Summary: Psycho-

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• 1 Psychopharmacology

• 1.1 Clozapine

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• FDA Black Box Warning for Clozapine

  IG My SON
  Increase mortality with elderly with dementia related psychosis
  GI hypomotility
  Myocarditis, Pericarditis, Cardiomyopathy
  Seizures
  Orthostatic Hypotension
  Neutropenia (Severe)

• How to initiate Clozapine

   Clozapine is typically initiated at 12.5 mg once a day, at night.
  On day 2, can increase to 12.5mg bd.
  , can increased by 25-50mg a day, until a therapeutic dose achieved.
  
  • Target dose :
  Female non smoker = 250mg/d
  Male non smoker = 350mg/d
  Female smoker =450mg/day.
  Male moker = 550mg/d.
  
  Min effective dose : 300 -900 mg/day.
  Max dose: 900mg/day •
  Aim plasma level : 350ng/ml. •
  
  Treatment breaks and blood monitoring for patients who have been on clozapine for • more than 18 weeks:

• Cut off point and management based on TWC and ANC for Clozapine

  TWC > 3.5 OR  ANC > 2 : Continue treatment 
  TWC 3 - 3.5  OR ANC 1.5 - 2 : Monitor FBC biweekly
  TWC < 3 OR ANC < 1.5 : Stop treatment, daily FBC monitoring, referral to Haematology --Do not rechallenge

• 1.1.1 Agranulocytosis in Clozapine use

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• Risk of Agranulocytosis in Clozapine use

  Risk of neutropenia is similar to general population and other antipsychotics.  Risk is highest in first 18 weeks, then declines to negligible after 1 year.

• 1.1.2 Clozapine induced Hypersalivation

• Causes of Hypersalivation secondary to Clozapine use

   Muscarinic (M4) stimulation
  o Alpha-2 blockade
  o Reduced swallowing reflex (most likely)

• Pharmacological management of Hypersalivation due to Clozapine use

    First-line (most evidence):
  Antimuscarinics (e.g. propantheline, diphenhydramine NHS recommended Hyocine HYdrobomide – patches (behind ear 1-2 patches every 72hourly) or tablet (max 300mcg 3x/day) 
  
  Topical treatments preferred (fewer side effects):
  Atropine drops – 1-2 drops subligually 4-6hourly if needed, sofpironium gel
  
  Second-line: Metoclopramide Caution: Antimuscarinics may worsen constipation/GI hypomotility (serious with clozapine)

• 1.1.3 Clozapine induced Myocarditis

• Define Myocarditis induced by Clozapine use

   Inflammation of the heart muscle (myocardium) due to a hypersensitivity reaction.

• Clinical Presentation of Clozapine induced Myocarditis

  Symptoms:
  Fatigue, fever, flu-like symptoms, tachycardia, hypotension, chest pain, shortness of breath.
  
  • Signs/Investigations:
  ECG changes (ST depression), enlarged heart on echo/X-ray, eosinophilia, elevated CRP and troponin.

• Risk factor for Clozapine induced Myocarditis

  • Rapid titration
  • Concomitant sodium valproate
  • Older age (31% increased risk per decade)
  • Pre-existing heart disease, family history, illicit drug use
  • Other psychotropics (lithium, risperidone, haloperidol, chlorpromazine, fluphenazine)

• Management of Clozapine induced Myocarditis

  Immediate clozapine cessation if myocarditis suspected.
  • Cardiology referral essential.
  • Rechallenge: Possible in selected beta-blockers, ACE inhibitors, mineralocorticoid antagonists; 62% success rate.
  • Slow titration example: 6.25 mg increases every 3–4 days until 75 mg, then gradually faster.