II. Indications
- Psychosis (e.g. Schizophrenia, Acute Mania)
-
Sedation in Excited Delirium
- Especially Haloperidol, Olanzapine, Ziprasidone
- Other uses
- Antipsychotics should primarily be used for Psychotic Disorders (see precautions below)
- Refractory Major Depression adjunct
- Atypical Antipsychotics, especially Quetiapine, Aripiprazole
- Bipolar Disorder adjunct
- Atypical Antipsychotics, especially Quetiapine, Olanzapine, Aripiprazole
- Refractory Obsessive Compulsive Disorder adjunct
- Atypical Antipsychotics, especially Risperidone, Aripiprazole
- Autism related severe maladaptive behaviors
- Atypical Antipsychotics, especially Risperidone, Aripiprazole, Olanzapine
III. Mechanism
IV. Efficacy: Newer low potency agents
- Atypicals are only slightly better than high potency agents
- Similar efficacy in control of Psychosis
- Slightly less Extrapyramidal Side Effects (EPSE)
- Clozapine has much less EPSE, but has diabetes risk
- Higher weight, lipid and diabetes related conditions
- Compliance is similar for both types of agents
- Atypical Antipsychotics are much more expensive
- References
V. Preparations: D2 Antipsychotic Agents - High Potency
- General: Extrapyramidal Side Effects (EPSE) with all
-
Haloperidol (Haldol) or Haloperidol Decanoate
- Dosing Range
- Adult: 5-10 mg PO, IM, or IV
- Peds: 0.5-1 mg PO, IM or IV
- Adolescent: 1-5 mg PO, IM or IV
- Elderly: 0.5-2 mg PO, IM or IV
- Dosing Intervals: Scheduled and repeated dosing intervals
- May repeat every 30-60 minutes
- Maximum: 300 mg/24 hours (avoid cummulative dose over 100 mg in 24 hours)
- May dose regularly every 6-8 hours
- Typical effective dose: 5 mg PO, IV, or IM tid (lower doses in the elderly)
- Total dose >3 mg/day is associated with Extrapyramidal Side Effects
- Schizophrenia
- Dose: 1 to 5 mg start dose titrated to 5-20 mg/day
- Common Adverse Effects
- Dosing Range
- Perphenazine (Trilafon)
- Phenothiazine
- Schizophrenia and other Psychotic Disorders
- Start 4 to 8 mg orally every 8 hours
- May use up to 8 to 16 mg orally every 6 to 12 hours in hospitalized patients
- May titrate to 32 mg/day
- Maximum: 64 mg/day
- Start 4 to 8 mg orally every 8 hours
- Refractory Nausea or Vomiting
- Dose 8 to 16 mg/day in divided doses
- Maximum: 24 mg/day
- Common Adverse Effects
- Well tolerated with similar efficacy to other agents
- Pimozide (Orap)
- Phenothiazine
- Risk of QTc Prolongation
- Obtain baseline EKG
- Avoid combining with other causes of Drug-Induced QTc Prolongation
- Avoid with strong CYP3A4 and CYP2D6 Inhibitors
- Tourette Syndrome (age over 12 years and adults)
- Start 0.05 mg/kg up to 1 to 2 mg at bedtime
- May increase dose every few days to target dose 1 to 10 mg/day in divided doses
- Maximum 0.2 mg/kg/day up to 10 mg/day in divided doses
- Thiothixene HCl (Navane)
- Thioxanthine
- Dosing (Adults and teens age >12 years)
- Start 2 mg orally three times daily
- May start with up to 5 mg twice daily in severe cases
- Typical Dose: 10 mg three times daily
- Maximum Dose: 60 mg/day
- Start 2 mg orally three times daily
-
Fluphenazine HCl (Prolixin)
- Phenothiazine
- Schizophrenia: 2.5 mg orally twice daily starting to 10-20 mg/day
- Maximum Dose: 40 mg orally or 100 mg IM per day
- Common Adverse Effects: Akathisia, Parkinsonism, Dystonia, Hyperprolactinemia
- Trifluoperazine (Stelazine)
- Phenothiazine
- Psychosis
- Adult (and over age 12 years)
- Start 2 to 5 mg orally twice daily
- Target 15 to 20 mg/day (up to 40 mg in severe cases)
- Child age 6 to 12 years
- Start 1 mg orally twice daily
- Titrate gradually as needed
- Maximum: 15 mg/day
- Adult (and over age 12 years)
- Short-term Anxiety (Adults)
- Start 1 to 2 mg orally twice daily
- May advance as needed to maximum of 6 mg/day
- Avoid use longer than 12 weeks
VI. Preparations: D2 Antipsychotic Agents - Medium Potency
- Loxapine (Loxitane)
- Indicated in Schizophrenia and other Psychotic Disorders
- An inhaled 10 mg daily dose is available but is associated with bronchospasm and respiratory arrest and requires REMS
- Dosing
- Start 10 mg orally twice daily
- Target 60 to 100 mg/day divided twice daily to four times daily
- Maximum: 250 mg/day
- Common Adverse Effects
- Molindone (Moban)
- Indicated in Schizophrenia
- Dosing (adults and teens over age 12 years)
- Start 50 to 75 mg/day divided every 6 to 8 hours
- May increase to 100 mg/day after 3-4 days
- Maximum: 225 mg/day
VII. Preparations: D2 Antipsychotic Agents - Low Potency
- Strong Anticholinergic effects with both agents
-
Chlorpromazine HCl (Thorazine) - not available in U.S.
- Phenothiazine
- Schizophrenia: 25 to 100 mg starting dose titrated to 400 mg/day (range 200 to 800 mg/day, maximum 1000 mg/day)
- Common Adverse Effects
- Alpha adrenergic blockade (Postural Hypotension, Tachycardia)
- Anticholinergic Symptoms (Dry Mouth, sedation)
- Extrapyramidal Side Effects
- Hyperprolactinemia
- Weight gain and Glucose Intolerance
- Thioridazine HCl (Mellaril) - not available in U.S.
- Phenothiazine
- Risk of QTc Prolongation and Torsades de Pointes and not considered a first-line Antipsychotic
- Adverse effects include Anticholinergic Symptoms, Alpha adrenergic blockade (Hypotension), Sedation
- Refractory Schizophrenia
- Adult Dosing
- Start 50 to 100 mg orally three times daily
- Target 200 to 800 mg/day
- Maximum: 800 mg/day
- Child Dosing (age 2 to 12 years)
- Start 0.5 mg/kg/day divided three times daily
- Maximum: 3 mg/kg/day
- Adult Dosing
VIII. Preparations: Atypical Antipsychotics (Second Generation) - Serotonin-Dopamine Antagonists
- Dibenzodiazepine (Clozapine, Clozaril)
- Schizophrenia: start 12.5 to 25 mg twice daily, and titrate to 150-225 mg twice daily (300-600 mg/day)
- Oldest second generation Antipsychotic (introduced in 1989)
- Among the most effective agents in Schizophrenia
- Most adverse side effect profile of second generation agents
- Agranulocytosis (unique to Clozapine and FDA limits prescribers due to this effect)
- Causes Anticholinergic effects, sedation, Postural Hypotension, Seizures, weight gain, dyslipidemia
- Severe CNS depression in Overdose
- Illoperidone (Fanapt, Fanapta, Zomaril)
- Typical maintenance dose: 6-12 mg orally twice daily
- Higher risk of QTc Prolongation
-
Lurasidone (Latuda)
- Typical maintenance dose: 40-160 mg/day
- Schizophrenia: Start at 40 mg/day and titrate to 40 to 160 mg/day
- Significant CNS depression in Overdose
- Common Adverse Effects: Hyperlipidemia, diabetes, Parkinsonism, Somnolence, Nausea
-
Olanzapine (Zyprexa)
- Typical maintenance dose: 10-20 mg/day
- Agitation: 10-20 mg oral or IM
- Schizophrenia: Start 5 to 10 mg/day and titrate to 10 to 20 mg/day
- May cause elevated Creatine Kinase (CK)
- Significant CNS depression in Overdose
- Common Adverse Effects: weight gain, diabetes, Hyperlipidemia, Akathisia, Hyperprolactinemia, Postural Hypotension
-
Paliperidone (Invega)
- Sustained release formulation of the active metabolite of Risperidone
- Common Adverse Effects: Hyperprolactinemia, Hyperlipidemia, weight gain, Priapism
- Typical maintenance dose (including Schizophrenia): 3-6 mg/day (maximum: 12 mg/day)
- Also available as long acting formulation
- Initial dose: 234 mg IM
- Next dose: 156 mg IM at 1 week after initial dose
- Next dose: 39 to 234 mg IM monthly, at 1 month after second dose
-
Quetiapine (Seroquel)
- Schizophrenia start at 50 mg immediate release and titrate to 400 to 800 mg/day
- Typical maintenance dose: 250-600 mg/day
- May cause Tachycardia
- Severe CNS depression in Overdose
- Common Adverse Effects: Hyperlipidemia, Agitation, Dizziness, Dry Mouth, Hypotension, Somnolence, weight gain
-
Risperidone (Risperdal)
- Schizophrenia: Start 2 mg/day and titrate to 2 to 8 mg/day
- Typical maintenance dose: 3-6 mg/day
- Agitation: 4 mg orally daily
- May cause Dystonia
- Common Adverse Effects: Anxiety, Hyperprolactinemia, Hypotension, Insomnia, Nausea, weight gain, diabetes
-
Ziprasidone (Geodon)
- Schizophrenia: Start at 40 mg/day and titrate to 80 to 160 mg/day
- Typical maintenance dose: 40-80 mg/day
- Agitation: 10 mg IM every 2 hours or 20 mg IM every 4 hours
- Higher risk of QTc Prolongation than other Antipsychotics
- Significant CNS depression in Overdose
- Common Adverse Effects: Agitation, Hypotension, Tachycardia, weight gain, diabetes, Somnolence, Nausea
-
Aripiprazole (Abilify)
- Typical maintenance dose: 10-30 mg/day
