)

Tablet (brand):

2.5 mg (30): $373.25

5 mg (30): $440.53

7.5 mg (30): $536.11

10 mg (30): $663.84

15 mg (30): $995.76

20 mg (30): $1327.68

Tablet (generic):

2.5 mg (30): $335.55

5 mg (30): $396.04

7.5 mg (30): $481.96

10 mg (30): $596.79

15 mg (30): $895.19

20 mg (30): $1193.58

ODT (brand):

5 mg (30): $475.81

10 mg (30): $699.12

15 mg (30): $1031.04

20 mg (30): $1362.96

ODT (generic):

5 mg (30): $427.75

10 mg (30): $628.51

15 mg (30): $926.90

20 mg (30): $1225.30

IM, acute (brand):

10-mg vial: $46.87

IM, acute (generic):

10-mg vial: $36.25

IM, depot (brand only):

210 mg: $667.80

300 mg: $954.00

405 mg: $1287.90

Invega

Paliperidone

Janssen

PO

IM

ER tablet

IM, depot

PO: 1.5-12 mg daily

IM, depot:

  • Loading dose: 234 mg IM on day 1 and then 156 mg IM one week later. This is the same for all patients
  • Maintenance dose: for most patients, 117 mg monthly. However, the dose may range from 39-235 mg monthly, depending upon patient-specific factors

ER tablet:

1.5 mg (30): $875.46

3 mg (30): $875.46

6 mg (30): $875.46

9 mg (30): $1313.20

IM, depot:

39 mg: $375.52

78 mg: $751.09

117 mg: $1126.63

156 mg: $1502.23

234 mg: $2253.31

Seroquel

Quetiapine

Astra Zeneca

Multiple generic companies

PO

Tablet

ER tablet

25-800 mg/day

Immediate-release tablet: give BID with doses > 400 mg total daily

Tablet (brand):

25 mg (100): $466.21

50 mg (100): $766.10

100 mg (100): $800.04

200 mg (100): $1509.30

300 mg (60): $1187.38

400 mg (100): $2325.72

Tablet (generic):

25 mg (100): $399.61

50 mg (100): $656.66

100 mg (100): $685.75

200 mg (100): $1293.69

300 mg (100): $1677.35

400 mg (100): $1993.47

ER tablet (brand only):

50 mg (60): $506.92

150 mg (60): $910.25

200 mg (60): $1001.86

300 mg (60): $1313.56

400 mg (60): $1543.76

Risperdal

Risperidone

Multiple generic companies

PO

IM

Tablet

ODT

Solution

IM, depot

PO:

2-4 mg for most patients

Lower doses for elderly and antipsychotic-naive patients

Maximum 8 mg daily

IM, depot:

12.5-50 mg q 2 weeks

Tablet (brand):

0.25 mg (60): $461.52

0.5 mg (60): $506.45

1 mg (60): $538.42

2 mg (60): $899.80

3 mg (60): $1056.85

4 mg (60): $1419.49


Tablet (generic):

0.25 mg (60): $234.08

0.5 mg (60): $256.87

1 mg (60): $273.09

2 mg (60): $456.41

3 mg (60): $536.02

4 mg (60): $720.01


ODT (brand):

0.5 mg (28): $246.94

1 mg (30): $309.19

2 mg (28): $469.12

3 mg (28): $591.82

ODT (generic):

0.25 mg (28): $134.41

0.5 mg (28): $131.86

1 mg (28): $160.83

2 mg (28): $250.49

3 mg (28): $316.12

4 mg (28): $443.09

Liquid (1 mg/mL), 30-mL bottle (brand):

$300.78

Liquid (1 mg/mL), 30-mL bottle (generic):

$152.56

IM, depot (brand only):

12.5 mg: $193.26

25 mg: $386.47

37.5 mg: $579.72

50 mg: $772.98

Geodon

Ziprasidone

Pfizer

Multiple generic companies

PO

IM

Capsule

PO: 20-80 mg BID

IM, acute: 10 mg q 2 hours or 20 mg q 4 hours, to a maximum of 40 mg/day

Capsule (brand):

20 mg (60): $843.52

40 mg (60): $843.52

60 mg (60): $1023.65

80 mg (60): $1023.65

Capsule (generic):

