Results that Matter,
When they Matter

Therapeutic drug monitoring of antipsychotics.

Perry PJ. Therapeutic drug monitoring of antipsychotics. Psychopharmacol Bull. 2001;35(3):19-29.

Therapeutic drug monitoring of conventional and atypical antipsychotics offers numerous clinical advantages to the clinician. These include cost savings decreased risk of toxicity, and improved compliance. Among these drugs, studies of haloperidol, olanzapine, and clozapine have provided the most compelling data to justify therapeutic drug monitoring. Among atypical antipsychotics, although data document the utility of routine monitoring of clozapine and olanzapine blood levels, there are no similar data available for either risperidone or quetiapine. Additionally, the utility of therapeutic drug monitoring is enhanced by the availability of prospective dosing schemes for haloperidol, olanzapine, and clozapine.

The Role of Antipsychotic Plasma Levels in the Treatment of Schizophrenia

Horvitz-Lennon M, Mattke S, Predmore Z, Howes OD. Am J Psychiatry. 2017 1;174(5):421-426

In this article, we review the clinical circumstances inwhich antipsychotic plasma levels may be used to guide the management of patients with schizophrenia who exhibit poor response or poor tolerance—patients who are currently managed largely on a trial-and-error basis. We first review thepotential causes of these complicated treatment courses and the role of antipsychotic plasma levels in discerning among them. We then provide recommendations for the evidence based use of antipsychotic plasma levels, and we end with a discussion of practical considerations.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology

Hiemke C, Bergemann N, Clement HW, et al.Pharmacopsychiatry. 2018;51(1-02):9-62.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs. 

Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia

McCutcheon R, Beck K, D'Ambrosio E, et al. Acta Psychiatr Scand.2018;137(1):39-46

Objective: Treatment resistance is a challenge for the management of schizophrenia. It is not always clear whether inadequate response is secondary to medication ineffectiveness, as opposed to medication underexposure due to non-adherence or pharmacokinetic factors. We investigated the prevalence of subtherapeutic antipsychotic plasma levels in patients identified as treatment-resistant by their treating clinician.

Method: Between January 2012 and April 2017, antipsychotic plasma levels were measured in 99 individuals provisionally diagnosed with treatment-resistant schizophrenia by their treating clinicians, but not prescribed clozapine. Patients were followed up to determine whether they were subsequently admitted to hospital.

Results: Thirty-five per cent of plasma levels were subtherapeutic, and of these, 34% were undetectable. Black ethnicity (P = 0.006) and lower dose (P < 0.001) were significantly associated with subtherapeutic/undetectable plasma levels. Individuals with subtherapeutic/undetectable levels were significantly more likely to be admitted to hospital (P = 0.02).

Conclusion: A significant proportion of patients considered treatment-resistant have subtherapeutic antipsychotic plasma levels, and this is associated with subsequent admission. The presence of subtherapeutic plasma levels may suggest a need to address adherence or pharmacokinetic factors as opposed to commencing clozapine treatment. While antipsychotic levels are not recommended for the routine adjustment of dosing, they may assist with the assessment of potential treatment resistance in schizophrenia.

Plasma levels of second-generation antipsychotics and clinical response in acute psychosis: A review of the literature

McCutcheon R, Beck K, D'Ambrosio E, et al. Acta Psychiatr Scand.2018;137(1):39-46

Objective: The objective of the study is to assess the relationships between plasma concentrations (Cps) of second-generation antipsychotics (SGAs) and clinical outcome in order to establish the clinical value of therapeutic drug monitoring.

Method: In April 2012, we searched PubMed and MEDLINE databases for English-language articles using the keywords risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, iloperidone, asenapine, lurasidone, therapeutic drug monitoring, serum level, and plasma level. One hundred and ninety-one articles were retrieved from the initial search. Articles were selected for inclusion if they involved an attempt to correlate Cps with efficacy measures, if they were prospective in nature, and if they examined patients experiencing an acute exacerbation of a psychotic illness. Ultimately 11 articles were selected.

Results: Of the nine compounds involved in the search, only four were included in relevant articles, and only two of these were involved in multiple trials. No studies involving the most recently developed compounds (paliperidone, iloperidone, asenapine, and lurasidone) were identified. Studies varied widely in methodology, with only four studies adopting a fixed-dose model. Results differed considerably between studies regarding both clinical and adverse effects, with 6 of the 11 studies revealing a positive correlation between Cps and response.

Conclusion: The utility of therapeutic drug monitoring of SGAs (other than clozapine) remains an open question, although limited evidence from fixed-dose studies is encouraging. We discuss the potentially significant clinical value of antipsychotic Cps and the consequent need for further research in this area.

Accuracy of Clinician Assessments of Medication Status in the Emergency Setting: A Comparison of Clinician Assessment of Antipsychotic Usage

Lopez LV, Shaikh A, Merson J, Greenberg J, Suckow RF, Kane JM. JClin Psychopharmacol. 2017;37(3):310-314.

The present study aimed to assess the level of agreement between clinicians’ routine assessments of medication status and plasma levels of commonly prescribed antipsychotic medications in patients presenting to an emergency room with an exacerbation of psychosis.

