Background: Clozapine is the only medication approved for those patients with schizophrenia who do not achieve a clinical response to standard antipsychotic treatment, yet it is still underused. Furthermore, in the case of a partial or minimal response to clozapine treatment, there is no clarity on the next pharmacologic intervention. Methods: The National Psychosis Service is a tertiary referral inpatient unit for individuals with refractory psychosis. Data from 2 pooled data sets (for a total of 325 medical records) were analyzed for treatment trajectories between admission and discharge (2001-2016). Effectiveness of pharmacologic treatment was determined using change in symptoms, assessed using the Operational Criteria (OPCRIT) system applied retrospectively to the medical records. Analysis was focused on identifying the optimal medication regimens impacting clinical status during the admission. Results: Less than a quarter of the patients were on clozapine treatment at the time of admission; this rate increased to 63.4% at the time of discharge. Initiating clozapine during admission (n = 136) was associated with a 47.9% reduction of symptoms as reflected by their OPCRIT score. In cases in which clozapine monotherapy did not achieve sufficient improvement in symptoms, the most effective clozapine augmentation strategy was adding amisulpride (n = 22, 60.8% reduction of symptoms), followed by adding a mood stabilizer (n = 36, 53.7% reduction). A less favorable option was addition of quetiapine (n = 15, 26.7% reduction). Conclusions: Many people with longer-term and complex refractory illness do respond to clozapine treatment with suitable augmentation strategies when necessary. Furthermore, it is possible to advance clozapine prescribing in these complex patients when they are supported by a skilled and dedicated multidisciplinary team. The optimal therapeutic approach relies on confirmation of diagnosis and compliance and optimization of clozapine dose using therapeutic drug monitoring, followed by augmentation of clozapine with amisulpride or mood stabilizers. There is some preliminary evidence suggesting that augmentation strategies may impact differentially depending on the symptom profile.