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This overview should help researchers formulate questions to advance the understanding and management of TRS, and how to consider TRS in the context of a heterogeneous disease such as schizophrenia. This review presents an overview of the significant findings in TRS compared to patients that respond to antipsychotic treatment, known as non-treatment resistant schizophrenia (non-TRS), focusing on the clinical profile, neuroimaging, neurobiology, treatment options, and guidelines for defining TRS, with the purpose of providing neurobiologists with an introduction to the field. Finally, TRS costs 3–11 fold more than schizophrenia patients in remission, adding an estimated $34 billion to the US medical system ( Kennedy et al., 2014). Furthermore, persistent positive, negative, and cognitive symptoms lead to worsened social functioning ( Burton et al., 2013 Galderisi et al., 2014) and long-term disability ( Dickinson et al., 2006 Iasevoli et al., 2016 Rocca et al., 2014 Rosenheck et al., 2006 Twamley et al., 2002). They also have worse achievement of functional milestones of everyday living, including lower marriage rates, and higher rates of residence in facilities ( Iasevoli et al., 2016).
TRS patients have poorer outcomes when compared to other patients with severe mental illnesses. While defining TRS has been a major challenge in the field and studies have used different criteria, most accept the failure of two different antipsychotics as a minimum criterion. Around 30–60% of these patients respond to clozapine ( Juul-Povlsen et al., 1985 Kuha and Miettinen, 1986 Lieberman et al., 1994 Lindström, 1988 Meltzer, 1989). Overall estimates suggest that one-fifth to one-half of patients have treatment resistant schizophrenia (TRS) ( Elkis, 2007 Essock et al., 1996 Lieberman 1999 Lindenmayer, 2000). Unfortunately, not all patients respond to antipsychotic medications. Medication treatment became available with the development of chlorpromazine in the 1950s, and antipsychotic medication development continues to this day. The disease is characterized by positive, negative, and cognitive symptoms, and can lead to significant functional impairment. Schizophrenia is a severe, lifelong mental disorder affecting around 1% of the world’s population ( Saha et al., 2005). We conclude by highlighting the most recent consensus for defining TRS proposed by the Treatment Response and Resistance in Psychosis (TRRIP) Working Group, and provide our overview of future perspectives and directions that could help advance the field of TRS research, including the concept of TRS as a potential subtype of schizophrenia. We further review the current treatment strategies available, addressing clozapine, the first-line pharmacological agent for TRS, as well as pharmacological and nonpharmacological augmentation of clozapine including medication combinations, electroconvulsive therapy, repetitive transcranial magnetic stimulation, deep brain stimulation, and psychotherapies. We begin by reviewing the clinical, neuroimaging, and neurobiological characteristics of TRS. While many definitions of TRS include failure of two different antipsychotics as a minimum criterion, the wide variability in inclusion criteria has challenged the consistency and reproducibility of results from studies of TRS.
Treatment resistant schizophrenia (TRS) refers to the significant proportion of schizophrenia patients who continue to have symptoms and poor outcomes despite treatment.
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