Editor-in-Chief
Hatice Kübra Elçioğlu
Vice Editors
Levent Kabasakal
Esra Tatar
Online ISSN
2630-6344
Publisher
Marmara University
Frequency
Bimonthly (Six issues / year)
Abbreviation
J.Res.Pharm.
Former Name
Marmara Pharmaceutical Journal
Journal of Research in Pharmacy
2023 , Vol 27 , Issue Supp.
THERAPEUTIC DRUG MONITORING OF ANTIPSYCHOTICS
1Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
DOI :
10.29228/jrp.548
Antipsychotics are drugs that are primarily used in the management of
schizophrenia and other disorders with psychotic features [1]. There are many
antipsychotics available for clinical use [2]. They are traditionally divided into two
groups based on the receptor-binding profile, incidence of extrapyramidal side
effects and efficacy against negative symptoms: first-generation (also known as
‘typical’, ‘classical’ or ‘conventional’) antipsychotics such as haloperidol and
chlorpromazine, and second-generation antipsychotics (also known as ‘atypical’
antipsychotics) such as clozapine, risperidone and aripiprazole [1, 2]. Therapeutic
drug monitoring (TDM) refers to the quantification and interpretation of drug
concentrations in blood to optimize pharmacotherapy [3, 4]. TDM has a long history
in psychiatry, but routine TDM of antipsychotics has not yet been universally
accepted as a standard clinical practice [3, 4]. In 2020, the American Society of
Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of
the German Association of Neuropsychopharmacology and Pharmacopsychiatry
published a joint consensus statement with the aim to assist clinicians who regularly
prescribe antipsychotics to effectively implement TDM of antipsychotics in their
clinical practice [4]. The consensus statement provides four levels of
recommendations regarding TDM for specific antipsychotics, their therapeutic
reference range in blood and laboratory alert level (threshold level above which the
risk for adverse drug reactions is expected to increase) [4]. Antipsychotics for which
TDM is strongly recommended (level 1 recommendation) include clozapine,
fluphenazine, haloperidol, olanzapine, perazine and perphenazine [4]. For these
drugs, blood level within the therapeutic range is associated with favorable clinical
outcomes in terms of efficacy, as well as safety and tolerability [4]. For aripiprazole,
chlorpromazine, flupenthixol, paliperidone, quetiapine, risperidone, sertindole, and
ziprasidone, there are fewer data linking therapeutic blood level ranges to benefit or
harm, so TDM is recommended, but with a lower level of clinical confidence (level 2
recommendation) [4]. For brexpiprazole, cariprazine, chlorprothixene, iloperidone,
loxapine, lurasidone, melperone, and pimozide, TDM is considered to be useful
(level 3 recommendation), but the evidence is less supportive (the link between blood
level and clinical effects has not been addressed yet or only retrospectively or in
single case reports, so there is a need for more data) [4]. For asenapine, there is no
available evidence associating clinical effects and blood level, so TDM is only
considered potentially useful (level 4 recommendation) [4]. In addition, TDM is
strongly recommended for a number of specific indications regardless of the level of
recommendation for any particular antipsychotic [4]. These indications include, for example, uncertain adherence to antipsychotics, lack of clinical response within
established therapeutic dose ranges, recurrence or relapse of symptoms during
maintenance treatment, adverse drug reactions, concomitant use of medications
which may interfere with the metabolism of antipsychotics, specific patient
populations (e.g. patients with abnormally high or low body weight or body mass
index, pregnant patients, lactating patients, children, adolescents, elderly, patients
with intellectual disabilities, patients with hepatic or renal dysfunction, patients with
severe cardiovascular disease…), switching between the original and generic forms
of antipsychotics, switching between oral antipsychotics and long-acting injectable
antipsychotics (LAIs), et cetera [4]. Blood sample should be taken at steady-state [4].
Appropriate sampling time during stable dosing of oral formulations is considered to
be immediately before intake of the morning dose, i.e. 24 hours after the last dose if
the antipsychotic is given once daily in the morning (for drugs taken in the evening
the blood draw interval is 12 hours) or immediately before the next injection for LAIs
[4]. It should be noted that the therapeutic reference ranges given in the consensus
statement are an orienting, population-based tool that may not always be applicable
to all patients, that they are derived mainly from studies on oral antipsychotics and
that they apply to the primary/specific indication of antipsychotics (schizophrenia)
[4]. The following information is needed for adequate interpretation of antipsychotic
blood level: demographic and clinical characteristics of the patient, comedications,
indication for the TDM request, formulation of the antipsychotic, time point of the
blood draw, time since the last dose change, and clinical information regarding
symptom severity and response or remission, as well as adverse drug reactions [4].
Despite the promise of TDM to improve the effectiveness and safety of antipsychotics
in clinical practice, some limitations should be acknowledged: (A) Therapeutic blood
level ranges are derived from groups of patients who agree to be studied and their
data may not generalize to usual care patients who have more comorbidities and
receive multiple medications; (B) Blood level ranges of antipsychotics are almost
exclusively derived from patients with schizophrenia, so more data should be
collected for many other approved and off-label indications of antipsychotics; (C)
TDM results are only helpful if blood sample is obtained at an appropriate time and
sufficient contextual information is available; (D) There is a need for more data
regarding relationship between blood level ranges for many specific antipsychotics
and clinical efficacy and tolerability, as well as for more evidence in specific
populations of patients (e.g. elderly, children, adolescents); (E) Lack of laboratories
for TDM and costs may be significant barriers for implementing TDM of
antipsychotics in some clinical care settings [4]. Despite these limitations which could
mostly be addressed by additional research, TDM has the potential to become a
valuable tool for solving problems in antipsychotic treatment and improving efficacy
and safety of antipsychotics in clinical practice [3, 4].
Keywords :
Therapeutic drug monitoring; antipsychotics; recommendations