Treatment-resistant schizophrenia: challenges and implications for clinical practice.

Despite pharmacological advances in the treatment of schizophrenia, significant number of patients continue to be treatment-resistant. Poor control of symptoms could be related to low concentration of antipsychotics because of non-adherence or pharmacokinetic issues. However, there is growing evidence that "true" treatment-resistance might be associated with biological changes, i.e. alterations in dopaminergic and glutaminergic systems, genetics, neurodegeneration and neuroinflamation. Clozapine is recommended as first-line treatment for treatment-resistant schizophrenia (TRS) in all guidelines. Clozapine-ECT combination is effective in majority of those patients, at least in short-term. However, more than half of patients with TRS have resistance or intolerance to clozapine, and more interventions are needed. Different combination and augmentation strategies may offer some advantage, but evidence is limited. Given the severity and complexity of TRS, there is an urgent need for better treatment. Treatment strategies beyond dopamine, such as glutamate-modelling agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal treatment, are under investigation.