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Hiemke C, Bergemann N, Clement HW, et al. Pharmacopsychiatry. 2018;51(1-02):9-62.
ABSTRACT
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.
Schoretsanitis G, Kane JM, Correll CU, et al. J Clin Psychiatry. 2020;81(3).
ABSTRACT
OBJECTIVE: The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. PARTICIPANTS: Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). EVIDENCE: TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. CONSENSUS PROCESS: A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. CONCLUSIONS: The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.
A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia.
Correll CU, Agid O, Crespo-Facorro B, et al. CNS Drugs. 2022;36(7):659-679.
ABSTRACT
Treatment-resistant schizophrenia (TRS) will affect about one in three patients with schizophrenia. Clozapine is the only treatment approved for TRS, and patients should be treated as soon as possible to improve their chances of achieving remission. Despite its effectiveness, concern over side effects, monitoring requirements, and inexperience with prescribing often result in long delays that can expose patients to unnecessary risks and compromise their chances of achieving favorable long-term outcomes. We critically reviewed the literature on clozapine use in TRS, focusing on guidelines, systematic reviews, and algorithms to identify strategies for improving clozapine safety and tolerability. Based on this, we have provided an overview of strategies to support early initiation of clozapine in patients with TRS based on the latest evidence and our clinical experience, and have summarized the key elements in a practical, evidence-based checklist for identifying and managing patients with TRS, with the aim of increasing confidence in prescribing and monitoring clozapine therapy.
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.
Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis
Siskind D, Sharma M, Pawar M, et al. Acta Psychiatr Scand. 2021;144(5):422-432.
Objectives: Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta-analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels.
Methods: We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta-analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta-regression by study duration was conducted.
Results: Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40-3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85-2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00-0.49, p = 0.05), and lower rates of relapse (SMD -0.72, 95% CI -1.26 to -0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome.
Conclusions: Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavorable risk-benefit ratio.
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.
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 in which 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 the potential 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.
Personalizing Antipsychotic Treatment of Schizophrenia: Monitoring Plasma Levels for Improved Treatment Decisions
Horvitz-Lennon M, Predmore Z, Mattke S. Santa Monica, CA: RAND Corporation, 2017. https://www.rand.org/pubs/perspectives/PE174.html
Despite the availability of efficacious antipsychotic drugs, the pharmacological management of schizophrenia remains a challenge, and it largely follows a trial-and-error paradigm. With notoriously high rates of poor antipsychotic drug adherence and limited means to detect it, prescribers are often uncertain whether a lack of treatment response is due to poor adherence or true lack of effect. Moreover, when encountering a patient with intolerable side effects, prescribers do not know whether to switch to another drug or merely reduce the dose. This uncertainty results in unnecessarily high rates of unwarranted treatment changes and antipsychotic polypharmacy, loss of adherence and disease control, and ultimately poor patient and societal outcomes. In this Perspective, we argue that point-of-care information on antipsychotic plasma levels — the amount of drug circulating in the patient’s blood — will result in better patient care, which should lead to better health and better value for the health care system. While tests for antipsychotic plasma levels have long been available through specialized labs, they are not routinely used, in part because of delays in obtaining results. Access to information on antipsychotic plasma levels at the point of care would facilitate better use of currently available drugs and reduce the uncertainty associated with the management of complicated presentations by providing prescribers with a tool to “personalize” treatment to patients’ characteristics, including responsiveness to specific medications, metabolism, and adherence behavior.
Association Between Clozapine Plasma Concentrations and Treatment Response: A Systematic Review, Meta-analysis and Individual Participant Data Meta-analysis
Tralongo F, Konecki C, Feliu C, Kaladjian A, Djerada Z. Clin Pharmacokinet. 2023.
ABSTRACT
Background and objectives: Although therapeutic drug monitoring of clozapine is recommended, its optimisation is often adjusted only on the basis of dosage. The aim of this study was to assess the link between clozapine plasma concentrations and clinical response by a meta-analysis of published studies and by an individual participant data meta-analysis.
Methods: We conducted a computerised search of bibliographic databases (EMBASE, PubMed, Clinical Trials, and Web of Science) to identify studies that assessed the relationship between clozapine serum or plasma concentrations and clinical efficacy. Using pooled data, we investigated the association between improvement of clinical outcome and clozapine or norclozapine plasma concentrations, the sum of clozapine and norclozapine plasma concentrations, and the coefficient of variation of clozapine plasma concentrations. Using available individual data, we assessed the relationship between clozapine plasma concentrations and clinical response (changes in the Brief Psychiatric Rating Scale score) and identified a threshold level for a favourable clinical response.
