Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options.

Treatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.

Clozapine treatment: Ensuring ongoing monitoring during the COVID-19 pandemic.

The current coronavirus pandemic (COVID-19) has led mental health systems to uncertainty regarding safe continuation of clozapine monitoring protocols. Clozapine is without doubt the only antipsychotic available with repeatedly proven efficacy in treatment resistant schizophrenia.1 Replacing clozapine with an alternative antipsychotic in patients stabilized with clozapine can potentially lead to higher risk of relapse or exacerbation of severity of illness.1 Clozapine, as already known, has a number of side effects, some of which can be serious, thus patients receiving clozapine require ongoing scheduled monitoring. Side effects of clozapine include neutropenia or agranulocytosis, myocarditis, fever, hypersalivation, weight gain and constipation. These side effects can be detected and treated when recognized on time decreasing the possibility of serious consequences making the implementation of an ongoing treatment monitoring protocol for patients on clozapine mandatory.2 Since it was advised for all mental health providers in most countries worldwide to limit non-urgent hospital visits and procedures to reduce the risk of contamination a challenge arose for patients' ability to access health care facilities for their routine clozapine monitoring. Nevertheless, the majority of Mental Health Care Authorities decided to ensure access for all patients on clozapine to their routine monitoring protocol.3,4 To date, no data exist on any potential relationship between antipsychotic use and the risk of contamination with SARS-CoV-2 or the development of severe symptoms of the infection. The literature suggests that patients receiving antipsychotics, especially clozapine, have an increased risk of developing pneumonia, leading to the assumption that patients receiving clozapine are at higher risk to develop COVID-19. 1 Balancing the importance of monitoring continuation against the increased risk for COVID-19, an International Consensus Statement was recently published addressing a monitoring protocol with reduced visits. The Consensus suggested reduced hematologic monitoring frequency of every 3 months with a prescription of 90 days clozapine supply (if safe). The above applies to patients receiving clozapine for at least one year without neutropenia. Τhe risk of neutropenia after 12 months of clozapine treatment falls significantly.4 Based on the above it is suggested to all clozapine clinics to implement a guidance monitoring protocol for all patients on clozapine to ensure safety during the pandemic. Besides hematological monitoring that requires physical contact with healthcare workers it is significant to implement a telemedicine appointment in frequent intervals to monitor symptoms of infection, symptoms of cardiovascular diseases and constipation. Patient should also be advised to regularly monitor one's blood pressure and pulses and ideally be educated on how by a member of the staff. If a patient is detected with any symptoms related to the above an emergency appointment for evaluation should be planned. Overall, since both the consequences and the duration of the pandemic are unknown, mental health services must work jointly to implement a clozapine monitoring plan to ensure safe continuation in such a vulnerable population.

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology.

Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level.