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Antipsychotic Medication

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Antipsychotic Medication, Antipsychotic, Anti-Psychotic, Neuroleptic, Atypical Antipsychotic, Thioridazine, Mellaril, Perphenazine, Trilafon, Trifluoperazine, Stelazine, Thiothixene, Navane, Loxapine, Loxitane, Molindone, Moban, Pimozide, Orap

  • See Also
  1. Extrapyramidal Side Effect
  2. Neuroleptic Malignant Syndrome
  • Indications
  1. Psychosis (e.g. Schizophrenia, Acute Mania)
  2. Sedation in Excited Delirium
    1. Especially Haloperidol, Olanzapine, Ziprasidone
  3. Other uses
    1. Antipsychotics should primarily be used for Psychotic Disorders (see precautions below)
    2. Refractory Major Depression adjunct
      1. Atypical Antipsychotics, especially Quetiapine, Aripiprazole
    3. Bipolar Disorder adjunct
      1. Atypical Antipsychotics, especially Quetiapine, Olanzapine, Aripiprazole
    4. Refractory Obsessive Compulsive Disorder adjunct
      1. Atypical Antipsychotics, especially Risperidone, Aripiprazole
    5. Autism related severe maladaptive behaviors
      1. Atypical Antipsychotics, especially Risperidone, Aripiprazole, Olanzapine
  • Mechanism
  1. Psychosis is thought to be associated with increased Dopamine neurotransmission
  2. All Antipsychotic agents block Dopamine D2 Receptors
  3. Antipsychotic drugs also inhibit Dopamine triggered cAMP generation
    1. Unclear mechanism (cAMP is typically mediated by D1 which is not targeted by most Antipsychotics)
  • Efficacy
  • Newer low potency agents
  1. Atypicals are only slightly better than high potency agents
    1. Similar efficacy in control of Psychosis
    2. Slightly less Extrapyramidal Side Effects (EPSE)
      1. Clozapine has much less EPSE, but has diabetes risk
    3. Higher weight, lipid and diabetes related conditions
    4. Compliance is similar for both types of agents
    5. Atypical Antipsychotics are much more expensive
  2. References
    1. Barry (2003) Am Fam Physician 68(5):943-4 [PubMed]
    2. Leucht (2003) Lancet 361:1581-9 [PubMed]
  • Preparations
  • D2 Antipsychotic Agents - High Potency
  1. General: Extrapyramidal Side Effects (EPSE) with all
  2. Haloperidol (Haldol) or Haloperidol Decanoate
    1. Dosing Range
      1. Adult: 5-10 mg PO, IM, or IV
      2. Peds: 0.5-1 mg PO, IM or IV
      3. Adolescent: 1-5 mg PO, IM or IV
      4. Elderly: 0.5-2 mg PO, IM or IV
    2. Dosing Intervals: Scheduled and repeated dosing intervals
      1. May repeat every 30-60 minutes
      2. Maximum: 300 mg/24 hours (avoid cummulative dose over 100 mg in 24 hours)
      3. May dose regularly every 6-8 hours
      4. Typical effective dose: 5 mg PO, IV, or IM tid (lower doses in the elderly)
      5. Total dose >3 mg/day is associated with Extrapyramidal Side Effects
    3. Schizophrenia
      1. Dose: 1 to 5 mg start dose titrated to 5-20 mg/day
    4. Common Adverse Effects
      1. Dry Mouth, Extrapyramidal Side Effects, Galactorrhea, Hyperprolactinemia, Hypotension, Tachycardia, Somnolence
  3. Perphenazine (Trilafon)
    1. Phenothiazine
    2. Schizophrenia and other Psychotic Disorders
      1. Start 4 to 8 mg orally every 8 hours
        1. May use up to 8 to 16 mg orally every 6 to 12 hours in hospitalized patients
      2. May titrate to 32 mg/day
      3. Maximum: 64 mg/day
    3. Refractory Nausea or Vomiting
      1. Dose 8 to 16 mg/day in divided doses
      2. Maximum: 24 mg/day
    4. Common Adverse Effects
      1. Dry Mouth, Extrapyramidal Side Effects, Galactorrhea, Hyperprolactinemia, Hypotension, Tachycardia, Somnolence
    5. Well tolerated with similar efficacy to other agents
      1. Lieberman (2005) N Engl J Med 353:1209-23 [PubMed]
  4. Pimozide (Orap)
    1. Phenothiazine
    2. Risk of QTc Prolongation
      1. Obtain baseline EKG
      2. Avoid combining with other causes of Drug-Induced QTc Prolongation
      3. Avoid with strong CYP3A4 and CYP2D6 Inhibitors
    3. Tourette Syndrome (age over 12 years and adults)
      1. Start 0.05 mg/kg up to 1 to 2 mg at bedtime
      2. May increase dose every few days to target dose 1 to 10 mg/day in divided doses
      3. Maximum 0.2 mg/kg/day up to 10 mg/day in divided doses
  5. Thiothixene HCl (Navane)
    1. Thioxanthine
    2. Dosing (Adults and teens age >12 years)
      1. Start 2 mg orally three times daily
        1. May start with up to 5 mg twice daily in severe cases
      2. Typical Dose: 10 mg three times daily
      3. Maximum Dose: 60 mg/day
  6. Fluphenazine HCl (Prolixin)
    1. Phenothiazine
    2. Schizophrenia: 2.5 mg orally twice daily starting to 10-20 mg/day
    3. Maximum Dose: 40 mg orally or 100 mg IM per day
    4. Common Adverse Effects: Akathisia, Parkinsonism, Dystonia, Hyperprolactinemia
  7. Trifluoperazine (Stelazine)
    1. Phenothiazine
    2. Psychosis
      1. Adult (and over age 12 years)
        1. Start 2 to 5 mg orally twice daily
        2. Target 15 to 20 mg/day (up to 40 mg in severe cases)
      2. Child age 6 to 12 years
        1. Start 1 mg orally twice daily
        2. Titrate gradually as needed
        3. Maximum: 15 mg/day
    3. Short-term Anxiety (Adults)
      1. Start 1 to 2 mg orally twice daily
      2. May advance as needed to maximum of 6 mg/day
      3. Avoid use longer than 12 weeks
  • Preparations
  • D2 Antipsychotic Agents - Medium Potency
  1. Loxapine (Loxitane)
    1. Indicated in Schizophrenia and other Psychotic Disorders
    2. An inhaled 10 mg daily dose is available but is associated with bronchospasm and respiratory arrest and requires REMS
    3. Dosing
      1. Start 10 mg orally twice daily
      2. Target 60 to 100 mg/day divided twice daily to four times daily
      3. Maximum: 250 mg/day
    4. Common Adverse Effects
      1. Dry Mouth, Extrapyramidal Side Effects, Galactorrhea, Hyperprolactinemia, Hypotension, Tachycardia, Somnolence
  2. Molindone (Moban)
    1. Indicated in Schizophrenia
    2. Dosing (adults and teens over age 12 years)
      1. Start 50 to 75 mg/day divided every 6 to 8 hours
      2. May increase to 100 mg/day after 3-4 days
      3. Maximum: 225 mg/day
  • Preparations
  • D2 Antipsychotic Agents - Low Potency
  1. Strong Anticholinergic effects with both agents
  2. Chlorpromazine HCl (Thorazine) - not available in U.S.
    1. Phenothiazine
    2. Schizophrenia: 25 to 100 mg starting dose titrated to 400 mg/day (range 200 to 800 mg/day, maximum 1000 mg/day)
    3. Common Adverse Effects
      1. Alpha adrenergic blockade (Postural Hypotension, Tachycardia)
      2. Anticholinergic Symptoms (Dry Mouth, sedation)
      3. Extrapyramidal Side Effects
      4. Hyperprolactinemia
      5. Weight gain and Glucose Intolerance
  3. Thioridazine HCl (Mellaril) - not available in U.S.
    1. Phenothiazine
    2. Risk of QTc Prolongation and Torsades de Pointes and not considered a first-line Antipsychotic
    3. Adverse effects include Anticholinergic Symptoms, Alpha adrenergic blockade (Hypotension), Sedation
    4. Refractory Schizophrenia
      1. Adult Dosing
        1. Start 50 to 100 mg orally three times daily
        2. Target 200 to 800 mg/day
        3. Maximum: 800 mg/day
      2. Child Dosing (age 2 to 12 years)
        1. Start 0.5 mg/kg/day divided three times daily
        2. Maximum: 3 mg/kg/day
  1. Dibenzodiazepine (Clozapine, Clozaril)
    1. Schizophrenia: start 12.5 to 25 mg twice daily, and titrate to 150-225 mg twice daily (300-600 mg/day)
    2. Oldest second generation Antipsychotic (introduced in 1989)
    3. Among the most effective agents in Schizophrenia
    4. Most adverse side effect profile of second generation agents
      1. Agranulocytosis (unique to Clozapine and FDA limits prescribers due to this effect)
      2. Causes Anticholinergic effects, sedation, Postural Hypotension, Seizures, weight gain, dyslipidemia
      3. Severe CNS depression in Overdose
  2. Illoperidone (Fanapt, Fanapta, Zomaril)
    1. Typical maintenance dose: 6-12 mg orally twice daily
    2. Higher risk of QTc Prolongation
  3. Lurasidone (Latuda)
    1. Typical maintenance dose: 40-160 mg/day
    2. Schizophrenia: Start at 40 mg/day and titrate to 40 to 160 mg/day
    3. Significant CNS depression in Overdose
    4. Common Adverse Effects: Hyperlipidemia, diabetes, Parkinsonism, Somnolence, Nausea
  4. Olanzapine (Zyprexa)
    1. Typical maintenance dose: 10-20 mg/day
    2. Agitation: 10-20 mg oral or IM
    3. Schizophrenia: Start 5 to 10 mg/day and titrate to 10 to 20 mg/day
    4. May cause elevated Creatine Kinase (CK)
    5. Significant CNS depression in Overdose
    6. Common Adverse Effects: weight gain, diabetes, Hyperlipidemia, Akathisia, Hyperprolactinemia, Postural Hypotension
  5. Paliperidone (Invega)
    1. Sustained release formulation of the active metabolite of Risperidone
    2. Common Adverse Effects: Hyperprolactinemia, Hyperlipidemia, weight gain, Priapism
    3. Typical maintenance dose (including Schizophrenia): 3-6 mg/day (maximum: 12 mg/day)
    4. Also available as long acting formulation
      1. Initial dose: 234 mg IM
      2. Next dose: 156 mg IM at 1 week after initial dose
      3. Next dose: 39 to 234 mg IM monthly, at 1 month after second dose
  6. Quetiapine (Seroquel)
    1. Schizophrenia start at 50 mg immediate release and titrate to 400 to 800 mg/day
    2. Typical maintenance dose: 250-600 mg/day
    3. May cause Tachycardia
    4. Severe CNS depression in Overdose
    5. Common Adverse Effects: Hyperlipidemia, Agitation, Dizziness, Dry Mouth, Hypotension, Somnolence, weight gain
  7. Risperidone (Risperdal)
    1. Schizophrenia: Start 2 mg/day and titrate to 2 to 8 mg/day
    2. Typical maintenance dose: 3-6 mg/day
    3. Agitation: 4 mg orally daily
    4. May cause Dystonia
    5. Common Adverse Effects: Anxiety, Hyperprolactinemia, Hypotension, Insomnia, Nausea, weight gain, diabetes
  8. Ziprasidone (Geodon)
    1. Schizophrenia: Start at 40 mg/day and titrate to 80 to 160 mg/day
    2. Typical maintenance dose: 40-80 mg/day
    3. Agitation: 10 mg IM every 2 hours or 20 mg IM every 4 hours
    4. Higher risk of QTc Prolongation than other Antipsychotics
    5. Significant CNS depression in Overdose
    6. Common Adverse Effects: Agitation, Hypotension, Tachycardia, weight gain, diabetes, Somnolence, Nausea
  9. Aripiprazole (Abilify)
    1. Typical maintenance dose: 10-30 mg/day
    2. Schizophrenia: Start at 10-15 mg daily and titrate to 10-30 mg/day
    3. Significant CNS depression in Overdose
    4. Common Adverse Effects: Anxiety, Constipation, Dizziness, Headache, Insomnia
  10. Lumateperone (Caplyta)
    1. Low risk of weight gain, Diabetes Mellitus, Extrapyramidal Side Effects and QT Prolongation
    2. Moderately sedating, FDA approved only for Schizophrenia and is very expensive ($1300/month)
