Antipsychotics

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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 D2/5HT2/5-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

Antipsychotics

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