T197. TREATMENT STRATEGIES FOR ULTRA-RESISTANT SCHIZOPHRENIAS

BACKGROUND: Treatment-resistant schizophrenias include a heterogeneous group of patients with significant individual and societal consequences, and a high number of these patients fail to respond to clozapine (almost 50%). Patients who did not respond to the second line antipsychotics are a challenge for their treating physicians and although many augmentation strategies have been tried, including other agents with antipsychotic properties, mood-stabilizers, antidepressants, glutamatergic agents and neuromodulation techniques. METHODS: A literature review was conducted in the main electronic databases (PubMed, Cochrane, EMBASE, CINAHL), and papers published between January 2000 and August 2019 were included. The search paradigm was “ultra-resistant schizophrenia” or “clozapine-resistant schizophrenia” or “add-on to schizophrenia” and non-proprietary names of currently marketed antipsychotics, mood stabilizers, antipsychotics, nootropics, “neuromodulation techniques” and “psychotherapy”. RESULTS: A number of 197 papers resulted from the primary search, and 45 papers remained after de-duplication and application of inclusion and exclusion criteria. Electroconvulsive therapy seems to be efficient and the response rate ranges from 37.5 to 100% in cases of ultra-resistant schizophrenia [1]. Transcranial direct-current stimulation (tDCS) lead to meaningful improvement in positive symptoms and overall symptomatology when compared to no standard treatment of the control group, in a 4 weeks trial [2]. A 21-week pragmatic trial did not find any significant lasting effect of the cognitive-behavioral therapy (CBT) on total symptoms of schizophrenia compared to treatment as usual, although improvements were detected [3]. Pharmacological augmentation of clozapine included amisulpride (results were not significant), memantine (positive effects, but the trial included a small number of patients), reboxetine (uncertain efficacy), ziprasidone (possible effective on negative and cognitive symptoms), aripiprazole (uncertain effect based on multiple trials), lamotrigine (not efficient), pimozide (not efficient), sertindole (no benefits detected, possible worsen psychosis in several cases), tetrabenazine (not effective), duloxetine (possible efficacy on negative and general psychopathology, but not on the executive cognitive functions), topiramate (no efficacy), valproic acid (possible efficacy, larger trials needed), risperidone (not efficient), donepezil (not efficient), mirtazapine (possible efficacy), sulpiride (possible efficacy in a subgroup of schizophrenia patients). DISCUSSION: Until now no single pharmacological augmentation strategy to clozapine has been proven superior to other in double-blind randomized, large-scale placebo-controlled data. Electroconvulsive therapy seems to be the only non-pharmacological technique with enough data to support its efficacy in ultra-resistant cases of schizophrenia. Other neuromodulatory techniques, like tDCS, are still in early phase of investigation, and psychotherapy does not have enough evidence to support its efficacy. REFERENCES: 1. Grover S, Hazari N, Kate N. Combined use of clozapine and ECT: a review. Acta Neuropsychiatr 2015;27(3):131–142. 2. Lindenmayer JP, Kulsa MKC, Sultana T, et al. Transcranial direct-current stimulation in ultra-treatment-resistant schizophrenia. Brain Stimul 2019;12(4):54–61. 3. Morrison AP, Pyle M, Gumley A, et al. Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Lancet Psychiatry 2018;5(8):633–643.