Schizophrenia

  • Diagnosis
  • Monitoring
  • Pharmacogenetics
  • Background
  • Lab Tests
  • References
  • Related Topics
  • 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

 

PARENT DRUG

METABOLITES

Aripiprazole

Rapid metabolizers

Aripiprazole

Dehydroaripiprazole

    Time to peak plasma level

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

Accumulates at 40% of aripiprazole concentration

    Half-life

47-68 hrs

94 hrs

    Therapeutic range*

150-500 ng/mL

150-500 ng/mL

    Toxic threshold

Not well established

 

Poor metabolizers

Aripiprazole

Dehydroaripiprazole

    Time to peak plasma level

60% higher exposure to drugs

 

Asenapine

Rapid metabolizers

Asenapine

 

    Time to peak plasma level

0.5-1.5 hrs

 

    Half-life

14-24 hrs

 

    Therapeutic range

Not established

 

Brexpiprazole

Rapid metabolizers

Brexpiprazole

 

    Time to peak plasma level

65 hrs (IV)

82 hrs (PO)

 

    Half-life

91 hrs

 

    Therapeutic range

Not well established

 

Cariprazine

Rapid metabolizers

Cariprazine

Desmethylcariprazine, didesmethyl cariprazine

    Half-life

48-144 hrs

 2-3 wks

    Therapeutic range

Not established

 

Chlorpromazine

Rapid metabolizers

Chlorpromazine

7-hydroxychlorpromazine

    Time to peak plasma level

30 mins – 8 hrs (highly variable)

 

    Half-life

23-37 hrs

10-40 hrs

    Therapeutic range*

≤11 yrs of age – 30-80 ng/mL

≥12 yrs of age – 50-300 ng/mL

 

    Toxic threshold (when available)

≤11 yrs of age – >200 ng/mL

≥12 yrs of age – >750 ng/mL

 

Fluphenazine

Rapid metabolizers

Fluphenazine

7-hydroxyfluphenazine

    Time to peak plasma level

1-8 hrs (but peak plasma with steady state may be 3 mos)

 

    Half-life

Hydrochloride salt – 6-8 hrs
Decanoate – 24-72 hrs

 

    Therapeutic range*

0.5-2.0 ng/mL

 

    Toxic threshold

Not well established

 

Haloperidol

Rapid metabolizers

Haloperidol

Hydroxyperidol

    Time to peak plasma level

2-6 hrs (PO)
10-20 mins (IM)

 

    Half-life

24 hrs (PO)
21 hrs (IM)

 

    Therapeutic range*

5-20 ng/mL

 

    Toxic threshold

>42 ng/mL

 

Iloperidone

Rapid metabolizers

Iloperidone

 

    Time to peak plasma level

2-3 hrs

 

    Half-life

5.4 hrs (PO)
12 hrs (IM)

 

    Therapeutic range

Not established

 

Loxapine

Rapid metabolizers

Loxapine

8-hydroxyloxapine; 8-hydroxyamoxapine

    Time to peak plasma level

1.5-3 hrs (PO)
20-30 mins (IM)

 

    Half-life

4 hrs (PO)
12 hrs (IM)

 

    Therapeutic range

Not established

 

Lurasidone

Rapid metabolizers

Lurasidone

 Exo-hydroxylrasidone

    Time to peak plasma level

1-3 hrs

 

    Half-life

28-37 hrs

 7.5-10 hrs

    Therapeutic range

Not established

 

Olanzapine

Rapid metabolizers

Olanzapine

 

    Time to peak plasma level

6 hrs (PO)
15-45 mins (IM)

 

    Half-life

21-54 hrs

 

    Therapeutic range*

20-80 ng/mL

 

    Toxic threshold

Not well established

 

Paliperidone

Rapid metabolizers

Paliperidone

 

    Time to peak plasma level

24 hrs

 

    Half-life

23 hrs

 

    Therapeutic range*

20-60 ng/mL

 

    Toxic threshold

Not well established

 

Perphenazine

Rapid metabolizers

Perphenazine

 

    Time to peak plasma level

4-8 hrs (PO)
30-60 mins (IM)

 

    Half-life

9-12 hrs

 

    Therapeutic range*

0.6-2.4 ng/mL

 

    Toxic threshold

>12 ng/mL

 

