Antipsychotics

  • Antipsychotics black box
  • Increase the all-cause mortality of elderly patients with dementia
  • Antipsychotic Most likely to cause hyperprolactinemia
  • Partial dopamine agonists inhibit full dopamine antagonists
  • Aripiprazole decreases Haloperidol efficacy
  • 1st generation antipsychotics (Typical Antipsychotics)
  • General
    • Extrapyramidal Side Effects (EPS) via D2 receptor blockade in the Nigrostriatal pathway
  • Class: Butyrophenone
    • Haloperidol (Haldol)
    • High Potency
    • D2 Inverse agonist, D2 Receptor Antagonist and Alpha Antagonist
    • CI: Lewy body dementia
    • QTc Prolongation (7 to 15ms)

  • Class: Phenothiazine

    • Derived from methylene blue
    • Use: Schizophrenia, Acute Mania
      • Improves positive symptoms, may worse negative
    • SE: Decrease seizure threshold
    • Chlorpromazine (Thorazine)
    • Low Potency
    • MOA: D2 Antagonist, H1 receptor antagonist, Alpha Antagonist
      • Cholinergic Antagonist, alpha-adrenergic receptor antagonist
    • SE: Purple-grey metallic rash over sun exposed areas and jaundice
      • Orthostatic Hypotension, sedation
    • CI : Pregnancy, cardiac patients, acute glaucoma
    • Fluphenazine (Prolixin)
    • High Potency
    • Antipsychotic can cause hypothermia
    • Methylene Blue
    • Prochlorperazine
    • Thioridazine (Mellaril)
    • Low Potency
    • Cholinergic Antagonist
    • Used in the past for resistant schizophrenia
    • SE: Severe QTc Prolongation, Retinitis pigmentosa (decreased vision, poor night vision), blindness
      • 33-41ms
    • Class: Thioxanthene
    • Thiothixene (Navane)
    • High Potency
    • Class: Mesoridazine
    • SE: Worst QTc Prolongation, Cardiac arrythmias (Torsades de pointes)
    • 39-53ms
    • Class: Miscellaneous
    • Pimozide (High Potency)
    • Used in OCD
    • Perfenazine (Trilafon)
    • Medium Potency
    • Molindone (Moban)
    • Medium Potency
    • Loxipine (Loxitane)
    • Medium Potency
    • Cheap, similar to atypical
    • Potency (EPS):
    • (Haloperidol/Trifluoperazine/Fluphenazine/Perphenazine/Thiothixene/Molindone) ≥ (Chlorpromazine/thioridazine)
    • 20% get Tardive Dyskinesia
    • 2nd geneneration antipsychotics (Atypical Antipsychotics)
    • Block D2 and antagonizes 5HT2A receptors
    • Decreased extrapyramidal SE compared to 1st gen
    • 7-9% get Tardive Dyskinesia
    • Fasting glucose and Lipids
    • High Potency
    • Risperidone (Risperdal)
    • Dose: Daily
      • Pill, M-tabs, depot
    • MOA: 5HT2A receptor antagonist
      • Metabolite made by 2D6, thus avoid paroxetine, fluoxetine
    • Use: Mania, Psychosis, Autistic Aggression
      • Available as LAI
      • Least likely to prolong QT (3.5-10ms)
    • SE: Most likely to cause EPS, Most likely to cause galactorrhea and increased prolactin (Hyperprolactinemia), Elevated LFTs
      • Strongest binding at dopamine receptors in pituitary
      • Prolactin ≥200 ng/mL
      • Average metabolic profile
      • 3rd worst for Weight Gain
      • Osteoporosis, decreased sex drive
      • Diffuse Edema/Pedal Edema
      • Starts after several days of treatment, resolves with cessation, no long-term effects
    • Paliperidone (Invega)
    • MOA: 5HT2A receptor antagonist
      • Active metabolite of risperidone (avoids liver metabolism)
    • Use:
      • Available as LAI
      • Low weight gain, low dyslipidemia, low diabetes risk
      • No QTc prolongation (2 to 4ms)?
    • Low Potency:
    • Clozapine (Clozaril)
    • MOA: 5HT2A antagonist, H1 receptor antagonist
      • Weak D2 receptor antagonism
    • Use:
      • Parkinson Disease Psychosis
      • 6.25-75mg daily
      • Treatment resistant schizophrenia after 2 other antipsychotics fail or if EPS on risperidone
      • Decreases suicide risk in schizophrenia
      • Least likely to cause EPS
      • Least likely to cause hyperprolactinemia
    • Monitoring
      • Fasting glucose and lipids
    • SE: Most Weight Gain, Risk for diabetes and worsening lipid profile
      • QTc Prolongation: 10ms
      • Neutropenia often caused by drug-induced agranulocytosis/aplastic anemia
      • Get WBC and ANA (absolute neutrophil) counts
      • Agranulocytosis - Neutrophil deficiency
      • Pneumonia, bronchitis, sinusitis, URI
      • Seizures (high risk), myocarditis
      • Usually Tonic-Clonic
    • Olanzapine (Zyprexa)
    • Pill, Zydis tabs, Relprevv injections (post-injection delirium/sedation syndrome)
    • MOA: Weak D2 Antagonist, 5HT2A Inverse Agonist, Adrenergic Antagonist