Results: Fifteen studies satisfied inclusion criteria. Our meta-analysis showed that responders had clozapine plasma concentrations that were, on average, 117 ng/mL higher than non-responders. The patients with plasma clozapine concentrations above the thresholds identified in each study had a higher likelihood of responding (odds ratio = 2.94, p < 0.001). Norclozapine plasma concentrations were not associated with a clinical response. The meta-analysis of individual data supported this result and confirmed the link between clozapine concentrations and a change in the Brief Psychiatric Rating Scale score and/or the probability of clinical response. Finally, with the analysis of the coefficient of variation of clozapine plasma concentrations, we found that a greater inter-individual fluctuation in plasma concentrations was associated with a loss of clinical response. Conclusions: Our work confirmed that, in contrast to clozapine doses, clozapine plasma concentrations were related to a favourable clinical response, with a mean difference between responders and non-responders of 117 ng/mL. A threshold for a treatment response of 407 ng/mL was determined, with a high discriminatory capacity, and a sensitivity and specificity of 71% and 89.1%, respectively.
Iatrogenic clozapine intoxication after hospital admission: A case-based rationale for an inpatient pharmacy clozapine monitoring service
Leung JG, Rakocevic DB, Courtis SN, Leloux MR, Allen ND. J Am Pharm Assoc (2003). 2022.
Clozapine must be retitrated after 2 consecutive days or more of missed doses owing to the risk of severe hypotension, bradycardia, and cardiac arrest. However, other important adverse events such as somnolence, sialorrhea, or respiratory depression can occur without severe cardiovascular sequalae. These other unintended consequences are not well characterized in the literature. Three cases are reported, highlighting the concerns for continuing clozapine without retitration after periods of not taking the medication. Implications are discussed as well as how pharmacists can collaborate with other disciplines to mitigate safety risks associated with clozapine for hospitalized patients.
McCutcheon R, Beck K, D’Ambrosio E, et al. Acta Psychiatr Scand.2018;137(1):39-46.
Abstract
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.
Acceptability of point of care testing for antipsychotic medication levels in schizophrenia.
Atkins M, Taylor D, Harland R, et al. Psychiatry Research Communications. 2022;2(4):100070.
Recently, it has become possible to measure antipsychotic medication levels using a small fingerprick sample of capillary blood. Moreover, the analysis can be performed with a small portable device at the point of testing, providing a result in a few minutes These Point of Care (POC) assays can be as accurate as conventional lab-based assays that use venous blood samples. However, while the POC approach has been evaluated from a technical perspective, its acceptability to patients with schizophrenia has not yet been formally evaluated. In the present study, we addressed this issue by assessing the acceptability of POC testing to patients with schizophrenia and to staff involved in their clinical care.
We surveyed 106 patients with schizophrenia who were being treated with either oral clozapine or oral aripiprazole. For each patient, the plasma level of the medication was measured using i) a venous blood sample and a conventional lab-based assay and ii) a novel point of care assay that used a capillary blood sample taken with a fingerprick. Immediately after providing the two samples, participants completed a brief questionnaire. We also surveyed 10 members of staff who were directly involved in the care of these patients.
98% of patients found the capillary point-of-care approach acceptable, and 85% preferred it to the conventional venous blood procedure. 78% of patients said it was useful to have access to the result at the point of care (as opposed to at a later date), and 90% felt that POC testing improved clinical care. 83% said that the POC test made them feel more involved in their treatment. 100% of staff said their experience with the POC test was good, that it was easier than venous collection, and that it was very useful to receive the medication level while the patient was still in the clinic.
First Use of Clozapine Point of Care Testing in Acute Inpatient Psychiatry: Preliminary Report.
Boland X, Dratcu L. J Psychiatr Pract. 2022;28(1):62-66.
