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Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie

Schoretsanitis G, Kane JM, Correll CU, et al. J Clin Psychiatry. 2020;81(3):19cs13169.


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.

The American Psychiatric Association Practice Guidelines For The Treatment of Patients With Schizophrenia Third Edition; Use of Clozapine Levels During Treatment With Clozapine
3rd ed: American Psychiatric Association Publishing; 2019.

While the dose of clozapine is being titrated, it is useful to obtain blood levels of clozapine and its major active metabolite, norclozapine (N-desmethylclozapine) (Couchman et al. 2010). Blood levels can also be helpful if there are questions about medication adherence, less efficacy or more side effects than expected, potential medication interactions, or other factors that may be influencing clozapine levels. Although there is substantial variation between individuals, clozapine levels on a specific dosage will generally be greater in nonsmokers than in smokers, in heavy caffeine users than in nonusers, in women than in men, and in older individuals than in younger individuals (Carrillo et al. 1998; Ismail et al. 2012). In addition, changing between different generic forms of clozapine can lead to a 5%–10% difference in blood levels. Levels of clozapine should be drawn at steady state (3 days or more after a dose change) and at a trough in medication levels (about 12 hours after the last dose). Typically, patients will receive a bedtime dose of clozapine and then have a level drawn the following morning before receiving an additional dose. There is not an absolute level of clozapine that is associated with either efficacy or toxicity (Remington et al. 2013; Spina et al. 2000; Stark and Scott 2012; Suzuki et al. 2011; VanderZwaag et al. 1996). In most patients, efficacy will be highest at levels greater than 350 ng/mL of clozapine, but some patients will show response or prevention of relapse at levels as low as 200 ng/mL. The risk of developing seizures increases with the blood level of clozapine.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017

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.

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 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.


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.ce

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.


Therapeutic drug monitoring of antipsychotics.

Perry PJ. 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.


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.

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.


Potential Benefits to Patients and Payers From Increased Measurement of Antipsychotic Plasma Levels in the Management of Schizophrenia

Predmore Z, Mattke S, Horvitz-Lennon M. Psychiatr Serv. 2018 Jan 1;69(1):12-14.

Approximately 40% of patients with schizophrenia either do not respond to the prescribed antipsychotic drug or cannot tolerate it because of side effects, resulting in poor disease control and negative health and economic outcomes. Identifying the root cause of such complicated courses of treatment is a critical step in the treatment of these patients. Although measurement of antipsychotic plasma levels can be used to discern potential root causes, this tool is not routinely used in the United States. The authors of this column discuss the potential effects on patient outcomes and on the value of care from greater use of this diagnostic tool, especially under emerging payment models and delivery system reform efforts.


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.

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.

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.