Clozapine is the standard of care for treatment-resistant schizophrenia. However, up to a third of patients will have a partial or no response to treatment despite an adequate trial of clozapine. There are no accepted guidelines for alternative pharmacological regimens in the treatment of clozapine-resistant schizophrenia (CRS) and electroconvulsive therapy is not always a feasible option. This paper is a scoping review of PubMed literature, reviewing various pharmacological regimens attempted for treating CRS.

A systematic search using the [Title/Abstract] filter was conducted on PubMed to identify articles related to clozapine-resistant schizophrenia (or similar terms). Three researchers reviewed a total of 130 abstracts. The inclusion criteria were limited to observational articles that assessed psychopharmacological modifications with objective measurement tools. After screening 27 full-text articles, only 18 were included in the final analysis.

In this scoping review, the most commonly tested medication was amisulpride, which was explored both as an adjunct and a replacement for clozapine in patients with CRS. The randomized controlled trials and retrospective studies on amisulpride demonstrated significant improvements in symptoms on objective assessments such as the Positive and Negative Symptom Scale (PANSS), The Brief Psychiatric Rating Scale (BPRS), and Scales for the Assessment of Negative Symptoms (SANS). Other assessment tools used by researchers included the SAPS, CGI, RBANS, GAF, and UKU scales, among others.

As adjuncts to clozapine, several medications exhibited significant improvements on the PANSS negative subscale score, such as Amisulpride, Brexipiprazole, Memantine, Ropinirole, and Sodium Nitroprusside. Papers also reported positive outcomes after switching from clozapine to cariprazine or clotiapine, as measured by the SANS and PANSS, respectively. Quetiapine, Loxapine and Fluvoxamine augmentation also showed a significant improvement on the BPRS.

In contrast, one study indicated no significant improvement in outcomes when augmenting clozapine with olanzapine compared to placebo, using the Global Assessment of Functioning (GAF) and Clinical Global Impression Scale (CGIS).

Managing CRS can be challenging, particularly due to the absence of set guidelines on the pharmacological treatment of CRS. Most clinicians choose to add adjunctive medications to clozapine, while others opt to switch to a different medication altogether. Both approaches are viable options with varying results. The findings in this study underscore the potential benefits of various pharmacological regimens in the treatment of CRS. However, it is crucial to consider each patient’s individual needs when making treatment decisions. It is prudent to do further objective analyses on the treatment of CRS.

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