20 mg (60): $531.83

40 mg (60): $531.83

60 mg (60): $645.41

80 mg (60): $645.41

IM, acute (20-mg vial):

$28.57

*Prices are representative of "Average Wholesale Price" (AWP)

ADULT DOSING

USUAL

  • Aripiprazole (Abilify®): The starting dose is 10 mg orally daily; the dose can be increased every 2 weeks by 10 mg/day. The maximum dose is 30 mg daily. Immediate-release intramuscular doses of 5.25–15 mg can be given for agitation up to every 2 hours, with a maximum dose of 30 mg/day. Long-acting intramuscular injections (Abilify Maintenna) can be given as 400 mg monthly; the oral dose should be continued for 2 weeks after the initial injection.
  • Asenapine (Saphris®): The initial dose is 5 mg sublingually twice a day and the maximum dose is 10 mg twice a day. Patients should avoid eating and drinking for 10 minutes after each dose.
  • Clozapine (Clozaril®): Given the risk of agranulocytosis, one needs to obtain a CBC with differential before initiating the medication. The WBC count has to be greater than 3500/mm3 and ANC greater than 2000/mm3. The provider also needs to be registered with the Clozaril National Registry. The starting dose is 12.5 mg daily, increased 25 mg/day to the usual target dose of 300-450 mg/day in divided doses. The maximum dose is 900 mg total daily.
  • Iloperidone (Fanapt®): The starting dose is 1 mg twice a day, but the dose can be increased by 4 mg total/day. The maximum dose is 12 mg twice a day.
  • Lurasidone (Latuda®): The initial dose is 20 mg daily with food (greater than 350 calories). No titration is needed. The maximum dose is 160 mg daily.
  • Olanzapine (Zyprexa®): The starting dose is 5 mg daily, and the dose can by increased by 5 mg weekly. The maximum dose is 20 mg/day. IM doses of 10 mg can be given for agitation, with a maximum daily dose of 30 mg total/day, given in 2- to 4-hour intervals. An IV dose of 10 mg can be given for nausea and vomiting induced by chemotherapy.
  • Paliperidone (Invega®): The starting dose is 6 mg/day orally. This can be increased 3 mg/day weekly, with a maximum dose of 12 mg/day. For long-acting IM dosing, start with 234 mg IM, and give 156 mg IM one week later. Administer initial injections in deltoid muscles. [2] The maximum IM dose is 234 mg IM monthly, but the usual monthly maintenance dose is 117 mg IM. Maintenance doses can be given either in deltoid or gluteal muscles. The monthly dose is dependent on the daily oral dose: a 3-mg daily oral dose requires 39- to 78-mg IM monthly dose; a 6-mg oral daily dose requires a 117-mg IM monthly dose; and a 12-mg oral daily dose requires a 234-mg IM monthly dose.
  • Quetiapine (Seroquel®): For the immediate-release formulation, the starting dose is 25 mg twice a day. The dose can be increased by 25 to 50 mg daily, with a usual target dose of 400 mg/day in divided doses. The maximum dose is 750 mg/day (divided doses). For the extended-release formulation, the initial dose is 300 mg daily, with a target dose of 400-800 mg/day. The maximum dose is 800 mg/day. The immediate-release form can be converted to the extended-release form by converting the total daily dose of the immediate-release form to a single dose of the extended-release form.
  • Risperidone (Risperdal®): The starting dose is 2 mg/day orally. The dose can be increased by 1-2 mg/day. The maximum dose is 16 mg/day. Orally-disintegrating tablets are bioequivalent to the regular tablets. The starting dose of the long-acting preparation (Risperdal Consta) is 25 mg IM every 2 weeks and can be increased to 37.5 or 50 mg in 4 weeks. The maximum long-acting IM dose is 50 mg every 2 weeks. Before using the IM form, make sure that the patient is tolerant of the oral form and is continued on the oral form for 4-6 weeks after initiation of the IM form.
  • Ziprasidone (Geodon®): The starting dose is 20 mg twice a day orally with food (greater than 500 calories). Increase by 20 mg every other day to a maximum dose of 80 mg twice a day orally. The usual dose for IM ziprasidone for agitation is 10 mg IM every 2 hours, with a maximum total dose of 40 mg/day.