Pimozide

Rapid metabolizers

Pimozide

 

    Time to peak plasma level

4-12 hrs

 

    Half-life

55 hrs

 

    Therapeutic range

Not well established

 

Poor metabolizers

Pimozide

 

    Half-life

150 hrs

 

Quetiapine

Rapid metabolizers

Quetiapine

N-desalkylquetiapine

    Time to peak plasma level

1.5 hrs (IR)
6 hrs (ER)

 

    Half-life

6-12 hrs

9-12 hrs

    Therapeutic range*

70-170 ng/mL

 

    Toxic threshold

>1000 ng/mL

 

Risperidone

Rapid metabolizers

Risperidone

9-hydroxyrisperidone

    Time to peak plasma level

1-2 hrs (steady state = 1 day)

Steady state = 5-6 days

    Half-life

3 hrs

20 hrs

    Therapeutic range (total)*

20-60 ng/mL

Suggested 20-60 ng/mL

Poor metabolizers

Risperidone

9-hydroxyrisperidone

    Time to peak plasma level

1 hr (steady state = 1 day)

17 hrs 
(steady state = 6-8 hrs)

    Half-life

20 hrs

30 hrs

Thioridazine

Rapid metabolizers

Thioridazine

 

    Time to peak plasma level

2-4 hrs

 

    Half-life

12-36 hrs

 

    Therapeutic range

1.0-1.5 µg/mL

 

Thiothixene

Rapid metabolizers

Thiothixene

 

    Time to peak plasma level

1-3 hrs

 

    Half-life

12-36 hrs

 

    Therapeutic range*

1-15 ng/mL

 

    Toxic threshold

Not well established

 

Trifluoperazine

Rapid metabolizers

Trifluoperazine

 

    Time to peak plasma level

2-3 hrs

 

    Half-life

7-18 hrs

 

    Therapeutic range

Not established

 

Ziprasidone

Rapid metabolizers

Ziprasidone

 

    Time to peak plasma level

6-8 hrs (PO)
<60 mins (IM)

 

    Half-life

2-7 hrs

 

    Therapeutic range*

Not well established

Proposed dose-related range –  50-200 ng/mL

 

    Toxic threshold

Not well established

 

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
  • United States drugs for treatment of schizophrenia
    • Dopamine D2 antagonists
      • Chlorpromazine
      • Clozapine
      • Fluphenazine, fluphenazine decanoate
      • Haloperidol, haloperidol decanoate
      • Loxapine
      • Perphenazine
      • ​Pimozide
      • Thioridazine
      • Thiothixene
      • Trifluoperazine
    • Atypical mixed neuroreceptor antagonists – low-affinity D2 antagonists, high-affinity 5-HTR2A antagonists
      • Aripiprazole
      • Asenapine
      • ​Brexpiprazole
      • Cariprazine
      • Cloperidone
      • Iloperidone
      • Lurasidone
      • Olanzapine
      • Paliperidone
      • Quetiapine
      • Risperidone
      • Ziprasidone
  • Hepatic phase 1 oxidation is catalyzed by cytochrome P450 (CYP) enzymes
    • Inheritance of clinically significant CYP2D6 variants alter drug metabolism

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 and Metabolites, Serum or Plasma, Quantitative 2013433
Method: Quantitative 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 Genotype Panel 2013098
Method: Polymerase Chain Reaction/Primer Extension (CYP2D6)
Polymerase Chain Reaction/Fluorescence Monitoring (CYP2C9, CYP2C19, CYP3A5)

Limitations

Only the targeted CYP2D6, CYP2C9, CYP2C19, and CYP3A5  variants will be detected

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6, CYP2C9, CYP2C19, or CYP3A5 substrates may be affected by genetic and nongenetic factors that are not detected by this test

Variant detection does not replace therapeutic drug and clinical monitoring

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 by this panel

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

Related Tests

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 MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. 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 SH, North SW, Shields CG. Schizophrenia: a review. Am Fam Physician. 2007; 75(12): 1821-9. PubMed

Shin JK, Malone DT, Crosby IT, 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 JM, Crouch BI, Anderson KT. Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays. Ann Pharmacother. 2005; 39(9): 1446-9. PubMed

Juenke JM, Brown PI, Urry FM, Johnson-Davis KL, McMillin GA. 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

Medical Reviewers

Last Update: July 2016