SG, HK docs delay prescribing clozapine for treatment-resistant schizophrenia

Clinicians in Singapore and Hong Kong appear to delay the initiation of clozapine for treatment-resistant schizophrenia (TRS) despite familiarity with treatment guidelines, as reported in a study.

In a survey conducted among 156 clinicians in Singapore and 105 in Hong Kong, the majority of the respondents (87.9 percent and 99.0 percent, respectively) reported being “fairly” or “very” familiar with treatment guidelines. However, 57.7 percent and 45.7 percent of clinicians, respectively, said they would prescribe clozapine only after failure of two antipsychotics. [Front Psychiatry 2022;13:1005373]

“One respondent from Singapore reported starting clozapine early (after one antipsychotic trial), while none of the respondents from Hong Kong would do so,” the investigators noted.

The rest of the respondents would delay the initiation of clozapine after the failure of three antipsychotics (31.4 percent in Singapore and 39.0 percent in Hong Kong) or after four or more antipsychotics (10.3 percent and 15.2 percent, respectively).

“The delay in clozapine prescription is a common problem across various countries,” with the barriers to prescription being often complex and going beyond a simple lack of knowledge, according to the investigators.

“Our earlier publication suggested that clinicians were deterred from prescribing clozapine due to the need for frequent blood monitoring and concerns about clozapine’s tolerability and its medical complications. Health system factors were also identified as a barrier and clinicians in Hong Kong and Singapore reported a greater need for outpatient resources in terms of clinic and administrative support to improve clozapine prescription,” they said, adding that these findings were echoed by similar surveys of clinicians in other countries. [J Clin Psychiatry 2022;83:21m14231; BMC Psychiatry 2022;22:534; Psychiatry Res 2019;275:155-161; Ther Adv Psychopharmacol 2021;11:20451253211020236; Acta Psychiatr Scand 2014;130:16-24]

Clozapine resistance

An atypical antipsychotic, clozapine has been found to be “the only drug” effective in patients with schizophrenia refractory to treatment with other antipsychotic drugs. What’s more important is that every 1-year delay in its initiation is said to increase the odds of long-term clozapine-resistance by 6 percent. One study described that a delay in prescription is a strong predictor of clozapine resistance, while another suggested that the risk of clozapine resistance jumps from 30.8 percent to 81.6 percent after a critical treatment window of 3 years from TRS onset. [Br Med Bull 2020:135:73-89; Eur Arch Psychiatry Clin Neurosci 2020;270:11-22; Schizophr Bull 2021;47:485-494; Psychiatry Res 2017;250:65-70]

“When clozapine fails, the navigation of treatment choices becomes a challenge due to the scarcity of robust evidence to guide clinicians’ choice beyond clozapine,” the investigators said. “In today’s clinical practice, the treatment of clozapine-resistance is heterogeneous and determined by the clinician’s experience and the patient’s individual response to the offered intervention.” [Am J Psychiatry 2020;177:868-872; World Psychiatry 2017;16:77-89; JAMA Psychiatry 2017;74:675-684; J Psychopharmacol 2019;33:423-435]

Nearly half or more of the clinicians in Singapore and Hong Kong in the current study reported that they would use high-dose antipsychotics, long-acting injectable antipsychotics, and antipsychotic polypharmacy as an alternative to clozapine.

Meanwhile, the adjuvant use of mood stabilizers and electroconvulsive therapy differed between Singapore and Hong Kong. For clozapine-resistant schizophrenia, 10–20 percent of the respondents added adjuvant mood stabilizers or antipsychotics and 3–10 percent used an antidepressant.

Augmentation strategies

“In existing literature, the recommendations on augmentation strategies for clozapine nonresponse have varied across different guidelines,” the investigators noted. [Schizophr Res 2021;236:142-155]

The Treatment Response and Resistance in Psychosis (TRRIP) Working Group provides recommendations based on an international expert consensus. Its guidelines say to combine clozapine with an antipsychotic, particularly amisulpride or aripiprazole, for patients with persistent positive or mixed symptoms or persistent aggression. On the other hand, adjuvant mood stabilizers (namely, lithium and lamotrigine) can be used for patients with persistent aggression and/or suicidal ideation, and adjuvant antidepressants for patients with persistent negative symptoms or suicidal ideation. [Schizophr Bull 2020;46:1459-1470]

“Clozapine is the only evidence-based treatment in patients with TRS. However, its initiation across the world is often delayed, and this delay in turn leads to higher incidences of clozapine-resistance and poorer outcomes for patients,” the investigators said.

“There is a need to examine and address the factors that are preventing the timely prescription of clozapine in order to facilitate its earlier adoption. More research into the biological mechanisms that underpin treatment-resistance and clozapine-resistance in schizophrenia is needed in order to guide the search for effective treatments beyond clozapine,” they added.