Crocker Candice E, Tibbo Philip G
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
Department of Diagnostic Imaging, Nova Scotia Health Authority, Halifax, NS, Canada.
Front Pharmacol. 2018 Oct 18;9:1172. doi: 10.3389/fphar.2018.01172. eCollection 2018.
Despite development of comprehensive approaches to treat schizophrenia and other psychotic disorders and improve outcomes, there remains a proportion (approximately one-third) of patients who are treatment resistant and will not have remission of psychotic symptoms despite adequate trials of pharmacotherapy. This level of treatment response is stable across all stages of the spectrum of psychotic disorders, including early phase psychosis and chronic schizophrenia. Our current pharmacotherapies are beneficial in decreasing positive symptomology in most cases, however, with little to no impact on negative or cognitive symptoms. Not all individuals with treatment resistant psychosis unfortunately, even benefit from the potential pharmacological reductions in positive symptoms. The existing pharmacotherapy for psychosis is targeted at neurotransmitter receptors. The current first and second generation antipsychotic medications all act on dopamine type 2 receptors with the second generation drugs also interacting significantly with serotonin type 1 and 2 receptors, and with varying pharmacodynamic profiles overall. This focus on developing dopaminergic/serotonergic antipsychotics, while beneficial, has not reduced the proportion of patients experiencing treatment resistance to date. Another pharmacological approach is imperative to address treatment resistance both for response overall and for negative symptoms in particular. There is research suggesting that changes in white matter integrity occur in schizophrenia and these may be more associated with cognition and even negative symptomology. Here we review the evidence that white matter abnormalities in the brain may be contributing to the symptomology of psychotic disorders. Additionally, we propose that white matter may be a viable pharmacological target for pharmacoresistant schizophrenia and discuss current treatments in development for schizophrenia that target white matter.
尽管已经开发出综合方法来治疗精神分裂症和其他精神障碍并改善治疗效果，但仍有一部分患者（约三分之一）对治疗有抵抗性，尽管进行了充分的药物治疗试验，其精神病症状仍无法缓解。这种治疗反应水平在精神障碍谱系的所有阶段都是稳定的，包括早期精神病和慢性精神分裂症。我们目前的药物治疗在大多数情况下有助于减轻阳性症状，然而，对阴性或认知症状几乎没有影响。不幸的是，并非所有对治疗有抵抗性的精神病患者都能从阳性症状的潜在药物减轻中获益。现有的精神病药物治疗针对神经递质受体。目前的第一代和第二代抗精神病药物均作用于多巴胺2型受体，第二代药物还与5-羟色胺1型和2型受体有显著相互作用，总体上具有不同的药效学特征。这种对开发多巴胺能/5-羟色胺能抗精神病药物的关注虽然有益，但迄今为止尚未降低对治疗有抵抗性的患者比例。必须采取另一种药物治疗方法来解决治疗抵抗问题，无论是总体反应还是特别是阴性症状。有研究表明，精神分裂症患者的白质完整性会发生变化，这些变化可能与认知甚至阴性症状学更相关。在此，我们综述了大脑白质异常可能导致精神障碍症状的证据。此外，我们提出白质可能是对药物治疗有抵抗性的精神分裂症的一个可行的药物靶点，并讨论了目前正在开发的针对白质的精神分裂症治疗方法。