Methods: We studied 105 patients presenting to an emergency room and admitted to an inpatient psychiatric unit with a diagnosis of schizophrenia, schizoaffective disorder, bipolar I disorder, or psychotic disorder not otherwise specified and a prior outpatient medication regimen including risperidone, olanzapine, quetiapine, aripiprazole, or paliperidone. Plasma levels of antipsychotics were drawn and sent to a specialty laboratory for testing.

Findings: Of the 97 patients with usable samples, 33 (34%) were found to have therapeutic antipsychotic levels. Of these, 22 were judged by emergency room staff to be taking their medications at the appropriately prescribed doses, whereas 11 were judged not to be taking medication at all. Sixty-four patients were found to have subtherapeutic antipsychotic levels, 31 of whom had been assessed to be taking medication as prescribed. Emergency assessment of medication status predicted therapeutic and nontherapeutic antipsychotic levels at rates of 41.5% and 75%, respectively. Emergency staff assessment was statistically independent from the likelihood of having a therapeutic antipsychotic level.

Implications: In patients presenting to emergency rooms with exacerbations of psychosis who are subsequently admitted to an inpatient facility, common assessments of medication status are frequently misleading. Readily available methods for rapidly measuring antipsychotic plasma levels in clinical settings are needed for clinicians to make reliable assessments.

Partial Compliance with Antipsychotics

Kozma CM, Weiden PJ. Am Health Drug Benefits. 2009;2(1):31-8.

Objective: To investigate the relationship between partial compliance with antipsychoticmedication and mental health hospitalization in managed care patients with schizophrenia.Study Design: We performed a retrospective evaluation of 1499 outpatients with greater than or equal to 1 antipsychoticclaims and a diagnosis of schizophrenia in a managed care database (PHARMetrics).

Methods: Patients were followed for 12 months after their initial oral antipsychotic prescribing.

Results: The managed care cohort had an overall hospitalization risk of 5.9% during follow up.

Conclusion: Small decreases in compliance with antipsychotics are associated with increased hospitalization risk.

Treatment adherence in schizophrenia: A patient-level metaanalysis of combined CATIE and EUFEST studies

Czobor P, Van Dorn RA, Citrome L, Kahn RS, Fleischhacker WW, Volavka J, et al. Eur Neuropsychopharmacol, 2015;25(8):1158-66.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) obtained a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) studied a sample of 498 patients. We have combined these two samples to study the predictors and correlates of adherence to treatment. Here we report on adherence to pharmacological treatment at the six and twelve month assessments of these trials with a combined subsample of 1154 schizophrenia patients. Individual patients’ data were used for analyses. We used logistic regression to examine the effects of substance use, akathisia, parkinsonism, dyskinesia, hostility, and insight on pharmacological adherence. The results showed that reduced adherence to pharmacological treatment was associated with substance use (p=0.0003), higher levels of hostility (p=0.0002), and impaired insight (p<0.0001). Furthermore, poor adherence to study medication was associated with earlier discontinuation in the combined data. The clinical implications of the results point to the importance of routine assessments and interventions to address patients’ insight and comorbid substance use and the establishment of therapeutic alliance.

Improving Antipsychotic Adherence Among Patients With Schizophrenia: Savings for States

Predmore ZS, Mattke S, Horvitz-Lennon M. Psychiatr Serv. 2015;1;66(4):343-5.

This column presents findings of an analysis conducted to quantify the potential net savings to state budgets from interventions to improve adherence to antipsychotic drugs among patients with schizophrenia. Using a financial model based on published data, the authors estimated costs of direct medical care and criminal justice system involvement at state and national levels and validated it against findings from other cost studies. The model estimated an annual cost of $21.4 billion (in 2013 dollars) to Medicaid programs and other state agencies for people with schizophrenia. On the basis of data on the effect on outcomes of increased medication adherence, better adherence could yield annual net savings of $3.28 billion to states or $1,580 per patient per year. Innovations to improve adherence to antipsychotic drugs among schizophrenia patients can yield substantial savings in state budgets. States should consider interventions shown to increase medication adherence in this patient group.

Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms

McCutcheon R, Beck K, Bloomfield MA, Marques TR, Rogdaki M,Howes OD. J Psychopharmacol. 2015;29(8):892-897.

A large proportion of individuals with schizophrenia show an inadequate response to treatment with antipsychotics. It can be unclear whether this is secondary to subtherapeutic antipsychotic plasma levels or to medication ineffectiveness. The purpose of the present study was to determine the extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. In addition we investigated the frequency of antipsychotic plasma level monitoring in standard clinical practice. Antipsychotic plasma levels were measured in 36 patients identified as having treatment-resistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range. Subtherapeutic plasma levels were significantly associated with black ethnicity, shorter duration of current treatment and antipsychotics other than olanzapine and amisulpride. Antipsychotic plasma levels had been measured in only one patient in the year prior to our study. We found over one-third of patients identified as treatment-resistant have subtherapeutic antipsychotic levels. This indicates that they may be under-treated rather than treatment-resistant, and thus should receive different management. Currently the measurement of antipsychotic levels may be under-utilized.