Treatment-resistant schizophrenia: pathogenesis and treatment strategies

Erikas Vasiliauskas1, Akvilė Gaupšaitė1

1Vilnius University, Faculty of Medicine


Treatment-resistant schizophrenia (TRS) is most defined as an inadequate response in schizophrenia symptoms, despite adequate treatment with two or more antipsychotic medications. Approximately one-third of schizophrenia patients develop treatment resistant schizophrenia (TRS). The cause of TRS is unknown, as is the exact pathogenesis of the disorder. Dopamine supersensitivity and glutamatergic dysfunction are main hypotheses explaining phenomenon of treatment-resistant schizophrenia. Neuroimaging studies of TRS implies, that TRS is heterogeneous disease with different pathophysiological mechanism than treatment-responsive schizophrenia. There are no universally accepted diagnostic criteria of TRS. It is crucial to differentiate true TRS from pseudo-resistance due to inadequate treatment or misdiagnosis. Clozapine remains the “gold standard“ medication for TRS treatment. Despite that fact approximately 40-60% patients do not respond, or respond only partially, to clozapine. The combination of clozapine and mood stabilizers or non-pharmacological interventions might be effective even to clozapine-resistant patients.  Augmentation of clozapine with electroconvulsive therapy probably the most effective therapy in TRS and clozapine-refractory schizophrenia. Further research is needed to understand the pathophysiology of TRS, to choose the most suitable treatment strategy.

Keywords: treatment-resistant schizophrenia, pathophysiology of schizophrenia, clozapine and clozapine augmentation therapy; schizophrenia and electroconvulsive therapy.