The Physician's Guide to Laboratory Test Selection and InterpretationSchizophrenia
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
OlanzapineAmiodarone
Cimetidine
CiprofloxacinOmeprazole
24 plus wild-type (also 9 predicted haplotypes)
2C19
R-mephobarbital
Chloramphenicol
Cimetidine
Felbamate
Fluoxetine
Ketoconazole
Lansoprazole
Omeprazole
Oxcarbazepine
TopiramateCarbamazepine
Prednisone
Rifampin
Mephenytoin2D6
Aripiprazole
Chlorpromazine
Haloperidol
Risperidone
ThioridazineBupropion
Celecoxib
Chlorpromazine
Cimetidine
Clomipramine
Diphenhydramine
Doxepin
Fluoxetine
Methadone
Paroxetine
Ranitidine
Sertraline
QuinidineDexamethasone
Rifampin94 plus wild-type
3A4/5/7
Aripiprazole
Haloperidol
Quetiapine
Risperidone
ZiprasidoneCimetidine
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
HIV antivirals
Ketoconazole
Norfloxacin
Verapamil
VoriconazoleCarbamazepine
Dexamethasone
HIV antivirals
Phenytoin
Rifampin
St. John's wort38 plus wild-type
- Pharmacokinetics of antischizophrenic therapeutics (see table below)
Pharmacokinetics of Antischizophrenic Therapeutics Aripiprazole Rapid Metabolizers Aripiprazole Dehydroaripiprazole Time to peak plasma level
3-5 hours (PO)
1-3 hours (IM)Half-life
47-68 hours
94 hours
Therapeutic range
No published data
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 hoursTherapeutic 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
20-52 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
0.8-2.4 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
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
Not established
Zotepine Rapid Metabolizers Zotepine 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
- Cannabis use
- CNS infection in childhood
- Maternal obstetrical complications
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 |
Monitor aripiprazole Evaluate compliance |
||
| Chlorpromazine 0090870 Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry |
Monitor chlorpromazine Evaluate compliance |
||
| Clozapine 0098930 Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry |
Monitor clozapine Evaluate compliance Use along with white blood cell and absolute neutrophil count tests |
||
| Clozapine and Metabolite, Serum or Plasma 2006476 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry |
Monitor clozapine Evaluate compliance |
||
| Fluphenazine 0099906 Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry |
Monitor fluphenazine Evaluate compliance |
||
| 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 not well established; 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 |
Monitor risperidone Evaluate compliance Use in conjunction with 9-hydroxyrisperidone testing to measure drug metabolism |
||
| Paliperidone, Serum or Plasma 2007949 Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry |
Monitor paliperidone Evaluate compliance |
||
| 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 |
Monitor ziprasidone Evaluate compliance |
||
| Cytochrome P450 2D6 (CYP2D6) 14 Mutations and Gene Duplication 0051232 Method: Polymerase Chain Reaction/Primer Extension |
Detect variants in coding for drug metabolizing enzymes Clinical sensitivity >95% in Caucasians; unknown in other ethnicities |
Only targeted CYP2D6 mutations will be detected; mutations in other genes will not be detected Rare diagnostic errors can occur due to primer site mutations |
|
| Cytochrome P450 2C19 (CYP2C19) 9 Mutations 0051104 Method: Polymerase Chain Reaction/Primer Extension |
Screen for potential adverse reactions to schizophrenic drugs |
Click the plus sign to expand the table of additional tests.
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