GERIATRIC

In general, with geriatric patients, start medications at the lowest dose and titrate slowly while assessing for side effects and potential drug interactions

  • Aripiprazole: No adjustment is needed
  • Asenapine: No adjustment is needed
  • Clozapine: Should be used with caution in the elderly
  • Iloperidone: No adjustment is needed
  • Lurasidone: Should be used with caution in the elderly
  • Olanzapine: Use a reduced dose. If using IM, give 5 mg per injection.
  • Paliperidone: No adjustment is needed
  • Quetiapine: No adjustment is needed, but start titration slowly while monitoring for side effects
  • Risperidone: The starting dose is 0.5 mg/day, with a slow increase by 0.5 mg twice a day or 1 mg/day. For IM dose, If using long-acting IM formulation, give 25 mg every 2 weeks.
  • Ziprasidone: No adjustment is needed

RENAL

  • Aripiprazole: No adjustment is needed
  • Asenapine: No adjustment is needed
  • Clozapine: Dose adjustment may be needed, depending on the serum clozapine level.
  • Iloperidone: No adjustment is needed
  • Lurasidone: The maximum dose is 80 mg/day for patients with moderate-to-severe renal impairment.
  • Olanzapine: No adjustment is needed
  • Paliperidone: In patients with severe renal impairment, this medication is not recommended. In patients with CrCl 50 mL/min to 10 mL/min, use 1.5 mg daily, with a maximum dose of 3 mg/day. In patients with CrCl 80 mL/min to 50 mL/min, start with 3 mg daily, and do not exceed 6 mg/day.
  • Quetiapine: No adjustment is needed
  • Risperidone: The starting dose is 0.5 mg/day - can be increased slowly by 0.5 mg twice a day or 1 mg/day. If administering long-acting IM form, give 12.5-25 mg every 2 weeks.
  • Ziprasidone: No adjustment is needed

HEPATIC

  • Aripiprazole: No adjustment is needed
  • Asenapine: No adjustment is needed, unless hepatic impairment is severe, in which case the drug should not be prescribed
  • Clozapine: Dose adjustment is needed for patients with hepatic impairment, depending on the serum clozapine level
  • Iloperidone: No adjustment is needed, unless hepatic impairment is severe, in which case the drug should not be prescribed
  • Lurasidone: The maximum dose is 40 mg/day for patients with severe hepatic failure, 80 mg/day for patients with moderate hepatic impairment.
  • Olanzapine: No adjustment is needed, but lower doses may be effective when augmenting an antidepressant
  • Paliperidone: Dose adjustment is needed for patients with hepatic impairment
  • Quetiapine: With the extended-release formulation, start at 50 mg/day, and increase slowly
  • Risperidone: The starting dose is 0.5 mg/day - can be increased slowly by 0.5 mg twice a day or 1 mg/day. If administering long-acting IM form, give 12.5-25 mg every 2 weeks.
  • Ziprasidone: No adjustment is needed.

PREGNANCY

  • Aripiprazole: Category C
  • Asenapine: Category C
  • Clozapine: Category B
  • Iloperidone: Category C
  • Lurasidone: Category B
  • Olanzapine: Category C
  • Paliperidone: Category C
  • Quetiapine: Category C
  • Risperidone: Category C
  • Ziprasidone: Category C

BREASTFEEDING

  • For all of the second-generation antipsychotics, there are insufficient data regarding their use during nursing, and infant risk cannot be ruled out.
  • All psychotropic agents can cross into the breast milk to some extent.
  • The baby should be monitored for side effects secondary to medication exposure from the breast milk.

