Schizophrenia

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Content
  • 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
  • Important to be aware of drug interactions  (see "CYPs with Major Roles in the in vivo Clearance of Antipsychotic Agents" in PGx section)
    • 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 PGx section)
  • Additional clinical testing (such as CBC and liver enzyme testing) is required for some drugs to detect toxicity
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

 Cytochrome P450 drug interaction table (Flockhart, 2007)

 

Pharmacokinetics of Antischizophrenic Therapeutics

Aripiprazole

Rapid Metabolizers Aripiprazole Dehydroaripiprazole

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 Metabolizers Aripiprazole Dehydroaripiprazole

Time to peak plasma level

60% higher exposure to drugs

 

Half-life

   

Asenapine

Rapid Metabolizers Asenapine  

Time to peak plasma level

0.5-1.5 hours

 

Half-life

14-24 hours

 

Therapeutic range

Not established

 

Cariprazine

Rapid Metabolizers Cariprazine Desmethylcariprazine, didesmethyl cariprazine

Time to peak plasma level

   

Half-life

48-144 hours

 2-3 weeks

Therapeutic range

Not established

 

Chlorpromazine

Rapid Metabolizers Chlorpromazine 7-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 Metabolizers Fluphenazine 7-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 Metabolizers Haloperidol Hydroxyperidol

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 Metabolizers Iloperidone  

Time to peak plasma level

2-3 hours

 

Half-life

5.4 hours (PO)
12 hours (IM)

 

Therapeutic range

Not established

 

Loxapine

Rapid Metabolizers Loxapine 8-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 Metabolizers Molindone  

Time to peak plasma level

1.5 hours

 

Half-life

1.2-2.8 hours

 

Therapeutic range

Not established

 

Olanzapine

Rapid Metabolizers Olanzapine  

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 Metabolizers Perphenazine  

Time to peak plasma level

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

 

Half-life

9 hours

 

Therapeutic range*

0.6-2.4 ng/mL

 

Quetiapine

Rapid Metabolizers Quetiapine N-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 Metabolizers Risperidone 9-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 Metabolizers Risperidone 9-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 Metabolizers Thioridazine  

Time to peak plasma level

2-4 hours

 

Half-life

12-36 hours

 

Therapeutic range

1.0-1.5 µg/mL

 

Thiothixene

Rapid Metabolizers Thiothixene  

Time to peak plasma level

1-3 hours

 

Half-life

12-36 hours

 

Therapeutic range*

1.0-15.0 ng/mL

 

Trifluoperazine

Rapid Metabolizers Trifluoperazine  

Time to peak plasma level

2-3 hours

 

Half-life

7-18 hours

 

Therapeutic range

Not established

 

Ziprasidone

Rapid Metabolizers Ziprasidone  

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 Metabolizers Zotepine  

Time to peak plasma level

4 hours

 

Half-life

13-18.6 hours

 

Therapeutic range

Not established

 
*The therapeutic range is based on serum pre-dose (trough) draw at steady-state concentration

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

Aripiprazole and Metabolite, Serum or Plasma 2007945
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

Therapeutic and toxic ranges – not well established

Chlorpromazine 0090870
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Clozapine 0098930
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Clozapine and Metabolite Quantitative, Serum or Plasma 2006476
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry

Fluphenazine 0099906
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Haloperidol 0099640
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

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

Lurasidone Quantitative, Serum or Plasma 2013018
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry

Olanzapine 0098833
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Perphenazine, Serum or Plasma 2011555
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

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

Limitations

Toxic and therapeutic ranges are not well established

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

Limitations

Toxic and therapeutic ranges are not well established

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

Thiothixene, Serum or Plasma 2011783
Method: Quantitative Liquid Chromatography/Tandem Mass Spectrometry

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

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

Limitations

Only the targeted CYP2D6 variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

It is not always possible to identify which allele is duplicated when a CYP2D6 duplication is detected

Cytochrome P450 2C19, CYP2C19 - 9 Variants 2012769
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

Only the targeted CYP2C19 mutations will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2C19 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

Additional Tests Available

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

General References

Baselt R. Disposition of Toxic Drugs and Chemicals in Man, 8th ed. Foster City, CA: Biomedical Publications, 2008.

Blanc O, Brousse G, Meary A, Leboyer M, Llorca P. Pharmacogenetic of response efficacy to antipsychotics in schizophrenia: pharmacodynamic aspects. Review and implications for clinical research. Fundam Clin Pharmacol. 2010; 24(2): 139-60. PubMed

Caccia S. Pharmacokinetics and metabolism update for some recent antipsychotics. Expert Opin Drug Metab Toxicol. 2011; 7(7): 829-46. PubMed

Clinical Pharmacology Research Institute. P450 Drug Interaction Table: Abbreviated "Clinically Relevant" Table. Indiana University School of Medicine. Indianapolis, IN [Accessed: Nov 2015]

Lawrie S, McIntosh A, Nadeem Z. Schizophrenia. Clin Evid. 2005; 1306-30. PubMed

Mauri M, Volonteri L, Colasanti A, Fiorentini A, De Gaspari I, Bareggi S. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007; 46(5): 359-88. PubMed

Murray M. Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents. J Pharm Pharmacol. 2006; 58(7): 871-85. PubMed

Nazirizadeh Y, Vogel F, Bader W, Haen E, Pfuhlmann B, Gründer G, Paulzen M, Schwarz M, Zernig G, Hiemke C. Serum concentrations of paliperidone versus risperidone and clinical effects. Eur J Clin Pharmacol. 2010; 66(8): 797-803. PubMed

Riedel M, Musil R, Seemüller F, Spellmann I, Möller H, Schennach-Wolff R. Safety evaluation of zotepine for the treatment of schizophrenia. Expert Opin Drug Saf. 2010; 9(4): 659-66. PubMed

Schultz S, North S, Shields C. Schizophrenia: a review. Am Fam Physician. 2007; 75(12): 1821-9. PubMed

Shin J, Malone D, Crosby I, Capuano B. Schizophrenia: a systematic review of the disease state, current therapeutics and their molecular mechanisms of action. Curr Med Chem. 2011; 18(9): 1380-404. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Caravati M, Juenke J, Crouch B, Anderson K. Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays. Ann Pharmacother. 2005; 39(9): 1446-9. PubMed

Juenke J, Brown P, Urry F, Johnson-Davis K, McMillin G. Simultaneous UPLC-MS/MS assay for the detection of the traditional antipsychotics haloperidol, fluphenazine, perphenazine, and thiothixene in serum and plasma. Clin Chim Acta. 2013; 423: 32-4. PubMed

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Last Update: January 2016