- Schizophrenia: Start at 10-15 mg daily and titrate to 10-30 mg/day
- Significant CNS depression in Overdose
- Common Adverse Effects: Anxiety, Constipation, Dizziness, Headache, Insomnia
- Lumateperone (Caplyta)
- Low risk of weight gain, Diabetes Mellitus, Extrapyramidal Side Effects and QT Prolongation
- Moderately sedating, FDA approved only for Schizophrenia and is very expensive ($1300/month)
- Single dose: 42 mg once daily with food
-
Asenapine sublingual (Saphris)
- Low to moderate risk of weight gain, and low risk of Diabetes Mellitus, Extrapyramidal Side Effects and QT Prolongation
- Generic in 2020
-
Asenapine patch (Secuado)
- First Antipsychotic patch released at the same time Asenapine will become generic
- Start dosing at 3.8 mg and increase to 5.7 mg after 1 week if needed (higher doses do not appear more effective)
- Costs $1200/month
- Brexipiprazole (Rexulti)
- Schizophrenia: Start 1 mg/day and titrate to 2 to 4 mg/day
- Common Adverse Effects: Hyperlipidemia, weight gain, Akathisia, Somnolence
-
Cariprazine (Vraylar)
- Schizophrenia: Start 1.5 mg/day and titrate to 1.5 to 6 mg/day
- Common Adverse Effects: Hyperprolactinemia, weight gain, Somnolence
IX. Preparations: Atypical Antipsychotics long acting injectables
- Background
- Consider injectable agents in non-compliant patients
- Most require insurance preauthorization or formulary selection
- Injectables cost >$1000/month
-
Invega Trinza IM every 3 months
- Start with Invega Sustenna for at least 4 months before starting Invega Trinza
-
Invega Sustenna IM every month
- Start with 2 injections spaced one week apart, then monthly
-
Abilify Maintena IM every month
- Overlap with oral Abilify for the first 2 weeks (then discontinue oral form)
-
Zyprexa Relprevv IM every 2-4 weeks
- No overlap needed with oral form
-
Risperdal Consta IM every 2 weeks
- Overlap with oral Risperdal for the first 3 weeks (then discontinue oral form)
- References
- (2015) Presc Lett 22(9): 53
X. Precautions
- Antipsychotics (both new and old) should primarily be used for Psychotic Disorders
- May be indicated in Hallucinations, Delusions or Dangerous Behavior outside of psychotic diagnosis
- May be appropriate as a low dose adjunct in severe refractory depression
- Trial on at least 2 different standard Antidepressants or combinations before adding Antipsychotics
- However should not be first-line therapy for non-psychotic conditions
- Not recommended in Insomnia
- Antipsychotics have potential for serious adverse effects (See adverse effects below)
- All Antipsychotics may cause Extrapyramidal Side Effects, QT Prolongation, sedation with Fall Risk
- Atypical Antipsychotics also risk weight gain and Diabetes Mellitus
- Atypical Antipsychotics increase mortality in Dementia (NNH 50-100 in 8-12 weeks)
- Taper off gradually when stopping medication
- Abruptly stopping may induce Movement Disorders and gastrointestinal symptoms
- Taper by 50% or less per week
- References
- (2015) Presc Lett 22(7):37-8
- (2016) Presc Lett 23(3): 17
XI. Adverse Effects: General
-
Agranulocytosis
- See below
-
Extrapyramidal Side Effect (EPSE)
- See Extrapyramidal Side Effect
- EPSE Effects
- Akathisia (motor restlessness)
- Acute Dystonia (face, neck and back spasms)
- Drug-induced Parkinsonism
- EPSE are more common with high potency first generation agents and Risperidone (Risperdal)
- EPSE are less common with Quetiapine (Seroquel) and Ziprasidone (Geodon)
-
Tardive Dyskinesia (up to 20% of patients)
- Extrapyramidal Side Effect resulting in permanent involuntary motor movements including Choreoathetosis
- All Antipsychotics can cause Tardive Dyskinesia
- More common with longterm Antipsychotic use (esp. Haloperidol, Phenothiazines)
-
Neuroleptic Malignant Syndrome
- Rare, but potentially fatal syndrome of Catatonia, rigidity, Altered Level of Consciousness, fever, autonomic instability (e.g. variable BP)
