What is known about therapeutic drug monitoring (TDM) for antipsychotic medications?

Basic premise

While therapeutic drug monitoring (TDM) is well established in psychiatry for lithium, tricyclic antidepressants, and clozapine, it is less established with antipsychotic medications (aside from clozapine). Drug levels can be routinely obtained for many antipsychotics, and clinicians should consider using them to guide dosing considering clinical context. TDM can aid clinical decision-making by informing clinicians when antipsychotic blood levels are surprisingly low or high. For many antipsychotics, expected therapeutic blood level ranges are known for a given dose based on correlations with responses in clinical trials. See Table 1 below. Deviations from expected drug levels point towards unusual pharmacokinetics or poor adherence. TDM is not helpful for fine-tuning of blood levels.

General clinical indications

  • Understanding poor response: TDM can provide information to differentiate between poor adherence and treatment resistance. This is an ideal point at which to identify a patient who is likely an ultra-rapid metabolizer.
  • Understanding poor tolerability: TDM can differentiate between poor tolerability due to high sensitivity to antipsychotic side effects (normal plasma level) or due to supra-therapeutic doses. This is an ideal point at which to identify a patient who is likely a poor metabolizer.
  • Establishing dose: TDM can guide upward dose adjustments during the titration phase to reach a dose that is sufficient for most people. It can help find the lowest effective dose during maintenance treatment, to avoid a relapse because of under-treatment. Although there is not yet strong evidence that TDM can guide dose adjustments during the titration phase. TDM may allow for “benchmarking” a patient’s therapeutic dose once a clinical response has been achieved.

Specific clinical indications

  • Suspected treatment resistance.
  • Suspected unusual pharmacokinetics due to drug-drug interactions, medical comorbidities, pregnancy, or age (children and geriatric patients).
  • Suspected unusual pharmacokinetics due to genetic factors.
  • A change in tobacco smoking status can affect blood levels of antipsychotics, particularly olanzapine and clozapine. TDM may be helpful to adjust doses when patients quit or start smoking.
  • Suspected presence of full or partial non-adherence.

Established benefit based on consensus paper

  • TDM is recommended (level 1) for the first-generation antipsychotics fluphenazine, haloperidol, and perphenazine; and the second-generation antipsychotic olanzapine.
  • TDM for other antipsychotics can be recommended (level 2) or may be useful (level 3) but is not as well established as for the aforementioned antipsychotics.

Practical issues

  • The best time to draw an antipsychotic drug level is during steady-state which, for most oral antipsychotics is after about one week (4-5 times the elimination half-life). Note that aripiprazole, brexpiprazole, and cariprazine have much longer half-lives.
  • For oral medications, the best time for the blood draw is in the morning, before the morning dose, if a morning dose is given.
    • Long-acting injectable (LAI) formulations have different pharmacokinetics. For LAIs, the best time is right before the next injection is due.
  • For LAI antipsychotics, TDM can also be used to determine if the injection interval should be shortened in patients who have a drop in antipsychotic blood levels prior to the next scheduled dose.
  • Antipsychotic point-of-care testing (similar to finger-stick glucose testing) can provide actionable information while the patient is at a clinical location. This is in development.

 

TABLE 1: Therapeutic reference ranges for antipsychotic medications where TDM is recommended (level 1) and for antipsychotic available as LAI

Drugs and active metabolite Therapeutic reference range (ng/mL) Laboratory alert level (ng/mL)
Clozapine 350–600 1,000
Fluphenazine 1-10 15
Haloperidol 1-10 15
Perphenazine 0.6-2.4 5
Olanzapine 20-80 100
Aripiprazole 100-350 1,000
Paliperidone 20-60 120
Risperidone + 9-hydroxyrisperidone 20-60 120

 

Further information

The American Society of Clinical Psychopharmacology (ASCP) and the TDM Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has published a joint consensus paper that summarizes the current status of TDM vis-à-vis antipsychotics. 

[Reference: Schoretsanitis G et al.  Blood levels to optimize antipsychotic treatment in clinical practice; a joint consensus of the American Society of Clinical Psychopharmacology (ASCP) and the therapeutic drug monitoring (TDM) task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). Journal of Clinical Psychiatry (in press).]

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