Table 1.

shows the included studies and their characteristics.

Year authors	Country	Methodology	Types of studies/data source	Study participants	Survey sample/response rate	Barriers identified	Facilitators identified	Quality tool	Risk of bias (low, moderate, high)
Rubio and Kane, 2020	USA	Narrative review	RCTs, prescriber and patient surveys, prescription registry data	Clozapine prescribers, patients with treatment-resistant schizophrenia	N/A	Prescriber lack of experience, perceived treatment burden, systems-level factors	Continued medical education, administrative partnerships, always discussing clozapine with patients despite perceived barriers/fears	AMSTAR-2	Moderate
Thien et al, 2017	UK, New Zealand, Canada, Denmark, India, Japan, Ireland, Singapore, Turkey	Narrative review	Retrospective chart reviews (n = 13) and surveys (n = 5)	Clozapine prescribers, clozapine-treated patients with treatment-resistant schizophrenia	N/A	Routine blood monitoring as a burden, physician perception of blood monitoring as a burden to patients, side effects, patient/care reluctance to comply with treatment, clinician's lack of knowledge/experience	Clinician education focused towards early eligible patient identification and care management after clozapine initiation	AMSTAR-2	Moderate
Kelly and Love, 2019	USA	Scoping review	Multiple studies	N/A	N/A	Patient and family barriers, provider barriers, resource availability, healthcare systems factors, administrative burden	Interdisciplinary teams utilizing clinical psychiatric pharmacists in managing clozapine patients, clozapine clinics, prescriber support	AMSTAR-2	High
Singh et al, 2018	USA	Survey/descriptive	N/A	164 US psychiatry residents	164 started but 162 completed survey, unknown actually received the survey.	Side effects, limited experience/inadequate training starting clozapine	Clozapine clinic training during residency	MMAT	Moderate
Leung et al, 2020	USA, Canada	Survey/descriptive	N/A	Clozapine prescribers, including attending/consultant psychiatrists (n = 115), psychiatric nurse practitioners/physician assistants (n = 21), and psychiatric residents (n = 71), did not disclose position (n = 5)	n = 211/1152, response rate = 18.3%	Lack of clozapine-eligible patients, no REMS registration, too much trouble, too many side effects and risk of blood dyscrasias (38.5%), more than 1 reason (38%), administrative burden (68.3%), perceived as burden for patient (60.6%), poor patient adherence (67.3%), presence of medical comorbidities (52.3%), poor social support (46.2%)	Standardized clozapine clinic model, multidisciplinary approach to clozapine management, improved patient education by pharmacists, point of care testing	MMAT	Moderate low-
Moody and Eatmon, 2019	USA	Survey/descriptive	N/A	97 clozapine prescribers (physicians, advanced practice nurses, physician assistants) in VHA	Low response rate. 98 responded but 1 removed due to administrative role.	Side effects, monitoring concerns, prescribing logistics, lack of experience	Appointing administrative contact person for assistance with administrative tasks, clozapine clinics, utilize outside laboratories, prescriber education/training	MMAT	Moderate
Kelly et al, 2019	USA	Survey/descriptive	N/A	277 psychiatrists (psychiatrists, psychiatry residents, and fellows) in Maryland	32% response rate but only 255 included in final analysis due to 16 incomplete and 6 declined	Patient adherence to blood work, patient discomfort with bloodwork, lack of education, dosing effects, registration, delayed labs	Point of care device for blood and antipsychotic level monitoring	MMAT	Moderate
Ismail et al, 2018	Qatar, Bahrain, Oman, KSA, UAE, Kuwait	Semi-structured interviews/mixed methods	N/A	13 participants: psychiatrists, psychiatric residents, psychiatric nurses, clinical/non-clinical pharmacists, mental health medical directors	Low response rate but excluded if non-English speaking or did not sign informed consent	Emergent side effect monitoring, hematological monitoring requirements, lack of patient education, poor patient adherence, diverse prescriber practices	Using interdisciplinary teams to support prescribers/assist with monitoring (clozapine clinics), patient/family education	MMAT	Moderate-high
Farooq et al, 2019	UK	Systematic review	Surveys (n = 5), case note reviews (n = 4), semi-structured interview/consultations with stakeholders (n = 3), interventional/quality improvement studies (n = 3)	Psychiatrist/resident/pharmacist/advanced practice nurses/mental health leadership staff, patients on clozapine, researchers, consultants	N/A	Patient non-adherence/refusal of bloodwork, concern for poor tolerance, lack of knowledge/experience, side effect management	Point of care devices, patient, provider, and family online education, prescriber support/consumer decision-making tools (shared decision making), clozapine training in residency	AMSTAR-2	Moderate
Verdoux et al, 2019	UK, Denmark, Netherlands, France, Serbia, USA, Canada, India, Thailand, New Zealand, Brazil	Systematic review	n = 13 (all studies describing clozapine use in adult TRS patients, 1 in children, and in 1 in elderly)	Psychiatrists, psychiatry trainees, physicians, Medicaid prescribers, mental health department officials, nurses, pharmacy staff	N/A	Lack of prescriber experience, monitoring and adverse event concerns, prescribing practices/preferences	Clozapine clinic, simplified blood monitoring, prescriber education, increased clozapine access	AMSTAR-2	Moderate

AMSTAR-2 = Measurement Tool to Assess Systematic Reviews 2, MMAT = Mixed Methods Appraisal Tool, REMS = Risk Evaluation and Mitigation Strategy, RCT = Randomized Controlled Trials, TRS = Treatment-Resistant Schizophrenia, VHA = Veterans Health Administration.