Schizophrenia

Diagnosis

  • Based on clinical presentation plus psychiatric evaluation

Differential Diagnosis

  • Brief psychotic episode
  • Delirium
  • Acute or chronic medical illness
  • Substance abuse
  • Schizophreniform disorders
  • Medication-induced disorder
  • Pervasive developmental disorder

Monitoring

  • Important to be aware of drug interactions  (see "CYPs with Major Roles in the In vivo Clearance of Antipsychotic Agents" in Pharmacogenetics)
    • CYP variants may affect drug metabolism
    • Inheritance of clinically significant CYP2D6 variants alter drug metabolism
  • Periodic drug monitoring is useful to assure compliance and to identify drug-drug interactions or other reasons to adjust dosing and may establish optimal therapeutic ranges for an individual patient
  • Suggested therapeutic ranges and toxic thresholds are available for some but not all commonly used antipsychotic drugs  (see "Pharmacokinetics of Antischizophrenic Therapeutics" in Pharmacogenetics)
  • Additional clinical testing (such as CBC and liver enzyme testing) is required for some drugs to detect toxicity

Pharmacogenetics and Therapeutic Drug Monitoring

  • Pharmacogenetic testing may guide drug and dose selection
    • CYPs with major roles in the in vivo clearance of antipsychotic agents (see table below)
    CYPs with Major Roles in the In vivo Clearance of Antipsychotic Agents

    CYP

    Antipsychotic drug

    Inhibitors

    Inducers

    Number of allelic variants

    1A2

    Clozapine
    Haloperidol
    Olanzapine

    Amiodarone
    Cimetidine
    Ciprofloxacin

    Omeprazole

    24 plus wild-type (also 9 predicted haplotypes)

    2C19

    R-mephobarbital

    Chloramphenicol
    Cimetidine
    Felbamate
    Fluoxetine
    Ketoconazole
    Lansoprazole
    Omeprazole
    Oxcarbazepine
    Topiramate
    Carbamazepine
    Prednisone
    Rifampin
    Mephenytoin
     

    2D6

    Aripiprazole
    Chlorpromazine
    Haloperidol
    Risperidone
    Thioridazine

    Bupropion
    Celecoxib
    Chlorpromazine
    Cimetidine
    Clomipramine
    Diphenhydramine
    Doxepin
    Fluoxetine
    Methadone
    Paroxetine
    Ranitidine
    Sertraline
    Quinidine

    Dexamethasone
    Rifampin

    94 plus wild-type

    3A4/5/7

    Aripiprazole
    Haloperidol
    Quetiapine
    Risperidone
    Ziprasidone

    Cimetidine
    Clarithromycin
    Diltiazem
    Erythromycin
    Fluconazole
    HIV antivirals
    Ketoconazole
    Norfloxacin
    Verapamil
    Voriconazole

    Carbamazepine
    Dexamethasone
    HIV antivirals
    Phenytoin
    Rifampin
    St. John's wort

    38 plus wild-type

    P450 Drug Interactions: Abbreviated Clinically Relevant Table (Indiana University School of Medicine)
    Cytochrome P450 drug interaction table (Indiana University School of Medicine)
    • Pharmacokinetics of antischizophrenic therapeutics (see table below)
    Pharmacokinetics of Antischizophrenic Therapeutics
    Aripiprazole
    Rapid MetabolizersAripiprazoleDehydroaripiprazole

    Time to peak plasma level

    3-5 hours (PO)
    1-3 hours (IM)

    Accumulates at 40% of aripiprazole concentration

    Half-life

    47-68 hours

    94 hours

    Therapeutic range

    Suggested 150-500 ng/mL

    Suggested 150-500 ng/mL
    Poor MetabolizersAripiprazoleDehydroaripiprazole

    Time to peak plasma level

    60% higher exposure to drugs

     

    Half-life

      
    Asenapine
    Rapid MetabolizersAsenapine 

    Time to peak plasma level

    0.5-1.5 hours

     

    Half-life

    14-24 hours

     

    Therapeutic range

    Not established

     
    Cariprazine
    Rapid MetabolizersCariprazineDesmethylcariprazine, didesmethyl cariprazine

    Time to peak plasma level

      

    Half-life

    48-144 hours

     2-3 weeks

    Therapeutic range

    Not established

     
    Chlorpromazine
    Rapid MetabolizersChlorpromazine7-hydroxychlorpromazine

    Time to peak plasma level

    30 minutes-8 hours (highly variable)

     

    Half-life

    23-37 hours

    10-40 hours

    Therapeutic range

    50-300 ng/mL

     
    Toxic threshold (when available)

    >750 ng/mL

     
    Fluphenazine
    Rapid MetabolizersFluphenazine7-hydroxyfluphenazine

    Time to peak plasma level

    1-8 hours (but peak plasma with steady state may be 3 months)

     

    Half-life

    Hydrochloride salt: 6-8 hours
    Decanoate: 24-72 hours

     