      • CYP1A2, concentrations cut in half by smoking, grapefruit juice (double the dose in smokers), Carbamazepine
      • 31-hour half life
      • Alcohol increases absorption by 25%
      • Fluvoxamine, cimetidine, ciprofloxacin increased concentration
      • Carbamazepine reduces olanzapine
    • Use:
      • Schizophrenia
      • Available as LAI
      • Nausea/Vomiting: 2.5-5mg IV/IM
      • Little to no QTc prolongation
      • Low prolactin risk
    • Add Fluoxetine for Bipolar depression
    • SE: Sedating, Little QTc Prolongation (2 to 6.5ms)
      • Diffuse Edema
      • Weight Gain (2nd worst to clozapine, 20kg average)
      • Risk for diabetes and worsening lipid profile
    • Quetiapine (Seroquel)
    • MOA: Weak D2 Antagonist, 5HT2A Antagonist, Adrenergic Antagonist, H1 agonist (Antihistamine activity)
      • Low potency compared to others
      • Dilantin increases clearance 5x
      • 7-hour half life
    • Use: Anxiety, PTSD, Insomnia
      • Most sedating, good for sleep, Dry mouth
      • Max 200mg for sleep prior to switching
      • Low Prolactin risk
    • SE: Torsade de pointes, SCD, orthostatic hypotension, Cataracts
      • Little QTc Prolongation (6 to 15ms)
      • 3rd worst for Weight Gain
    • Other Potency:
    • Ziprasidone (Geodon)
    • Better at 80mg to 20mg, BID dosing, improved absorption w/food
    • Use:
      • Low Metabolic risk profile
      • Decreases cholesterol, triglycerides
      • Minimal to no weight gain
      • May improve concentration/depression vis 5HT-7
    • SE: EPS (akathisia)
      • Moderate QTc Prolongation (16 to 21ms)
    • Aripiprazole (Abilify)
    • MOA: Partial D2 Agonist unlike the others, Partial 5HT2A agonist, strong 5HT2C agonist (less weight gain)
    • Use:
      • Available as LAI
      • Low Metabolic risk profile, Low Prolactin risk, low EPS
      • No QTc Prolongation (-1 to -4ms)
    • SE: Orthostatic hypotension, Nausea/GI effects, somnolence or insomnia
      • Akathisia is more common with aripiprazole
      • Treat with propranolol
    • Brexpiprazole (Rexulti)
    • Dose: 0.5-1mg daily up to 4mg daily
    • MOA: Partial D2 Agonist, Partial 5HT2A agonist
    • Use: Schizophrenia, adjunctive for depression
      • Schizophrenia 2-4mg daily
      • Depression: 2mg daily
      • Low Prolactin risk, Low EPS
    • SE: weight gain, akathisia, URI, somnolence, tremor, headache, fatigue, hyperglycemia, seizures (rare)
    • Cariprazine (Vraylar)
    • Dose: 1.5mg up to 6mg daily
    • MOA: 9x stronger at D3 than D2 partial agonist also
    • 10-14 days, 2 drugs, 4 weeks, 1 drug (that fixes)
    • Use: Bipolar 1 mania, Schizophrenia
      • Quiets mania/hypomania
      • Increases cognition
      • Not sedating
    • SE: akathisia, EPS, weight gain, sedation, GI symptoms
    • Lumateperone
    • Glutamate antagonist used in schizophrenia
    • Lurasidone (Latuda)
    • Dose: 20mg to start, 40, 60, 80, 120mg
      • 20-40 or 80mg max in liver damage
    • MOA: Strong D⅖HT⅖-HT7 antagonist, partial agonist at 5-HT1A receptor, highest atypical activity at 5-HT7
      • Metabolized via CYP3A4
      • Must be taken with food (350 calories minimum increased absorption 9-19%), may be given in evening to decrease somnolence
      • Peak 1-3 hours, steady state 7 days
    • Use: Schizophrenia, Bipolar Depression
      • 80% response on 40-80mg per day
      • Same as quetiapine, not superior to risperidone in schizophrenia
      • Trials: PREVAIL Trial (promising as adjunct or monotherapy in Acute Schizophrenia)
      • Minimal weight gain
      • Low metabolic risk profile
      • No QTc Prolongation
      • No increase in suicidal ideation or behavior
    • SE: sedation, akathisia, nausea, somnolence, Parkinsonism, prolactin increase, headache, 7% increase in body weight, ± TSH increase
    • Asenapine (Saphris)

  • Pregnancy

  • Category B
    • Clozapine, Lurasidone, Bupropion, Maprotiline, Buspirone, Zolpidem
  • Bipolar on maintenance therapy
    • Do not alter even if teratogenic
  • Bipolar needing meds
    • Lamotrigine (Category C) ≥ Lithium, valproate, carbamazepine (Category D)
    • Carbamazepine
    • Craniofacial defects, fingernail hypoplasia, developmental delay
    • Increase folic acid to 4.0 mg/day through 1st trimester
  • Lithium
    • Ebstein's anomaly
  • Valproate
    • Neural tube defects, folate doesn't help (increase to 4.0)
    • Formation occurs between 3rd and 4th week
    • Thrombocytopenia, inhibited platelet aggregation
  • IV Drug abuse
    • Commonly opioids
    • Associated with placenta abruption
    • Treatment
    • Methadone
    • Buprenorphine and Naloxone