Table 1.
Therapeutic drug monitoring of second- and third-generation antipsychotic drugs.
| Antipsychotic Drug (2nd and 3rd Generation) | Enzymes Involved in Drug Metabolism 1 | Therapeutic Reference Range | Alert Level | t1/2 | TDM Level of Recommendation 2 |
|---|---|---|---|---|---|
| Amisulpride | More than 90% is excreted unchanged via the kidney | 100–320 ng/mL | 640 ng/mL | 12–20 h | 1 |
| Comment: Some patients may need concentrations above 320 ng/mL to attain sufficient improvement. CL not affected by CYP enzymes. | |||||
| Aripiprazole plus dehydro-aripiprazole |
CYP2D6, CYP3A4 | 150–500 ng/mL | 1000 ng/mL | 60–80 h | 2 |
| Comment: Dehydro-aripiprazole concentrations amount to about 45% of the parent drug. Apparent elimination half-life 30–47 days. CAVE: Steady-state will be reached after approximately 14 days. | |||||
| Brexpiprazole | CYP3A4, CYP2D6 | 40–140 ng/mL | 280 ng/mL | 91 h | 3 |
| Comment: CAVE: Steady-state will be reached after approximately 19 days | |||||
| Cariprazine | CYP3A4 | 10–20 ng/mL | 40 ng/mL | 48–120 h | 3 |
| Comment: Active metabolites are N-desmethyl-cariprazine and N,N-di-desmethyl-cariprazine. CAVE: Steady-state will be reached after approximately 21 days. | |||||
| Clozapine | CYP1A2, CYP2C19 | 350–600 ng/mL | 1000 ng/mL | 12–16 h | 1 |
| Comment: CL may be enhanced in smokers due to induction of CYP1A2 and decreased during inflammation. A lower CRP value associated with a 100% increase in drug serum concentration: 25.5 mg/L *. CL/F is twofold higher in Asian than Caucasian patients. For clozapine, t1/2 is prolonged to 30 h in intoxicated patients. | |||||
| Lurasidone | CYP3A4 | 15–40 ng/mL | 120 ng/mL | 20–40 h | 3 |
| Comment: CL affected by food intake (fat content). | |||||
| Olanzapine | UGT1A4, CYP1A2 | 20–80 ng/mL | 100 ng/mL | 30–60 h | 1 |
| Comment: Apparent half-life for olanzapine pamoate 30 days, CL higher in males than in females and elevated in smokers due to induction of CYP1A2. | |||||
| Paliperidone | 60% is excreted unmetabolized | 20–60 ng/mL | 120 ng/mL | 17–23 h | 2 |
| Comment: Apparent half-life for paliperidone palmitate 25–49 days. CL not affected by CYP enzymes. | |||||
| Quetiapine | CYP3A4 | 100–500 ng/mL | 1000 ng/mL | 6–11 h | 2 |
| Comment: When the patient has taken the extended release (ER) formulation in the evening and blood was withdrawn in the morning, expected concentrations are 2-fold higher than trough levels. CL affected by gender and age. Trend for a drug concentration increase during inflammation (less than 15%) *. | |||||
| Risperidone plus 9-hydroxy-risperidone |
CYP2D6 | 20–60 ng/mL | 120 ng/mL | 2–4 h 17–23 h |
2 |
| Comment: Adverse reactions correlate with drug concentrations. To avoid neurological adverse reactions, > 40 ng/mL should be targeted only in cases of insufficient or absence of therapeutic response. Apparent half-life for long-acting injection formulation 26 days. CL affected by CYP2D6 and age, potentially decreased during inflammation. A lower CRP value associated with a 100% increase in RIS + OH-RIS serum concentration was detected at CRP ≥ 37.5 mg/L *. | |||||
| Sertindole | CYP2D6 | 50–100 ng/mL | 200 ng/mL | 55–90 h | 2 |
| Comment: Active metabolite dehydro-sertindole (concentration at therapeutic doses 40–60 ng/mL), concentration dependent increase of QT interval by blockade of potassium channels. | |||||
| Sulpiride | Not metabolized, renal excretion | 200–1000 ng/mL | 1000 ng/mL | 8–14 h | 2 |
| Comment: CL reduced in case of impaired renal function, CL not affected by CYP enzymes. | |||||
| Ziprasidone | - | 50–200 ng/mL | 400 ng/mL | 4–8 h | 2 |
| Comment: The drug should be taken with a meal, otherwise absorption is reduced and drug concentrations will be lower than expected. | |||||
CL: Clearance; CRP: C-reactive protein; CYP: cytochrome P450; F: bioavailability; t1/2: elimination half-life; UGT: UDP-glucuronosyltransferase; RIS: risperidone; OH-RIS: 9-hydroxy-risperidone. 1 When compounds are combined with strong or moderate inhibitors or inducers of listed enzymes, then the compounds’ concentrations in blood will significantly increase or decrease by ≥ 50%. Therefore, only clinically relevant enzymes involved in drug metabolism are listed. 2 Level of recommendation to use TDM: Level 1: Strongly recommended, Level 2: Recommended, Level 3: Useful, Level 4: Potentially useful. * Hefner et al. [40]. Besides Hefner et al. [40], this table also displays data from Hiemke et al. [9].