    Therapeutic range

    0.3-3.0 ng/mL

     
    Haloperidol
    Rapid MetabolizersHaloperidolHydroxyperidol

    Time to peak plasma level

    2-6 hours (PO)
    10-20 minutes (IM)

     

    Half-life

    24 hours (PO)
    21 hours (IM)

     

    Therapeutic range

    5.0-20.0 ng/mL (from LTD)

     
    Iloperidone
    Rapid MetabolizersIloperidone 

    Time to peak plasma level

    2-3 hours

     

    Half-life

    5.4 hours (PO)
    12 hours (IM)

     

    Therapeutic range

    Not established

     
    Loxapine
    Rapid MetabolizersLoxapine8-hydroxyloxapine; 8-hydroxyamoxapine

    Time to peak plasma level

    1.5-3 hours (PO)
    20-30 minutes (IM)

     

    Half-life

    4 hours (PO)
    12 hours (IM)

     

    Therapeutic range

    Not established

     

    Lurasidone

    Rapid Metabolizers

    Lurasidone

     Exo-hydroxylrasidone

    Time to peak plasma level

    1-3 hours

     

    Half-life

    28-37 hours

     7.5-10 hours

    Therapeutic range

    Not established

     
    Molindone
    Rapid MetabolizersMolindone 

    Time to peak plasma level

    1.5 hours

     

    Half-life

    1.2-2.8 hours

     

    Therapeutic range

    Not established

     
    Olanzapine
    Rapid MetabolizersOlanzapine 

    Time to peak plasma level

    6 hours (PO)
    15-45 minutes (IM)

     

    Half-life

    21-54 hours

     

    Therapeutic range

    5-75 ng/mL

     

    Paliperidone

    Rapid Metabolizers

    Paliperidone

     

    Time to peak plasma level

    24 hours

     

    Half-life

    23 hours

     

    Therapeutic range

    Suggested 20-60 ng/mL

     

    Perospirone

    Rapid Metabolizers

    Perospirone

    Hydroxyperospirone

    Time to peak plasma level

    1 hour

     

    Half-life

    1-3 hours

     2 hours

    Therapeutic range

    Not established

     
    Perphenazine
    Rapid MetabolizersPerphenazine 

    Time to peak plasma level

    4-8 hours (PO)
    30-60 minutes (IM)

     

    Half-life

    9 hours

     

    Therapeutic range

    0.8-2.4 ng/mL

     
    Quetiapine
    Rapid MetabolizersQuetiapineN-desalkylquetiapine

    Time to peak plasma level

    1.5 hours (IR)
    6 hours (ER)

     

    Half-life

    7 hours

    9-12 hours

    Therapeutic range

    Suggested range 70-170 ng/mL

     
    Risperidone
    Rapid MetabolizersRisperidone9-hydroxyrisperidone

    Time to peak plasma level

    1-2 hours (steady state = 1 day)

    Steady state = 5-6 days

    Half-life

    3 hours

    20 hours

    Therapeutic range

    Suggested 20-60 ng/mL

    Suggested 20-60 ng/mL

    Poor MetabolizersRisperidone9-hydroxyrisperidone

    Time to peak plasma level

    1 hour (steady state = 1 day)

    17 hours 
    (steady state = 6-8 hours)

    Half-life

    20 hours

    30 hours

    Therapeutic range

      
    Thioridazine
    Rapid MetabolizersThioridazine 

    Time to peak plasma level

    2-4 hours

     

    Half-life

    12-36 hours

     

    Therapeutic range

    1.0-1.5 µg/mL

     
    Thiothixene
    Rapid MetabolizersThiothixene 

    Time to peak plasma level

    1-3 hours

     

    Half-life

    12-36 hours

     

    Therapeutic range

    1.0-15.0 ng/mL

     
    Trifluoperazine
    Rapid MetabolizersTrifluoperazine 

    Time to peak plasma level

    2-3 hours

     

    Half-life

    7-18 hours

     

    Therapeutic range

    Not established

     
    Ziprasidone
    Rapid MetabolizersZiprasidone 

    Time to peak plasma level

    6-8 hours (PO)
    <60 minutes (IM)

     

    Half-life

    2-7 hours

     

    Therapeutic range

    Proposed 50-200 ng/mL

     
    Zotepine
    Rapid MetabolizersZotepine 

    Time to peak plasma level

    4 hours

     

    Half-life

    13-18.6 hours

     

    Therapeutic range

    Not established

     

Clinical Background

Schizophrenia is a mental illness that severely impairs social and mental functioning.