    3. Single dose: 42 mg once daily with food
  11. Asenapine sublingual (Saphris)
    1. Low to moderate risk of weight gain, and low risk of Diabetes Mellitus, Extrapyramidal Side Effects and QT Prolongation
    2. Generic in 2020
  12. Asenapine patch (Secuado)
    1. First Antipsychotic patch released at the same time Asenapine will become generic
    2. Start dosing at 3.8 mg and increase to 5.7 mg after 1 week if needed (higher doses do not appear more effective)
    3. Costs $1200/month
  13. Brexipiprazole (Rexulti)
    1. Schizophrenia: Start 1 mg/day and titrate to 2 to 4 mg/day
    2. Common Adverse Effects: Hyperlipidemia, weight gain, Akathisia, Somnolence
  14. Cariprazine (Vraylar)
    1. Schizophrenia: Start 1.5 mg/day and titrate to 1.5 to 6 mg/day
    2. Common Adverse Effects: Hyperprolactinemia, weight gain, Somnolence
  • Preparations
  • Atypical Antipsychotics long acting injectables
  1. Background
    1. Consider injectable agents in non-compliant patients
    2. Most require insurance preauthorization or formulary selection
      1. Injectables cost >$1000/month
  2. Invega Trinza IM every 3 months
    1. Start with Invega Sustenna for at least 4 months before starting Invega Trinza
  3. Invega Sustenna IM every month
    1. Start with 2 injections spaced one week apart, then monthly
  4. Abilify Maintena IM every month
    1. Overlap with oral Abilify for the first 2 weeks (then discontinue oral form)
  5. Zyprexa Relprevv IM every 2-4 weeks
    1. No overlap needed with oral form
  6. Risperdal Consta IM every 2 weeks
    1. Overlap with oral Risperdal for the first 3 weeks (then discontinue oral form)
  7. References
    1. (2015) Presc Lett 22(9): 53
  • Precautions
  1. Antipsychotics (both new and old) should primarily be used for Psychotic Disorders
    1. May be indicated in Hallucinations, Delusions or Dangerous Behavior outside of psychotic diagnosis
    2. May be appropriate as a low dose adjunct in severe refractory depression
      1. Trial on at least 2 different standard Antidepressants or combinations before adding Antipsychotics
    3. However should not be first-line therapy for non-psychotic conditions
    4. Not recommended in Insomnia
  2. Antipsychotics have potential for serious adverse effects (See adverse effects below)
    1. All Antipsychotics may cause Extrapyramidal Side Effects, QT Prolongation, sedation with Fall Risk
    2. Atypical Antipsychotics also risk weight gain and Diabetes Mellitus
    3. Atypical Antipsychotics increase mortality in Dementia (NNH 50-100 in 8-12 weeks)
  3. Taper off gradually when stopping medication
    1. Abruptly stopping may induce Movement Disorders and gastrointestinal symptoms
    2. Taper by 50% or less per week
  4. References
    1. (2015) Presc Lett 22(7):37-8
    2. (2016) Presc Lett 23(3): 17
  • Adverse Effects
  • General
  1. Agranulocytosis
    1. See below
  2. Extrapyramidal Side Effect (EPSE)
    1. See Extrapyramidal Side Effect
    2. EPSE Effects
      1. Akathisia (motor restlessness)
      2. Acute Dystonia (face, neck and back spasms)
      3. Drug-induced Parkinsonism
    3. EPSE are more common with high potency first generation agents and Risperidone (Risperdal)
    4. EPSE are less common with Quetiapine (Seroquel) and Ziprasidone (Geodon)
  3. Tardive Dyskinesia (up to 20% of patients)
    1. Extrapyramidal Side Effect resulting in permanent involuntary motor movements including Choreoathetosis
    2. All Antipsychotics can cause Tardive Dyskinesia
    3. More common with longterm Antipsychotic use (esp. Haloperidol, Phenothiazines)