- All Antipsychotics can cause Neuroleptic Malignant Syndrome
- Most common with Clozapine, but all other Atypical Antipsychotics have caused NMS
-
Anticholinergic effects
- May present with Constipation or Xerostomia
- Especially with Low potency first generation agents and Clozapine (Clozaril)
- Less common with Asenapine (Saphris) and Lurasidone (Latuda)
- Sedation
- Especially with Low potency first generation agents
- Most common with Clozapine (Clozaril), Olanzapine (Zyprexa) and Quetiapine (Seroquel)
- Aripiprazole (Abilify) may cause Insomnia
-
Hyperprolactinemia
- See Prolactin
- Especially with all first generation Antipsychotics and Risperidone (Risperdal), Paliperidone (Invega)
- Prolactin is not significantly affected by Aripiprazole (Abilify) or Quetiapine (Seroquel)
-
Postural Hypotension
- Especially with low potency first generation Antipsychotics
- Occurs more often with Clozapine (Clozaril), Quetiapine (Seroquel), and Risperidone (Risperdal)
-
Seizures
- Limited to Overdose and those predisposed to Seizures (agents lower Seizure threshold)
- Most common with Clozapine (3% of cases) and to a much lesser extent Risperidone
-
Sexual Dysfunction
- Especially with all first generation Antipsychotics and Risperidone (Risperdal)
-
Myocarditis
- Most common with Clozapine (and Chlorpromazine)
- Most cases occur within first 4-8 weeks (and mild, asymptomatic cases may occur in up to 66% on Clozapine)
- Fulminant Myocarditis has a high mortality (50%)
- Treated as Cardiomyopathy (ACE Inhibitors, Beta Blockers, Diuretics)
XII. Adverse Effects: Ventricular Arrhythmia (including Cardiac Arrest)
- Antipsychotic agent Relative Risk: 3.2
- Effects
- Antipsychotics may prolong QTc at standard doses
- Increases risk of Torsades and sudden death
- QRS Widening may also be seen with Antipsychotics in Overdose
- Antipsychotics may prolong QTc at standard doses
- Precautions
- See Prolonged QT Interval due to Medication
- Consider obtaining baseline EKG before starting therapy
- Consider Electrolyte and Magnesium monitoring with high risk agents (e.g. Thioridazine)
- Avoid concurrent use of other medications prolonging QT Interval
- Risk factors
- Elderly
- Female patients
- Hypokalemia
- Bradycardia
- Underlying cardiac disease
- Congenitally-acquired QTc Prolongation (very high risk)
- Antipsychotics that prolong QTc (from highest to lowest risk)
- Thioridazine (Mellaril)
- Ziprasidone (Geodon)
- Iloperidone (Fanapt)
- Haloperidol (Haldol)
- Quetiapine (Seroquel)
- Risperidone (Risperdal)
- Clozapine (Clozaril)
- Olanzapine (Zyprexa)
- Paliperidone (Invega)
- Can also prolong the QT Interval (but was released after this study)
- Aripiprazole and Lurasidone are lowest risk for QTc Prolongation
- Antipsychotics that predispose to sudden death
- Typical Antipsychotics (first generation) have been associated with Torsades and Sudden Cardiac Death
- Olanzapine, Risperidone and Quetiapine are not associated with Sudden Cardiac Death
- References
XIII. Adverse Effects: Second Generation Agents (atypicals)
- Weight gain and risk of Metabolic Syndrome or Diabetes Mellitus
- Causes
- Weight gain also with low potency first generation Antipsychotics (Chlorpromazine, Thioridazine)
- Weight gain with all second generation agents except Aripiprazole (Abilify) and Ziprasidone (Geodon)
- Highest risk with Clozapine (Clozaril) and Olanzapine (Zyprexa)
- Lowest risk with Ziprasidone (Geodon) and Aripiprazole (Abilify), as well as Lurasidone (Latuda)
- Management
- Consider starting Metformin with second generation Antipsychotics
- Consider Olanzapine/Samidorphan (Lybalvi)
- Samidorphan is an Opioid receptor Antagonist that reduces Olanzapine associated weight gain
- Causes
- Adverse Lipid effects