PEDIATRIC DOSING

USUAL

  • Aripiprazole: Dosing has not been established for certain age groups depending on the disorder: Less than 6 years of age for autistic disorder, less than 10 years of age for bipolar disorder, and less than 13 years of age for schizophrenia. The starting dose in children is 2 mg daily, and the dose can be increased to 5 mg daily after 2 days, if needed. Thereafter, the dose can be increased by 5 mg every 2 days, up to a maximum of 30 mg daily. The usual therapeutic dose is 10 mg daily.
  • Asenapine: Safety and efficacy is not established in children.
  • Clozapine: Safety and efficacy is not established in children.
  • Iloperidone: Safety and efficacy is not established in children.
  • Lurasidone: Safety and efficacy is not established in children.
  • Olanzapine: Safety and efficacy is not established in children younger than 13 years. The initial dose in children older than 13 years of age is 2.5 mg daily, with weekly adjustments of 2.5 mg daily. The maximum dose is 20 mg/day. Safety of the IM form is not established in children.
  • Paliperidone: Safety and efficacy is not established in children younger than 12 years. The initial dose in children older than 12 years of age (and weighing more than 51 kg) is 3 mg daily, with weekly adjustments of 5 mg daily. The maximum dose is 12 mg/day. For children less than 51 kg, the starting dose is 3 mg daily, and the dose can be increased to the maximum dose of 6 mg/day after a week. Safety of the IM formulation is not established in children.
  • Quetiapine: Safety and efficacy is not established in children younger than 10 years. For older children, the starting dose of the immediate-release form is 25 mg twice a day. The dose can be increased by 25 to 50 mg daily, with a target dose of 400 mg/day. The maximum dose is 600 mg/day. For the extended-release form, the initial dose is 50 mg daily, and the target dose is 400–800 mg/day (the maximum dose is 800 mg/day).
  • Risperidone: Safety and efficacy is not established in children younger than 13 years for schizophrenia, 10 years for bipolar disorder, and 5 years for autism. Safety and efficacy of the IM formulation is not established in children. The oral starting dose is 0.5 mg/day, and the dose can be increased slowly by 0.5 mg twice a day or 1 mg/day. The maximum dose for schizophrenia is 3 mg/day; for bipolar disorder, 2.5 mg/day; and autism, as tolerated, from 0.5 to 3 mg/day.
  • Ziprasidone: Safety and efficacy is not established in children.

RENAL

  • Aripiprazole: No adjustment is needed
  • Asenapine: No adjustment is needed
  • Clozapine: Dose adjustment may be needed
  • Iloperidone: No adjustment is needed
  • Lurasidone: Dose adjustment may be needed
  • Olanzapine: No adjustment is needed
  • Paliperidone: Dose adjustment is needed for children with renal impairment
  • Quetiapine: No adjustment is needed
  • Risperidone: Dose adjustment is needed for children with renal impairment
  • Ziprasidone: No adjustment is needed

ADVERSE DRUG REACTIONS

GENERAL

  • All neuroleptics have FDA black-box warnings regarding increased mortality in elderly patients with dementia.
  • Clozapine also has black-box warnings for agranulocytosis, myocarditits, seizure, adverse cardiovascular and respiratory effects, and orthostatic hypotension with or without syncope [3].
  • Clozapine and quetiapine are associated with orthostatic hypotension.
  • Concomitant use of clozapine and fluvoxamine is contraindicated - can lead to increased clozapine levels.
  • Ziprasidone is contraindicated in patients with cardiovascular risk factors such as a history of QTc prolongation, MI, or heart failure, or in patients on other QTc-prolonging agents [4].
  • Iloperidone is also associated with significant changes in the QTc interval, which should be monitored frequently [5].
  • Use of iloperidone with ritonzvir is contraindicated - can lead to increased iloperidone levels.

