Govil Preetika, Kantrowitz Joshua T
New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032, USA.
College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
CNS Drugs. 2025 Mar;39(3):243-262. doi: 10.1007/s40263-024-01151-7. Epub 2025 Jan 12.
The negative symptoms of schizophrenia include diminished emotional expression, avolition, alogia, anhedonia, and asociality, and due to their low responsiveness to available treatments, are a primary driver of functional disability in schizophrenia. This narrative review has the aim of providing a comprehensive overview of the current research developments in the treatment of negative symptoms in schizophrenia, and begins by introducing the concepts of primary, secondary, prominent, predominant, and broadly defined negative symptoms. We then compare and contrast commonly used research assessment scales for negative symptoms and review the evidence for the specific utility of widely available off-label and investigational treatments that have been studied for negative symptoms. Mechanism of action/putative treatments included are antipsychotics (DR antagonists), N-methyl-D-aspartate receptor (NMDAR) and other glutamatergic modulators, serotonin receptor (5-HTR) modulators, anti-inflammatory agents, antidepressants, pro-dopaminergic modulators (non-DR antagonists), acetylcholine modulators, oxytocin, and phosphodiesterase (PDE) inhibitors. With the caveat that no compounds are definitively proven as gold-standard treatments for broadly defined negative symptoms, the evidence base supports several potentially beneficial off-label and investigational medications for treating negative symptoms in schizophrenia, such as monotherapy with cariprazine, olanzapine, clozapine, and amisulpride, or adjunctive use of memantine, setrons such as ondansetron, minocycline, and antidepressants. These medications are widely available worldwide, generally tolerable and could be considered for an off-label, time-limited trial for a predesignated period of time, after which a decision to switch or stay can be made based on clinical response. Among investigational medications, NMDAR agonists, muscarinic agonists, and LB-102 remain under study. Suggestions for future research include reducing placebo effects by designing studies with a smaller number of high-quality study sites, potentially increasing the use of more precise rating scales for negative symptoms, and focused studies in people with predominant negative symptoms.
精神分裂症的阴性症状包括情感表达减少、意志缺乏、言语减少、快感缺失和社交障碍，由于它们对现有治疗反应不佳，是精神分裂症功能残疾的主要驱动因素。本叙述性综述旨在全面概述精神分裂症阴性症状治疗的当前研究进展，并首先介绍原发性、继发性、突出性、主导性和广义定义的阴性症状的概念。然后，我们比较和对比了常用的阴性症状研究评估量表，并回顾了已针对阴性症状进行研究的广泛可用的非标签和研究性治疗的具体效用证据。所包括的作用机制/假定治疗方法有抗精神病药（多巴胺受体拮抗剂）、N-甲基-D-天冬氨酸受体（NMDAR）和其他谷氨酸能调节剂、5-羟色胺受体（5-HTR）调节剂、抗炎药、抗抑郁药、促多巴胺能调节剂（非多巴胺受体拮抗剂）、乙酰胆碱调节剂、催产素和磷酸二酯酶（PDE）抑制剂。需要注意的是，目前尚无化合物被明确证明是治疗广义定义阴性症状的金标准疗法，但现有证据支持几种可能有益的非标签和研究性药物用于治疗精神分裂症的阴性症状，如卡立普嗪、奥氮平、氯氮平和氨磺必利单药治疗，或美金刚、昂丹司琼等5-羟色胺受体拮抗剂、米诺环素和抗抑郁药的辅助使用。这些药物在全球广泛可得，一般耐受性良好，可考虑在预先指定的时间段内进行非标签、限时试验使用，之后可根据临床反应决定换药或继续用药。在研究性药物中，NMDAR激动剂、毒蕈碱激动剂和LB-102仍在研究中。对未来研究的建议包括通过设计高质量研究点数量较少的研究来减少安慰剂效应，可能增加使用更精确的阴性症状评定量表，以及针对主导性阴性症状患者进行重点研究。
