02735233

September 04, 2021, 22:51

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We appreciate Subho Chakrabarti’s review work and believe that this is a comprehensive paper for clozapine-resistant schizophrenia (CRS). I would like to raise two minor points. It is recommended that CRS is a subspecifier of treatment-resistant schizophrenia (TRS). Clinicians are recommended to exclude the possibility of nonadherence to clozapine (i.e., pseudo-resistance) and administer an adequate trial of clozapine. A diagnosis of CRS is made when blood levels of clozapine is ≥ 350 ng/mL; however, if obtaining blood samples is not feasible, a minimum dose of 500 mg/day is recommended. In the review article by Subho Chakrabarti, the adequate dose of clozapine (200 to 500 mg/day) in patients with CRS may be low. Besides, when assessing the available evidence for CRS, we need to exclude studies that were TRS but not CRS. For example, Subho Chakrabarti cited a study by Masoudzadeh and Khalillian[3] who compared clozapine, electroconvulsive therapy, and a combination of clozapine and electroconvulsive therapy. Patients in the clozapine group achieved a 40% reduction of the Positive and Negative Syndrome Scale scores. Therefore, participants in the study by by Masoudzadeh and Khalillian may be TRS but not CRS.

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Replied on September 11, 2021, 18:35

I thank the authors for their interest in this paper. They have have raised some interesting issues. My replies are detailed below along with some studies that pertain to the issues raised. 1. To meet the criteria for for clozapine resistance schizophrenia (CRS), patients have to meet the citeria for treatment resistant schizophrenia and fail to respond to an adequate trial of clozapine. The criteria for response differ a bit between different definitions. 2. An adequate dose of clozapine is defined as the dose needed to achieve plasma levels > 350 ng/mL. A daily clozapine dose of 400 mg has been shown to achieve a threshold of 350 ng/mL in most trials. The recommended clozapine dose range is from 300-900 mg/day. Average dosages are about 300 mg/day for women and 400 mg/ day for men. The minimum dose of clozapine required for establishing CRS is defined as the midpoint of the dose range. A Cochrane review comparing clozapine at very low doses (up to 149 mg/day), low doses (150 mg/day to 300 mg/day) and standard doses (301 mg/day to 600 mg/day) found no evidence of effect on mental state between standard, low and very low dose regimes. Additionally, the dose of clozapine required for adequate response among Asians patients varies from 150mg/day among women to 300 mg/day for men who smoke. Therefore, the recommendation of a dose range 200-500 mg/day of clozapine based on all these considerations cannot be considered low. 3. The authors are right in pointing out that the patients included in the study by by Masoudzadeh and Khalillian were suffering from treatment resistant schizophrenia rather than CRS. This is pointed out in table-4 of the paper. It has also been pointed out in the text that studies with ECT augmentation of clozapine response have been mainly conducted among patients with treatment resistant schizophrenia rather than those with CRS. Howes et al. Am J Psychiatry 2017; 174: 216-229 Mouaffak et al. Clin Neuropharmacol 2006; 29: 28-33 Lee et al. Can J Psychiatry 2015; 60: 515-522 Nielsen et al. Acta Psychiatr Scand 2011; 123: 411-422 Subramanian et al. Cochrane Database Syst Rev 2017; 6: CD009555 de Leon et al. Psychother Psychosom 2020; 89: 200-214 Masoudzadeh & Khalilian. Pak J Biol Sci 2007; 10: 4287-4290