COMMON

  • Aripiprazole: Metabolic syndrome, constipation, nausea, vomiting, extrapyramidal symptoms (EPS), akathisia, dizziness, headache, insomnia, sedation, tremor, blurred vision, anxiety, restlessness
  • Asenapine: Metabolic syndrome, oral hypoesthesia, EPS, akathisia, dizziness, sedation
  • Clozapine: Metabolic syndrome, hypotension, syncope, tachycardia, sweating, fever, constipation, excessive salivation, nausea, xerostomia, dizziness, headache, sedation, tremor, blurred vision
  • Iloperidone: Hypotension, tachycardia, metabolic syndrome, hyperprolactinemia, diarrhea, nausea, xerostomia, dizziness, sedation, nasal congestion
  • Lurasidone: Metabolic syndrome, diarrhea, nausea, vomiting, akathisia, sedation, EPS, parkinsonism, anxiety
  • Olanzapine: Hypotension, peripheral edema, metabolic syndrome, increased appetite, constipation, hyperprolactinemia, xerostomia, constipation, akathisia, asthenia, dizziness, sedation, tremor, personality disorder
  • Paliperidone: Metabolic syndrome, tachycardia, hyperprolactinemia, constipation, indigestion, akathisia, dyskinesia, dystonia, EPS, parkinsonism, sedation, tremor, nasopharyngitis, anxiety
  • Quetiapine: Tachycardia, hypotension, increased blood pressure in children, metabolic syndrome, constipation, indigestion, nausea, vomiting, xerostomia, increased appetite, increased liver enzymes, asthenia, dizziness, headache, EPS, insomnia, sedation, tremor, agitation, fatigue, pain, pharyngitits
  • Risperidone: Rash, metabolic syndrome, constipation, diarrhea, excessive salivation, increased appetite, GI disturbances, xerostomia, akathisia, dizziness, dystonia, parkinsonism, sedation, tremor, blurred vision, anxiety, nasal congestion, respiratory infection
  • Ziprasidone: Metabolic syndrome, constipation, diarrhea, GI disturbances, blurred vision, respiratory infection, akathisia, anxiety, asthenia, sedation, dizziness, EPS, headache, increased muscle tone, involuntary movement, tremor

OCCASIONAL

  • Aripiprazole: Prolonged QT interval, cardiorespiratory failure, MI, angioedema, suicidal behavior
  • Asenapine: Prolonged QT interval, cardiorespiratory failure, angioedema
  • Clozapine: Prolonged QT interval, cardiorespiratory failure, hypotension, angioedema, Stevens-Johnson syndrome, erythema multiforme, seizure, GI hypomotility
  • Iloperidone: Prolonged QT interval, cardiorespiratory failure, angioedema, suicidal behavior
  • Lurasidone: Hypotension, Prolonged QT interval, increased serum creatinine, suicidal behavior
  • Olanzapine: Prolonged QT interval, cardiorespiratory failure, suicidal behavior
  • Paliperidone: Prolonged QT interval
  • Quetiapine: Backache, nasal congestion, prolonged QT interval, cardiorespiratory failure
  • Risperidone:Prolonged QT interval, cardiorespiratory failure, nasopharyngitis, fatigue, generalized pain
  • Ziprasidone: Prolonged QT interval, rash, xerostomia, dysphagia

RARE

  • Aripiprazole: Diabetic ketoacidosis, pancreatitis, agranulocytosis, leukopenia, neutropenia, rhabdomyolysis, seizure, tardive dyskinesia (TD), stroke, neuroleptic malignant syndrome (NMS), fever, angioedema
  • Asenapine: NMS, hypersensitivity reaction
  • Clozapine: Diabetic ketoacidosis, agranulocytosis, leukopenia, neutropenia, eosinophilia, pneumonia, pulmonary embolism (PE), rhabdomyolysis, seizure, TD, stroke, NMS, cardiomyopathy, myocarditis, ventricular arrhythmia, torsades de pointes, close-angle glaucoma
  • Iloperidone: TD, stroke, NMS
  • Lurasidone: Syncope, agranulocytosis, stroke, seizure, TD, NMS
  • Olanzapine: Pancreatitis, stroke, seizure, PE
  • Paliperidone: Angranulocytosis, leukopenia, TD, dysphagia, priapism
  • Quetiapine: Diabetic ketoacidosis, pancreatitis, agranulocytosis, leukopenia, neutropenia, anaphylaxis, seizure, TD, NMS, suicidal ideation, priapism, hypothyrodism
  • Risperidone: Hyperprolactinemia, syncope, pancreatitis, agranulocytosis, leukopenia, neutropenia, seizure, TD, priapism, PE, NMS
  • Ziprasidone: Syncope, torsades de pointes, diabetes mellitus, hyperprolactinemia, bone marrow depression, NMS, TD, seizure, priapism

DRUG INTERACTIONS

Drug-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

Aripiprazole – carbamazepine (Tegretol)

Reduced levels of aripiprazole

Double the dose of aripiprazole

Clozapine – carbamazepine (Tegretol)+

Reduced levels of clozapine

Avoid use

If necessary, monitor clozapine levels, and adjust dose as needed

Paliperidone – carbamazepine (Tegretol)

Reduced levels of paliperidone

Monitor patient and adjust paliperidone dose as needed based on therapeutic response