  4. Neuroleptic Malignant Syndrome
    1. Rare, but potentially fatal syndrome of Catatonia, rigidity, Altered Level of Consciousness, fever, autonomic instability (e.g. variable BP)
    2. All Antipsychotics can cause Neuroleptic Malignant Syndrome
    3. Most common with Clozapine, but all other Atypical Antipsychotics have caused NMS
  5. Anticholinergic effects
    1. May present with Constipation or Xerostomia
    2. Especially with Low potency first generation agents and Clozapine (Clozaril)
    3. Less common with Asenapine (Saphris) and Lurasidone (Latuda)
  6. Sedation
    1. Especially with Low potency first generation agents
    2. Most common with Clozapine (Clozaril), Olanzapine (Zyprexa) and Quetiapine (Seroquel)
    3. Aripiprazole (Abilify) may cause Insomnia
  7. Hyperprolactinemia
    1. See Prolactin
    2. Especially with all first generation Antipsychotics and Risperidone (Risperdal), Paliperidone (Invega)
    3. Prolactin is not significantly affected by Aripiprazole (Abilify) or Quetiapine (Seroquel)
  8. Postural Hypotension
    1. Especially with low potency first generation Antipsychotics
    2. Occurs more often with Clozapine (Clozaril), Quetiapine (Seroquel), and Risperidone (Risperdal)
  9. Seizures
    1. Limited to Overdose and those predisposed to Seizures (agents lower Seizure threshold)
    2. Most common with Clozapine (3% of cases) and to a much lesser extent Risperidone
  10. Sexual Dysfunction
    1. Especially with all first generation Antipsychotics and Risperidone (Risperdal)
  11. Myocarditis
    1. Most common with Clozapine (and Chlorpromazine)
    2. Most cases occur within first 4-8 weeks (and mild, asymptomatic cases may occur in up to 66% on Clozapine)
    3. Fulminant Myocarditis has a high mortality (50%)
    4. Treated as Cardiomyopathy (ACE Inhibitors, Beta Blockers, Diuretics)
  1. Antipsychotic agent Relative Risk: 3.2
  2. Effects
    1. Antipsychotics may prolong QTc at standard doses
      1. Increases risk of Torsades and sudden death
    2. QRS Widening may also be seen with Antipsychotics in Overdose
  3. Precautions
    1. See Prolonged QT Interval due to Medication
    2. Consider obtaining baseline EKG before starting therapy
    3. Consider Electrolyte and Magnesium monitoring with high risk agents (e.g. Thioridazine)
    4. Avoid concurrent use of other medications prolonging QT Interval
      1. See Prolonged QT Interval due to Medication
  4. Risk factors
    1. Elderly
    2. Female patients
    3. Hypokalemia
    4. Bradycardia
    5. Underlying cardiac disease
    6. Congenitally-acquired QTc Prolongation (very high risk)
  5. Antipsychotics that prolong QTc (from highest to lowest risk)
    1. Thioridazine (Mellaril)
    2. Ziprasidone (Geodon)
    3. Iloperidone (Fanapt)
    4. Haloperidol (Haldol)
    5. Quetiapine (Seroquel)
    6. Risperidone (Risperdal)
    7. Clozapine (Clozaril)
    8. Olanzapine (Zyprexa)
    9. Paliperidone (Invega)
      1. Can also prolong the QT Interval (but was released after this study)
    10. Aripiprazole and Lurasidone are lowest risk for QTc Prolongation
  6. Antipsychotics that predispose to sudden death
    1. Typical Antipsychotics (first generation) have been associated with Torsades and Sudden Cardiac Death
    2. Olanzapine, Risperidone and Quetiapine are not associated with Sudden Cardiac Death
  7. References
    1. Hennessy (2002) BMJ 325:1070-2 [PubMed]
    2. Stroup (2007) Am J Psychiatry 164(3): 415-27 [PubMed]
    3. Titier (2005) Drug Saf 28: 35-51 [PubMed]
  • Adverse Effects
  • Second Generation Agents (atypicals)
