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. Medications: 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. Medications: 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. Medications: 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. Medications: 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. Medications: 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 (AIWG or Antipsychotic Induced Weight Gain)
- Increased risk of Metabolic Syndrome and 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
- Associated with 3-5 kg less weight gain over 12 weeks when starting an Antipsychotic
 - Indications
- Coadministration with agents at high risk of weight gain (e.g. Olanzapine)
 - Weight gain >3% over one year after starting Antipsychotic
 
 - Contraindications
- Avoid in low BMI (e.g. BMI 20) at baseline or after starting Metformin
 
 - Dosing
- Start Metformin XR 500 mg daily
 - May increase by 500 mg every 1-2 weeks as tolerated to 1000 to 2000 mg daily
 
 
 - Consider Olanzapine/Samidorphan (Lybalvi)
- Samidorphan is an Opioid receptor Antagonist that reduces Olanzapine associated weight gain
 
 - Consider Obesity Medications in baseline significant Obesity
- GLP1 Agonist (e.g. Semaglutide)
 - GIP/GLP1 Agonist (e.g. Tirzepatide)
 
 
 - Consider starting Metformin with second generation Antipsychotics
 - References
 
 - 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]
 
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