Clozapine – ciprofloxacin (Cipro)+

Increased levels of clozapine

Reduce clozapine dose by ~ one third

Ziprasidone – citalopram (Celexa)+

Increased risk of QTc prolongation

Avoid use

Olanzapine – clomipramine (Anafranil)

Increased risk of seizure

Avoid use

Clozapine, Iloperidone, Quetiapine, Ziprasidone – fluconazole (Diflucan)+

Increased risk of QTc prolongation

Avoid use

Olanzapine – divalproex (Depakote)

Reduced olanzapine levels

Monitor patient, and adjust olanzapine dose as needed based on therapeutic response

Risperidone - divalproex (Depakote)

Increased valproic acid and/or ammonium levels

Monitor valproic acid and ammonium levels

Ziprasidone – erythromycin+

Increased risk of QTc prolongation

Avoid use

Aripiprazole – fluoxetine (Prozac)

Increased levels of aripiprazole

Half the dose of aripiprazole, unless using for adjunctive treatment of depression

Iloperidone – fluoxetine (Prozac)

Increased levels of iloperidone and increased risk of QTc prolongation

Avoid use

If necessary, reduce iloperidone dose by half

Clozapine – fluvoxamine (Luvox)

Increased levels of clozapine

Reduce clozapine dose by ~ one third

Aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone – hydrocodone (i.e. Lortab)

May increase sedative effects

Reduce hydrocodone dose ~25%

Aripiprazole – ketoconazole

Increased aripiprazole levels and risk of QTc prolongation

Half the dose of aripiprazole

If used in addition to a CYP 2D6 inhibitor, reduce aripiprazole dose to one fourth of the usual dose

Risperidone - ketoconazole

Increased risperidone levels and risk of QTc prolongation

Avoid use

Clozapine, iloperidone, ziprasidone – ketoconazole+

Increased levels of antipsychotic and risk of QTc prolongation

Avoid use

Olanzapine - lorazepam (Ativan)

Increased risk of cardiorespiratory depression

Avoid use of parenteral benzodiazepines and IM olanzapine

Ziprasidone – methadone+

Increased risk of QTc prolongation

Avoid use

Aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone – metoclopramide (Reglan)+

Increased risk of extrapyramidal symptoms and neuroleptic malignant syndrome

Avoid use

Ziprasidone – moxifloxacin (Avelox)+

Increased risk of QTc prolongation

Avoid use

Aripiprazole - nelfinavir (Viracept)

Increased aripiprazole levels and risk of QTc prolongation

Half the dose of aripiprazole

If used in addition to a CYP 2D6 inhibitor, reduce aripiprazole dose to one fourth of the usual dose

Clozapine, Iloperidone – nelfinavir (Viracept)+

Increased levels of nelfinavir and risk of QTc prolongation

Avoid use

Quetiapine - nelfinavir (Viracept)+

Increased quetiapine levels

Avoid use

If necessary, reduce quetiapine dose to one sixth of the usual dose

Ziprasidone – ondansetron (Zofran)+

Increased risk of QTc prolongation

Avoid use

Aripiprazole – paroxetine (Paxil)

Increased levels of aripiprazole

Half the dose of aripiprazole, unless using for adjunctive treatment of depression

Asenapine, clozapine, iloperidone, paliperidone, quetiapine, risperidone, ziprasidone - pimozide (Orap)+

Increased risk of QTc prolongation

Avoid use

Aripiprazole – ritonavir (Norvir)

Increased levels of aripiprazole

Half the dose of aripiprazole, unless using for adjunctive treatment of depression

Aripiprazole – saquinavir (Invirase)+

Increased aripiprazole levels and risk of QTc prolongation

Half the dose of aripiprazole

If used in addition to a CYP 2D6 inhibitor, reduce aripiprazole dose to one fourth of the usual dose

Clozapine, ziprasidone - saquinavir (Invirase)+

Increased risk of QTc prolongation

Avoid use

Quetiapine - saquinavir (Invirase)+

Increased quetiapine levels and risk of QTc prolongation

Avoid use

Risperidone – simvastatin (Zocor)

