ReviewPsychopharmacology2013
Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold?
Review in Psychopharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 5 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 5 syntheses or guidelines pooled it, 96 citations in OpenAlex.
- Saliva Based Clozapine Therapeutic Drug Monitoring: A Systematic Review.Pharmacology research & perspectives · 2025Pooled it
- A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia.CNS drugs · 2022Guideline
- A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions.Psychopharmacology · 2021Pooled it
- Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.The American journal of psychiatry · 2017Pooled it
- Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine.BMJ open · 2014Pooled it
- The sense and nonsense of antipsychotic combinations: A model for dopamine DTranslational psychiatry · 2025Article
- Association of clozapine and norclozapine levels with patient and therapy characteristics-focus on interaction with valproic acid.European journal of clinical pharmacology · 2023Article
- Factors predicting serum clozapine levels in Middle Eastern patients: an observational study.BMC psychiatry · 2022Observational
- Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia.Translational and clinical pharmacology · 2021Article
- Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations.Therapeutic advances in psychopharmacology · 2021Article
- Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals.British medical bulletin · 2020Article
- Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide.BMC psychiatry · 2020Review
- Development of point-of-care testing devices to improve clozapine prescribing habits and patient outcomes.Neuropsychiatric disease and treatment · 2019Article
- Mapping the evidence on pharmacological interventions for non-affective psychosis in humanitarian non-specialised settings: a UNHCR clinical guidance.BMC medicine · 2017Article
- Clozapine-treated Patients Have Marked Gastrointestinal Hypomotility, the Probable Basis of Life-threatening Gastrointestinal Complications: A Cross Sectional Study.EBioMedicine · 2016Article
- Ciprofloxacin and Clozapine: A Potentially Fatal but Underappreciated Interaction.Case reports in psychiatry · 2016Article
- Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder.World psychiatry : official journal of the World Psychiatric Association (WPA) · 2015Article
- Current and emergent treatments for symptoms and neurocognitive impairment in schizophrenia.Current treatment options in psychiatry · 2015Article
- Review
- Psychosis and seizure disorder: challenges in diagnosis and treatment.Current psychiatry reports · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleClozapine levels are advocated in the monitoring of patients on this drug and have now been used for a number of years. A safety-related threshold has also been proposed, as well as therapeutic lower and upper thresholds. While there has been reasonable consensus regarding a lower therapeutic threshold, this is not the case for the upper thresholds.
objectivesOur aim was to review available evidence related to upper thresholds.
methodsWe carried out an electronic search of different databases and a manual search of articles between 1960 and 2011, cross-referencing the following terms with clozapine-interactions, monitoring, pharmacokinetics, plasma levels, serum levels, and toxicity.
resultsSixty-nine articles met our search criteria and these could be divided into reviews (11), studies (24), and case reports (35). Study quality was evaluated, and none met criteria for a prospective, randomized controlled trial specifically addressing higher plasma levels, e.g., >500 ng/ml. Case reports emphasize in particular the impact of interactions, e.g., antidepressants and smoking. There is clear evidence indicating a dose-related increased risk of seizures, at least to 500-600 mg/day, but a lack of data to suggest such a relationship between plasma levels, dose, and side effects linked to safety, e.g., seizures, myocarditis, and agranulocytosis. The very limited evidence addressing an upper threshold related to clinical response suggests a "ceiling effect" in the range of 600-838 ng/ml.
conclusionsIt appears that the current safety-related threshold is not supported by evidence. There may be an upper threshold for clinical response, beyond which chance of response falls off, although further studies are warranted.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.