Clozapine is the antipsychotic of choice in treatment-resistant schizophrenia. Serum clozapine concentration testing is essential to monitor adherence, adjust dosing, and ensure treatment safety. However, patients who are acutely unwell are frequently reluctant to undergo blood testing requiring venipuncture. Also, conventional laboratory-based measurement of clozapine plasma levels can take days, thus contributing to the suboptimal use of clozapine when it is most needed. We pioneered clozapine whole-blood point of care (POC) testing in the acute inpatient setting in the treatment of a group of actively psychotic patients receiving clozapine during the outbreak of the COVID-19 pandemic. POC clozapine testing using automated homogenous immunoassay requires only finger prick blood sampling and is more acceptable to patients. As it produces results in minutes, clozapine POC testing serves to promptly ascertain adherence with treatment and inform therapeutic dosing. POC testing offered a more practical, less invasive, and quicker alternative to conventional methods of monitoring clozapine levels. Near immediate availability of clozapine levels expedited clinical decisions and helped ensure safe clozapine prescribing to our severely psychotic patients in a time of crisis. By facilitating patients’ early safe discharge from the hospital, clozapine POC testing also reduced length of hospitalization.
Clozapine blood level assessment using a point-of-care device: feasibility and reliability.
Kamhi-Nesher S, Taub S, Halimi S, et al. Ther Adv Psychopharmacol. 2022;12:20451253221094435.
Background: Therapeutic drug monitoring (TDM) is useful to assess clozapine adherence and optimize treatment. However, analysis of venous blood levels by liquid chromatography tandem mass spectrometry (LC-MS/MS) is often logistically complicated and process time is prolonged.
Objective: To assess the feasibility and reliability of a new point-of-care device, (MyCare™ Insite), using capillary blood for clozapine therapeutic monitoring.
Methods: Matched venous and capillary blood samples were collected from patients treated with clozapine on a stable dose. Samples were analyzed by LC-MS/MS and MyCare Insite Clozapine Test. Clozapine plasma levels were compared between methods using linear regression model. Both patients and treatment team completed questionnaires about the feasibility of blood sampling.
Results: Of the total sample (44 patients, 61% males, mean age 43 ± 12 years), mean daily clozapine dose was 293 ± 134 mg/day. Linear regression model demonstrated high correlation with R 2 = 0.83 (p < 0.0001) and mean difference of 26 ± 162 ng/ml. More than 60% of the patients found the clozapine TDM to be important. Most of the participants (58%) favored the capillary sampling and 11% claimed that testing method would affect their adherence to TDM. Moreover, a larger portion (72%) strongly preferred to be tested at the office rather than at the lab.
Conclusions: The point-of-care device offers an accessible and satisfactory measurement of clozapine blood levels. Both patients and healthcare providers reported preference for capillary sampling as well as for the in-office TDM procedure. The immediate results provided by the device can facilitate rapid and informed clinical decisions and therefore improve clozapine treatment outcomes.
Keywords: clozapine; point of care; schizophrenia; therapeutic drug monitoring.
Point-of-care measurement of clozapine concentration using a finger-stick blood sample.
Taylor D, Atkins M, Harland R, et al. J Psychopharmacol. 2021:269881121991567.
Background: The use of clozapine demands regular monitoring of clozapine plasma concentrations and of white blood cell parameters. The delay between sending blood samples for analysis and receiving the results hinders clinical care. Point-of-care testing (POCT) can provide drug assay results within a few minutes.
Aim: This study aimed to investigate the utility of a novel point-of-care device that can measure clozapine concentrations using capillary blood samples collected via a finger stick.
Method: During a five-week period starting in June 2019 eligible patients were asked to provide a finger-stick capillary sample in addition to their usual venous blood sample. Samples were analysed by the novel point-of-care device and by the standard laboratory method. Capillary blood samples were tested by the MyCare™ Insite POCT analyser, and a quantitative measurement of clozapine concentration was provided within six minutes.
Results: A total of 309 patients agreed to measurements by the two methods. Analysis revealed clozapine concentrations in venous blood as determined by the laboratory method ranged from 20 to 1310 ng/mL and by POCT from 7 to 1425 ng/mL. There was a strong positive correlation (R = 0.89) between the results from the venous and the capillary sample methods. The slope of the association between standard assay and MyCare™ Insite was 1.0 with an intercept of -21 ng/mL, indicating minimal bias.
Conclusion: Clozapine concentrations can be accurately measured at the point of care using capillary blood samples collected via a finger stick. This approach may be more acceptable than venous sampling to patients and, with almost instant results available, more useful to clinicians.
Keywords: Clozapine; capillary blood sample; finger stick; point of care; schizophrenia.