Epidemiology

  • Incidence – 2-4/1,000
    • Lifetime prevalence of 0.5-1%
  • Age –  onset in 20s; younger age for men
    • Late-onset disease (>30 years) is unusual
  • Sex – M>F

Risk Factors

  • Family history is strongly correlated
  • Other less-correlated factors

Pathophysiology

  • Neurotransmitter is likely involved in dopamine transmission
    • Drugs that induce states similar to schizophrenia increase dopaminergic transmission
    • Drugs that treat schizophrenia decrease dopaminergic transmission
  • Other neurotransmitters such as serotonin and catecholamines may be involved in schizophrenia

Clinical Presentation

  • Signs and symptoms must be present >30 days in the absence of treatment
  • Hallucinations, delusions
  • Disorganized thoughts, speech, and behavior

Treatment

  • Antipsychotic drugs are the mainstay of therapy
  • Dopamine D2 antagonists
    • Chlorpromazine
    • Clozapine
    • Fluphenazine, fluphenazine decanoate
    • Haloperidol, haloperidol decanoate
    • Loxapine
    • Molindone
    • Perphenazine
    • Thioridazine
    • Thiothixene
    • Trifluoperazine
  • Atypical mixed neuroreceptor antagonists – low-affinity D2 antagonists, high-affinity 5-HTR2A antagonists
    • Aripiprazole
    • Asenapine
    • Cariprazine
    • Cloperidone
    • Lurasidone
    • Olanzapine
    • Perospirone
    • Quetiapine
    • Risperidone
    • Ziprasidone
    • Zotepine
  • Hepatic phase 1 oxidation is catalyzed by cytochrome P450 (CYP) enzymes
    • Inheritance of clinically significant CYP2D6 variants alter drug metabolism

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Aripiprazole and Metabolite, Serum or Plasma 2007945
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Therapeutic monitoring

Predose (trough) concentration at steady state should be assessed

Analytical sensitivity – limit of quantification is 5.0 ng/mL

Therapeutic and toxic ranges – not well established

 
Chlorpromazine 0090870
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Therapeutic monitoring    
Clozapine 0098930
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Therapeutic monitoring    
Clozapine and Metabolite Quantitative, Serum or Plasma 2006476
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry
Therapeutic monitoring    
Fluphenazine 0099906
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Therapeutic monitoring    
Haloperidol 0099640
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Monitor haloperidol

Evaluate compliance

Therapeutic range relates to the management of psychoses; lower concentrations may be therapeutic for Tourette syndrome and mania

Toxic range is >42 ng/mL; some patients experience toxicity within the therapeutic range

 
Loxapine, Urine 0091499
Method: High Performance Liquid Chromatography

Monitor loxapine

Evaluate compliance

Serum or plasma preferred for therapeutic monitoring

 
Loxapine, Serum or Plasma 0091295
Method: High Performance Liquid Chromatography

Monitor loxapine

Evaluate compliance

   
Olanzapine 0098833
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Monitor olanzapine

Evaluate compliance

   
Perphenazine 0099985
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Monitor perphenazine

Evaluate compliance

   
Risperidone and Metabolite, Serum or Plasma 2007951
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Therapeutic monitoring

Predose (trough) concentration at steady state should be assessed

Use in conjunction with 9-hydroxyrisperidone testing to measure drug metabolism

Analytic sensitivity – limit of detection is 5.0 ng/mL

  • Interferences from commonly used drugs and associated metabolites have not been observed

Toxic and therapeutic ranges are not well established

 
Paliperidone, Serum or Plasma 2007949
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Therapeutic monitoring

Predose (trough) concentration at steady state should be assessed

Analytical sensitivity – limit of detection is 5.0 ng/mL

  • Interferences from commonly used drugs and associated metabolites have not been observed

Toxic and therapeutic ranges are not well established

 
Quetiapine, Serum or Plasma 2003118
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Monitor quetiapine

Evaluate compliance

   
Thiothixene 0099904
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Monitor thiothixene.

Evaluate compliance

   
Ziprasidone, Serum or Plasma 2007955
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Therapeutic monitoring

Predose (trough) concentration at steady state should be assessed

Analytical sensitivity – limit of detection is 5.0 ng/mL

   
Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Primer Extension

Pre-therapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2D6 such as schizophrenia medications

Clinical sensitivity >95% in Caucasians; unknown in other ethnicities

Only targeted CYP2D6 mutations will be detected; mutations in other genes will not be detected

Phase and copy number of detected CYP2D6 mutations may not be determined

Mutations in other genes associated with drug metabolism or drug response will not be detected

Drug metabolism may be affected by non-genetic factors

Mutation detection is not a substitute for therapeutic drug or clinical monitoring

Diagnostic errors can occur due to rare sequence variations

Genotype results should be interpreted in the context of the individual clinical situation

 
Cytochrome P450 2C19 (CYP2C19) 9 Variants 0051104
Method: Polymerase Chain Reaction/Primer Extension

Pre-therapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2C19 such as antidepressants (amitriptyline, escitalopram)

Only targeted CYP2C19 mutations will be detected; mutations in other genes will not be detected

Mutations in other genes associated with drug metabolism or drug response will not be detected

Drug metabolism may be affected by nongenetic factors

Mutation detection is not a substitute for therapeutic drug or clinical monitoring

Diagnostic errors can occur due to rare sequence variations

Genotype results should be interpreted in the context of the individual clinical situation

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Lithium, Serum or Plasma 0020038
Method: Colorimetry
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry