Nefazodone

Aka: Nefazodone, Serzone

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II. Precautions: Risk of liver failure (one per 250,000)

  1. Hepatotoxicity resulted in removal from U.S. market in 2003
  2. Contraindicated in comorbid liver disease
  3. Patient and physician watch closely for hepatotoxicity
  4. Consider Liver Function Testing

III. Mechanism

  1. Serotonin Antagonist and Reuptake Inhibitor
    1. Binds postsynaptic Serotonin-2 Receptor (5-HT-2)
    2. More Serotonin binds Serotonin-1 Receptor (5-HT-1)
      1. Anti-depressant effect
    3. Blocks 5-HT-2 Activity
      1. Blocks 5-HT-2 inhibition of 5-HT-1
      2. Blocks Sexual Dysfunction
      3. Blocks Insomnia and anxiety effects
  2. Phenylpiperazine related to Trazodone (Desyrel)
    1. Less sedation than Trazodone
    2. Less Orthostasis than Trazodone
    3. No Priapism

IV. Indications

  1. Major Depression
    1. Consider for severe Refractory Depression Management
  2. Anxiety Disorder
  3. Post-Traumatic Stress Disorder (PTSD)

V. Contraindications

  1. Liver disease
  2. Concurrent medication use
    1. Cisapride
    2. MAO Inhibitor
    3. Triazolam
    4. Terfenadine
    5. Astemizole

VI. Efficacy

  1. Shown to be as effective as Imipramine
  2. No comparison trials with SSRIs

VII. Pharmacokinetics

  1. Half life: 18 hours
  2. Steady state in 4-5 days
  3. Inhibits Cytochrome P450 3A4
  4. Clearance decreased
    1. Elderly
    2. Hepatic dysfunction

VIII. Dosing: General

  1. Start: 100 mg PO qhs for 3 days
  2. Twice daily dosing (FDA approved dosing, or anxiety)
    1. Next: 100 mg PO bid for 7 days
    2. Next: Increase at 1 week intervals to 300 mg PO bid
  3. Once daily dosing (typical dosing by psychiatrists)
    1. Next: 200 mg PO qhs for 7 days
    2. Next: Increase at 1 week intervals upto 600 mg PO qhs
  4. Maximum: 600 mg per day

IX. Dosing: Elderly over age 65 years

  1. Start: 50 mg PO bid
  2. Next: 50-200 mg PO bid

X. Advantages

  1. Less Sexual Dysfunction than SSRIs
  2. Minimal Agitation compared with SSRIs
  3. Rapid onset
  4. May increase REM Sleep
  5. No cardiotoxicity

XI. Adverse effects (May be intolerable)

  1. Hepatotoxicity
    1. Resulted in removal from U.S. market in 2003
  2. Sedation (limiting adverse effect)
    1. Some psychiatrists dose only in evening
  3. Anticholinergic Symptoms increased over SSRIs
    1. Confusion
    2. Dry Mouth
    3. Constipation
    4. Nausea
    5. Dizziness
    6. Blurred Vision
  4. Other Adverse Effects
    1. Postural Hypotension
    2. Headaches
  5. Anxiety may occur due to metabolite (mCPP)
    1. See Drug Interactions below

XII. Drug Interactions

  1. Stop MAO Inhibitor 14 days prior to starting Serzone
  2. Inhibits Cytochrome P450 system (CYP3A4, CYP2D6)
    1. Metabolite mCPP cleared by Cytochrome P450-2D6
      1. Paxil and Prozac inhibit Cytochrome P450-2D6
      2. Excess mCPP (decreased clearance) causes Agitation
    2. Decreased clearance of
      1. Antihistamines
      2. Alprazolam
      3. Triazolam

XIII. References

  1. (1995) Med Lett Drugs Ther 37(946): 33-34 [PubMed]
  2. Sundberg (1995) Depression Primary Care, PGM, p. 45-57

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