  1. Weight gain and risk of Metabolic Syndrome or Diabetes Mellitus
    1. Causes
      1. Weight gain also with low potency first generation Antipsychotics (Chlorpromazine, Thioridazine)
      2. Weight gain with all second generation agents except Aripiprazole (Abilify) and Ziprasidone (Geodon)
        1. Highest risk with Clozapine (Clozaril) and Olanzapine (Zyprexa)
        2. Lowest risk with Ziprasidone (Geodon) and Aripiprazole (Abilify), as well as Lurasidone (Latuda)
    2. Management
      1. Consider starting Metformin with second generation Antipsychotics
      2. Consider Olanzapine/Samidorphan (Lybalvi)
        1. Samidorphan is an Opioid receptor Antagonist that reduces Olanzapine associated weight gain
  2. Adverse Lipid effects
    1. Serum Triglyceride increase most with Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel)
    2. HDL Cholesterol decrease is variable
  • Monitoring
  1. Agranulocytosis
    1. White Blood Cell Count <1.5 (and Granulocyte count <0.5)
      1. Occurs in 1% per year on Clozapine
      2. High mortality risk (up to 35%), especially in first 6 months, but can occur years after starting
    2. Can occur with nearly all the second generation agents (Atypical Antipsychotics)
      1. Exceptions: Does not appear to occur with Lurasidone and Paliperidone
      2. However only Clozapine requires scheduled Complete Blood Count
    3. Clozapine has unique monitoring parameters (prescription only allowed by U.S. centers following protocol)
      1. Highest risk of Agranulocytosis
      2. Monitoring includes Complete Blood Count (CBC)
        1. CBC weekly for 6 months, bimonthly for 6 months, then monthly
  2. Medical history and Family History (including Cardiovascular Risks and Arrhythmias)
    1. Obtain history at baseline and readdress annually
  3. Extrapyramidal Side Effects (EPSE) - all agents
    1. Screen for Tardive Dyskinesia at each visit
    2. Perform Abnormal Involuntary Movement Scale (AIMS) at least every 6 months
      1. https://dmh.mo.gov/media/21821/download
    3. Screen for other EPSE symptoms
    4. Educate about Neuroleptic Malignant Syndrome
  4. Obesity Monitoring (all Antipsychotics)
    1. Calculate BMI baseline, monthly for 3 months and then every 3 months thereafter
    2. Measure Waist Circumference annually
  5. Blood Pressure
    1. Obtain baseline, every 3 months and then annually
  6. Diabetes Mellitus Screening (newer, atypical agents)
    1. See adverse effects above
    2. Fasting Serum Glucose, 3 months and then annually
    3. Consider Hemoglobin A1C at four months after starting agent
    4. Screen for Polyuria and polydipsia at each visit
  7. Hyperlipidemia (Newer, atypical agents)
    1. Lipid profile baseline and at 3 months
    2. Repeat lipids every 6 months if abnormal
      1. May decrease frequency to every 2-5 years if normal
  8. References
    1. Marder (2004) Am J Psychiatry 161: 1334-49 [PubMed]
  • References
  1. Glauser and Peters (2016) Crit Dec Emerg Med 30(4): 17-27
  2. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 42-3
  3. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  4. Crawford (2022) Am Fam Physician 106(4): 388-96 [PubMed]
  5. Gardner (2005) CMAJ 172(13): 1703-11 [PubMed]
  6. Geddes (2000) BMJ 321:1371-6 [PubMed]
  7. Glick (2001) Ann Intern Med 134: 47-60 [PubMed]
  8. Haddad (2007) CNS Drugs 21(11): 911-36 [PubMed]
  9. Holder (1014) Am Fam Physician 90(11): 775-82 [PubMed]
  10. Lieberman (2005) N Engl J Med 353:1209-23 [PubMed]
  11. Muench (2010) Am Fam Physician 81(5): 617-22 [PubMed]
  12. Tandon (2011) J Clin Psychiatry 72(suppl 1): 4-8 [PubMed]