Increased simvastatin levels and risk of myopathy or rhabdomyolysis

Avoid use

If necessary, monitor for signs and symptoms of myopathy or rhabdomyolysis

Ziprasidone – tacrolimus (Prograf, Hecoria)+

Increased risk of QTc prolongation

Avoid use

Aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, ziprasidone – tapentadol (Nucynta)

Increased sedative effects

Start tapentadol at one third to one half the usual starting dose

Aripiprazole, clozapine, iloperidone, paliperidone, quetiapine, risperidone, ziprasidone - thioridazine (Mellaril)+

Increased risk of QTc prolongation

Avoid use

Lurasidone – strong CYP 3A4 inducers+ [phenytoin (Dilantin), carbamazepine (Tegretol), etc.]

Reduced levels of lurasidone

Avoid use

Lurasidone – strong CYP 3A4 inhibitors+ [ketoconazole, clarithromycin (Biaxin), nefazodone (Serzone), ritonavir (Norvir), saquinavir (Invirase), etc.]

Increased levels of lurasidone

Avoid use

+ = Contraindication

*This list is not all-inclusive. Please refer to standard drug information resources to check for specific interactions*

PHARMACOKINETIC

Absorption

  • Aripiprazole: 87% orally and 100% IM
  • Asenapine: 35%
  • Clozapine: 50-60%
  • Iloperidone: 96%
  • Lurasidone: 9-19%
  • Olanzapine: Well-absorbed orally and 100% IM
  • Paliperidone: 28% orally and 100% IM
  • Quetiapine: Well-absorbed orally
  • Risperidone: 70% orally and 100% IM
  • Ziprasidone: 60% orally and 100% IM

Metabolism and Excretion

  • Aripiprazole: Metabolized by the liver via CYP2D6 and CYP3A4. Thus, decrease dose of aripiprazole (up to 25-50% of usual dose) if used with other drugs that inhibit CYP2D6 or CYP3A4. Excreted mostly by feces and some by kidney
  • Asenapine: Metabolized by the liver via CYP1A2 and glucuronidated by UGT1A4; excreted by renal and fecal pathways
  • Clozapine: Metabolized by the liver via CYP2D6, CYP1A2, and CYP3A4 and excreted mostly by the kidney
  • Iloperidone: Metabolized by the liver via CYP3A4 and CYP2D6 and excreted by renal and fecal pathways
  • Lurasidone: Metabolized by the liver CYP3A4 and excreted mostly by feces and some by the kidney
  • Olanzapine: Metabolized by the liver via CYP1A2 and CYP2D6 and excreted mostly by the kidney and some by feces
  • Paliperidone: Metabolized by the liver and excreted by the kidney
  • Quetiapine: Metabolized by the liver via CYP3A4 and excreted mostly by the kidney and some by feces
  • Risperidone: Metabolized by the liver via CYP2D6 and excreted mostly by the kidney and some by feces
  • Ziprasidone: Metabolized by the liver via CYP3A4 and CYP1A2 and excreted mostly by feces and some by kidney

Protein Binding

  • Aripiprazole: 99%
  • Asenapine: 95%
  • Clozapine: 97%
  • Iloperidone: 95%
  • Lurasidone: 99%
  • Olanzapine: 93%
  • Paliperidone: 74%
  • Quetiapine: 83%
  • Risperidone: 90%
  • Ziprasidone: 99%

T1/2

  • Aripiprazole: 75 hours for oral form and 30 days for IM form
  • Asenapine: 24 hours
  • Clozapine: 12 hours
  • Iloperidone: 18-33 hours
  • Lurasidone: 18 hours
  • Olanzapine: 30 hours for oral form and 30 days for IM form
  • Paliperidone: 23 hours for oral form and 25-49 days for IM form
  • Quetiapine: 6-7 hours
  • Risperidone: 3-20 hour for oral form and 6 days for IM form
  • Ziprasidone: 7 hours for oral form and 2-5 hours for IM form

Distribution

  • Aripiprazole: 4.9 L/kg
  • Asenapine: 20-25 L/kg
  • Clozapine: 6 L/kg
  • Iloperidone: 19-40 L/kg
  • Lurasidone: 2.4-20 L/kg
  • Olanzapine: 10-18 L/kg
  • Paliperidone: 7 L/kg
  • Quetiapine: 10 L/kg
  • Risperidone: 1.1 L/kg
  • Ziprasidone: 1.5 L/kg

