“Advances in the Understanding and Management of Treatment Resistance in Schizophrenia: Practical Considerations”

Schizophrenia continues to present a major public health problem associated with enormous personal suffering, diminished functioning, family burden and societal costs. Although current treatments (ideally combinations of medication and psychosocial modalities) can substantially improve outcome for many affected individuals, a substantial subgroup qualifies as having “treatment resistant schizophrenia (TRS).” Estimates suggest that 15-20% of patients at their very first episode of psychosis do not derive expected/sufficient benefit from antipsychotic medications. Over time this proportion increase to greater than 30%. In recent decades considerable research has been done evaluating the efficacy of a variety of treatment for these individuals. At the same time there has been insufficient consensus on how to define treatment resistance and many clinical trials employed different criteria for inclusion of subjects. The TRIPP guidelines, published in 2017, were an attempt to provide a consensus of international experts on how to define TRS.

Clozapine remains the only specific medication that has received regulatory approval in many countries for the treatment of TRS. At the same time, however, it remains markedly underutilized. Although there remains some debate regarding clozapine’s unique qualities, a good deal of research supports its role in the management of TRS. Research also suggests that clozapine’s efficacy is greater if it is administered within one to two years after the emergence of TRS.

We still lack good biomarkers to identify those individuals likely to experience TRS and those most likely to benefit from clozapine; however, promising leads have emerged in prospective clinical assessment as well as the use of resting state MRI, PET and EEG perspectives.

Recent research has also suggested that psychotic relapse is associated with poorer response to standard treatment than that observed in prior episodes, suggesting that repeated relapse might also be part of the trajectory towards TRS.

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