What is an Adequate Trial with Clozapine?

  title={What is an Adequate Trial with Clozapine?},
  author={Peter F J Schulte},
  journal={Clinical Pharmacokinetics},
  • P. Schulte
  • Published 2003
  • Psychology, Medicine
  • Clinical Pharmacokinetics
Clozapine is the gold standard and ‘last resort’ in treatment of refractory schizophrenia. It is important to know whether a trial with Clozapine is adequate or not. Six studies show a significantly higher response rate at Clozapine plasma trough levels above a therapeutic threshold of 350–400 µg/L. The absolute risk reduction is about 40%. An additional study found best results with plasma levels between 300 and 700 µg/L, and one (probably too small) study could not detect a significantly… 

Clozapine Underutilization in the Treatment of Schizophrenia: How Can Clozapine Prescription Rates Be Improved?

C lozapine has a long-standing, unchallenged track record as the only effective and approved medication for treatment-refractory schizophrenia and is underprescribed, but doctors and patients may be concerned about, or unfamiliar with, the unusual and hazardous adverse effects of clozapine.

Augmentation of Aripiprazole with Low‐Dose Clozapine

The case of a 32‐year‐old man whose monotherapy with various antipsychotic agents failed is reported, and aripiprazole combined with low‐dose clozapine as maintenance therapy resulted in a positive clinical outcome despite a clozAPine serum level that is generally considered subtherapeutic.

Optimizing Clozapine Treatment: Part I

Practical information and literaturebased experience with clozapine, the most effective antipsychotic available for TRS, are summarized to help facilitate its increased use among clinicians.

Augmentation Strategies of Clozapine With Antipsychotics in the Treatment of Ultraresistant Schizophrenia

An operational definition of schizophrenia refractory to clozapine ("ultraresistant schizophrenia") is proposed for the implementation and homogenization of future therapeutic trials.

A review of the use of clozapine levels to guide treatment and determine cause of death

  • A. StarkJames Scott
  • Psychology, Medicine
    The Australian and New Zealand journal of psychiatry
  • 2012
The exact range of clozapine levels that corresponds to toxicity remains unclear, however, levels between 350 µG/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity.

Clozapine: more than 900 mg/day may be needed

Clinicians should be alert to the possibility of treatment failure because of rapid clozapine clearance secondary to genetic factors and heavy cigarette consumption, notably in young male smokers and anyone given relatively high-dose clozAPine (600 mg/day or more) should be monitored regularly for adverse events.

Title : Pharmacogenetic aspects of clozapine treatment

The dopamine D2 receptor gene is unlikely solely responsible for clozapine response in Caucasian subjects, and the next step in pharmacogenetic studies might be to perform polygenetic analysis in order to include several genes at once.

Clozapine resistance: Augmentation strategies

Compulsory treatment with clozapine: a retrospective long-term cohort study.




Therapeutic Drug Monitoring of Clozapine Treatment

  • O. Olesen
  • Psychology, Medicine
    Clinical pharmacokinetics
  • 1998
It is concluded that the antipsychotic effects and adverse effects of clozapine occur over a very broad range of serum concentrations and clinical judgement should always be primarily used for dose adjustments.

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.

Serum clozapine levels, if interpreted in relation to daily clozabine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozAPine treatment.

Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients.

Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%.

Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients.

There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6, however, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozAPine blood levels above 350 ng/ml.

Time to clozapine response in a standardized trial.

There appears to be little clinical gain in prolonging exposure to clozapine beyond 8 weeks at any particular dose if no response is seen, and all patients who responded to clazapine did so within 8 weeks of a change in dose.

Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia.

Steady-state blood clozapine concentrations in 58 schizophrenic patients varied more than 45-fold (40-1911 ng/mL) after fixed-dose treatment (400 mg/day) and discriminated between responders and nonresponders optimally distinguished responders.

Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics

The results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration.

Will Routine Therapeutic Drug Monitoring Have a Place in Clozapine Therapy?

It is concluded that therapeutic drug monitoring can play a useful role in the clinical management of patients treated with clozapine and that long term monitoring would, in this view, not be necessary.

Optimizing treatment with clozapine.

  • R. Conley
  • Psychology, Medicine
    The Journal of clinical psychiatry
  • 1998
If patients improve significantly during treatment with clozapine, they should continue to be treated with clazapine and should be withdrawn from this treatment only when medically warranted, although dosage must be individualized.