COMMENTS

  • Clozapine doses need to be adjusted in patients with infectious or inflammatory processes. Patients who smoke also may require dose adjustment because carcinogens can induce CYP1A2.
  • Clozapine is FDA-approved for reducing risk of suicide in patients with schizophrenia [6].
  • Clozapine, iloperidone, and paliperidone are only FDA-approved for schizophrenia, while other second-generation antipsychotics are approved for other uses.
  • Olanzapine doses may require adjustment in patients who smoke.
  • Increased risk of weight gain is more common and severe with olanzapine.
  • Use of IM olanzapine with IM lorazepam can increase the risk of cardiorespiratory depression [7].
  • Invega Sustenna is given in the deltoid initially, because plasma concentrations are 28% higher with deltoid injections verses gluteal injections [8].
  • Due to delayed peak onset of aripiprazole and paliperidone, they are not recommended for acute agitation.
  • Aripiprazole, olanzapine, and quetiapine are approved for adjunctive treatment of MDD.
  • Olanzapine and quetiapine have been used off-label for monotherapy for MDD, with moderate success [9].
  • Olanzapine and risperidone have been used to augment in treating OCD [10].
  • Risperidone has been used off-label for treating PTSD (combat-related) [11].
  • It is recommended to obtain slit-lamp eye exams every 5 years for patients on quetiapine, which has been shown to cause cataracts in animals [12].
  • Second-generation antipsychotics (SGAs) have been shown to improve behavioral problems in patients with dementia, but due to increased risk of death in elderly patients with dementia (black box warning), their use has decreased. A recent article showed that citalopram can reduce agitation in patients with dementia. [13]
  • While SGAs have been used in treating substance abuse and anorexia nervosa, their effectiveness has not been shown. This was surprising for anorexia nervosa, given that one of the side effects of SGAs is weight gain. [14]

References

  1. Tanahashi S et al: Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes. Br J Pharmacol 165:1543, 2012  [PMID:21880034]
  2. Invega Sustenna [package insert]. Titusville, NJ: Janssen; 2009.
  3. McDonagh M, et al. Drug Class Review: Atypical Antipsychotic Drugs: Final Update 3 Report [Internet]. Portland (OR): Oregon Health & Science University; 2010 Jul.
  4. Carnahan RM, Lund BC, Perry PJ: Ziprasidone, a new atypical antipsychotic drug. Pharmacotherapy 21:717, 2001  [PMID:11401184]
  5. Citrome L: Iloperidone for schizophrenia: a review of the efficacy and safety profile for this newly commercialised second-generation antipsychotic. Int J Clin Pract 63:1237, 2009  [PMID:19624791]
  6. Meltzer HY et al: Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82, 2003  [PMID:12511175]
  7. Wilson MP et al: Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients. J Emerg Med 43:889, 2012  [PMID:20542400]
  8. Kramer M et al: Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 13:635, 2010  [PMID:19941696]
  9. Maglione M, et al., Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. Report No.: 11-EHC087-EF
  10. Thomsen PH: Risperidone augmentation in the treatment of severe adolescent OCD in SSRI-refractory cases: a case-series. Ann Clin Psychiatry 16:201, 2004 Oct-Dec  [PMID:15702568]
  11. Wang HR, Woo YS, Bahk WM: Atypical antipsychotics in the treatment of posttraumatic stress disorder. Clin Neuropharmacol 36:216, 2013 Nov-Dec  [PMID:24201234]
  12. AstraZeneca Pharmaceuticals: Seroquel package insert. Wilmington, Del, AstraZeneca Pharmaceuticals, May 1999
  13. Porsteinsson AP et al: Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 311:682, 2014  [PMID:24549548]
  14. Bosanac P, Castle DJ: Review: antipsychotics do not increase weight in women with anorexia nervosa. Evid Based Ment Health 16:, 2013  [PMID:23220567]
  15. Mehnert A et al: Cost effectiveness of paliperidone palmitate versus risperidone long-acting injectable and olanzapine pamoate for the treatment of patients with schizophrenia in Sweden. J Med Econ 15:844, 2012  [PMID:22458756]
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Last updated: December 5, 2014