- Serum Triglyceride increase most with Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel)
- HDL Cholesterol decrease is variable
XIV. Monitoring
-
Agranulocytosis
-
White Blood Cell Count <1.5 (and Granulocyte count <0.5)
- Occurs in 1% per year on Clozapine
- High mortality risk (up to 35%), especially in first 6 months, but can occur years after starting
- Can occur with nearly all the second generation agents (Atypical Antipsychotics)
- Exceptions: Does not appear to occur with Lurasidone and Paliperidone
- However only Clozapine requires scheduled Complete Blood Count
-
Clozapine has unique monitoring parameters (prescription only allowed by U.S. centers following protocol)
- Highest risk of Agranulocytosis
- Monitoring includes Complete Blood Count (CBC)
- CBC weekly for 6 months, bimonthly for 6 months, then monthly
-
White Blood Cell Count <1.5 (and Granulocyte count <0.5)
- Medical history and Family History (including Cardiovascular Risks and Arrhythmias)
- Obtain history at baseline and readdress annually
-
Extrapyramidal Side Effects (EPSE) - all agents
- Screen for Tardive Dyskinesia at each visit
- Perform Abnormal Involuntary Movement Scale (AIMS) at least every 6 months
- Screen for other EPSE symptoms
- Educate about Neuroleptic Malignant Syndrome
-
Obesity Monitoring (all Antipsychotics)
- Calculate BMI baseline, monthly for 3 months and then every 3 months thereafter
- Measure Waist Circumference annually
-
Blood Pressure
- Obtain baseline, every 3 months and then annually
-
Diabetes Mellitus Screening (newer, atypical agents)
- See adverse effects above
- Fasting Serum Glucose, 3 months and then annually
- Consider Hemoglobin A1C at four months after starting agent
- Screen for Polyuria and polydipsia at each visit
-
Hyperlipidemia (Newer, atypical agents)
- Lipid profile baseline and at 3 months
- Repeat lipids every 6 months if abnormal
- May decrease frequency to every 2-5 years if normal
- References
XV. References
- Glauser and Peters (2016) Crit Dec Emerg Med 30(4): 17-27
- Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 42-3
- Hamilton (2020) Tarascon Pocket Pharmacopoeia
- Crawford (2022) Am Fam Physician 106(4): 388-96 [PubMed]
- Gardner (2005) CMAJ 172(13): 1703-11 [PubMed]
- Geddes (2000) BMJ 321:1371-6 [PubMed]
- Glick (2001) Ann Intern Med 134: 47-60 [PubMed]
- Haddad (2007) CNS Drugs 21(11): 911-36 [PubMed]
- Holder (1014) Am Fam Physician 90(11): 775-82 [PubMed]
- Lieberman (2005) N Engl J Med 353:1209-23 [PubMed]
- Muench (2010) Am Fam Physician 81(5): 617-22 [PubMed]
- Tandon (2011) J Clin Psychiatry 72(suppl 1): 4-8 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
thioridazine (on 7/19/2023 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
THIORIDAZINE 25 MG TABLET | Generic | $0.60 each |
THIORIDAZINE 50 MG TABLET | Generic | $0.82 each |
perphenazine (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
PERPHENAZINE 16 MG TABLET | Generic | $0.43 each |
PERPHENAZINE 2 MG TABLET | Generic | $0.25 each |
PERPHENAZINE 4 MG TABLET | Generic | $0.33 each |
PERPHENAZINE 8 MG TABLET | Generic | $0.43 each |
trifluoperazine (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
TRIFLUOPERAZINE 2 MG TABLET | Generic | $0.78 each |
TRIFLUOPERAZINE 5 MG TABLET | Generic | $0.66 each |
thiothixene (on 5/17/2023 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
THIOTHIXENE 10 MG CAPSULE | Generic | $2.63 each |
THIOTHIXENE 5 MG CAPSULE | Generic | $1.38 each |
loxapine (on 1/19/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
LOXAPINE 10 MG CAPSULE | Generic | $0.50 each |
LOXAPINE 25 MG CAPSULE | Generic | $0.65 each |
LOXAPINE 5 MG CAPSULE | Generic | $0.49 each |
LOXAPINE 50 MG CAPSULE | Generic | $0.97 each |
pimozide (on 10/19/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
PIMOZIDE 2 MG TABLET | Generic | $1.72 each |