Antipsychotic Medication

See Also

Indications

Psychosis (e.g. Schizophrenia)
Sedation in Excited Delirium
1. Especially Haloperidol, Olanzapine, Ziprasidone
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

Efficacy
Newer low potency agents

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
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

General: Extrapyramidal Side Effects (EPSE) with all
Haloperidol (Haldol) or Haloperidol decanoate
1. Typical dose: 10-15 mg/day
Perphenazine (Trilafon)
1. Well tolerated with similar efficacy to other agents
  1. Lieberman (2005) N Engl J Med 353:1209-23 [PubMed]
Thiothixene HCl (Navane)
1. Typical Dose: 10 mg three times daily
2. Maximum Dose: 60 mg per day
Fluphenazine HCl (Prolixin)
1. Typical Dose: 2.5 mg orally twice daily starting to 10-20 mg/day
2. Maximum Dose: 40 mg orally or 100 mg IM per day
Trifluoperazine (Stelazine)

Preparations
D2 Antipsychotic Agents - Medium Potency

Loxapine (Loxitane)
Molindone (Moban)

Preparations
D2 Antipsychotic Agents - Low Potency

Strong Anticholinergic effects with both agents
Chlorpromazine HCl (Thorazine) - not available in U.S.
1. Anticholinergic Symptoms
2. Alpha adrenergic blockade (Hypotension)
3. Sedation
4. Dosing: 400 mg/day (maximum 1000 mg/day)
Thioridazine HCl (Mellaril) - not available in U.S.
1. Anticholinergic Symptoms
2. Alpha adrenergic blockade (Hypotension)
3. Sedation
4. Dosing: 200-300 mg/day (maximum 800 mg/day)

Preparations
Atypical Antipsychotics (Second Generation) - Serotonin-Dopamine Antagonists

Dibenzodiazepine (Clozapine, Clozaril)
1. Typical maintenance dose: 150-225 mg twice daily (300-600 mg/day)
2. Oldest second generation Antipsychotic (introduced in 1989)
3. 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
Illoperidone (Fanapt, Fanapta, Zomaril)
1. Typical maintenance dose: 6-12 mg orally twice daily
2. Higher risk of QTc Prolongation
Lurasidone (Latuda)
1. Typical maintenance dose: 40-160 mg/day
2. Significant CNS depression in Overdose
Olanzapine (Zyprexa)
1. Typical maintenance dose: 10-20 mg/day
2. Agitation: 10-20 mg oral or IM
3. May cause elevated Creatine Kinase (CK)
4. Significant CNS depression in Overdose
Paliperidone (Invega)
1. Sustained release formulation of the active metabolite of Risperidone
2. Typical maintenance dose: 3-6 mg/day (maximum: 12 mg/day)
3. 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
Quetiapine (Seroquel)
1. Typical maintenance dose: 250-600 mg/day
2. May cause Tachycardia
3. Severe CNS depression in Overdose
Risperidone (Risperdal)
1. Typical maintenance dose: 3-6 mg/day
2. Agitation: 4 mg orally daily
3. May cause Dystonia
Ziprasidone (Geodon)
1. Typical maintenance dose: 40-80 mg/day
2. Agitation: 10 mg IM every 2 hours or 20 mg IM every 4 hours
3. Higher risk of QTc Prolongation
4. Significant CNS depression in Overdose
Aripiprazole (Abilify)
1. Typical maintenance dose: 10-30 mg/day
2. Significant CNS depression in Overdose
Caplyta (lumateperone)
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
Saphris (asenapine sublingual)
1. Low to moderate risk of weight gain, and low risk of Diabetes Mellitus, Extrapyramidal Side Effects and QT Prolongation
2. Generic in 2020
Secuado (asenapine patch)
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

Preparations
Atypical Antipsychotics long acting injectables

Background
1. Consider injectable agents in non-compliant patients
2. Most require insurance preauthorization or formulary selection
  1. Injectables cost >$1000/month
Invega Trinza IM every 3 months
1. Start with Invega Sustenna for at least 4 months before starting Invega Trinza
Invega Sustenna IM every month
1. Start with 2 injections spaced one week apart, then monthly
Abilify Maintena IM every month
1. Overlap with oral Abilify for the first 2 weeks (then discontinue oral form)
Zyprexa Relprevv IM every 2-4 weeks
1. No overlap needed with oral form
Risperdal Consta IM every 2 weeks
1. Overlap with oral Risperdal for the first 3 weeks (then discontinue oral form)
References
1. (2015) Presc Lett 22(9): 53

Precautions

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
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)
Taper off gradually when stopping medication
1. Abruptly stopping may induce Movement Disorders and gastrointestinal symptoms
2. Taper by 50% or less per week
References
1. (2015) Presc Lett 22(7):37-8
2. (2016) Presc Lett 23(3): 17

Adverse Effects
General

See Agranulocytosis below
See Extrapyramidal Side Effect (EPSE)
1. Especially with high potency first generation agents and Risperidone (Risperdal)
2. All Antipsychotics can cause Tardive Dyskinesia
Neuroleptic Malignant Syndrome
1. All Antipsychotics can cause Neuroleptic Malignant Syndrome
2. Most common with Clozapine, but all other Atypical Antipsychotics have caused NMS
Anticholinergic effects
1. Especially with Low potency first generation agents and Clozapine (Clozaril)
Sedation
1. Especially with Low potency first generation agents, Clozapine (Clozaril), Olanzapine (Zyprexa) and Quetiapine (Seroquel)
Hyperprolactinemia
1. See Prolactin
2. Especially with all first generation Antipsychotics and Risperidone (Risperdal)
Postural Hypotension
1. Especially with low potency first generation Antipsychotics, Clozapine (Clozaril), Quetiapine (Seroquel), and Risperidone (Risperdal)
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
Sexual Dysfunction
1. Especially with all first generation Antipsychotics and Risperidone (Risperdal)
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)
Ventricular Arrhythmia (including Cardiac Arrest)
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

Adverse Effects
Second generation agents (atypicals)

Weight gain and risk of Metabolic Syndrome or Diabetes Mellitus
1. Highest risk with Clozapine (Clozaril) and Olanzapine (Zyprexa)
2. Lowest risk with Ziprasidone (Geodon) and Aripiprazole (Abilify), as well as Lurasidone (Latuda)
3. Weight gain with all second generation agents except Aripiprazole (Abilify) and Ziprasidone (Geodon)
4. Also occurs with low potency first generation Antipsychotics (Chlorpromazine, Thioridazine)
Adverse Lipid effects
1. Serum Triglyceride increase most with Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel)
2. HDL Cholesterol decrease is variable

Monitoring

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
Medical history and Family History (including cardiovascular risks and Arrhythmias)
1. Obtain history at baseline and readdress annually
Extrapyramidal Side Effects (EPSE) - all agents
1. Screen for Tardive Dyskinesia at each visit
2. Screen for other EPSE symptoms
3. Educate about Neuroleptic Malignant Syndrome
Obesity Monitoring (all Antipsychotics)
1. Calculate BMI baseline, monthly for 3 months and then every 3 months thereafter
2. Measure Waist Circumference annually
Blood Pressure
1. Obtain baseline, every 3 months and then annually
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
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
References
1. Marder (2004) Am J Psychiatry 161: 1334-49 [PubMed]

References

Glauser and Peters (2016) Crit Dec Emerg Med 30(4): 17-27
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]