The question in science is: at what point is there enough evidence to shift paradigm? Strejilevich and colleagues argue in their editorial that the time is here for bipolar disorder (BD).¹ The authors argue that we have not been able to prove neuroprogression in BD and that holding on to it will harm patients. A (hyper)focus on prevention of new episodes in BD may lead to overprescribing medication that increases the risk for cardiovascular diseases, and both medication and cardiovascular diseases have been associated with cognitive impairment in BD.^{2, 3} This hyperfocus may also refrain clinicians and researchers from looking beyond a relatively narrow cause–effect treatment of BD that merely focuses on prevention of mood symptom recurrence. In our opinion, BD warrants a more differentiated, personalized approach, which also takes into account psychosocial and cognitive functioning. Thus, we should indeed shift focus: from prevention of the next episode to optimizing inter-episodic functioning by integrating psychiatric and physical care for individuals with BD.

The neuroprogression hypothesis has been appealing to many. On the one hand, clinicians are encouraged by the neuroprogression hypothesis to prevent new episodes, as according to this theory, each mood episode could be neurotoxic. Furthermore, neuroprogression provides focus for patients and their relatives: “The reality of the current episode cannot be changed, but we can aim to prevent the next.” It provides a clear goal and treatment direction for clinicians: reduction of (future) mood symptoms and clinical recovery. On the other hand, researchers are fond of the theory because it fuels the search for a neurobiological origin of BD. To date, the pathophysiological underpinnings of BD have not been pinpointed despite global efforts in numerous genetic and imaging studies and that is frustrating. As researchers, we have postulated a hypothesis and then tried to prove it, or preferably disprove it, and that is what we do. However, the persistent belief in the neuroprogression hypothesis could also be the result of an epiphenomenon, namely the observation that patients with the worst course of BD have the highest risk of poor physical health and use of multiple psychotropic drugs in high doses, both of which can ultimately lead to cognitive impairment. Time to take a step back?

As clinicians in the field of old age bipolar disorder (OABD, aged 50 years and over), we have observed few indications of neuroprogression. It is true that some patients develop dementia, but overall the cognitive course of OABD patients mimics the natural course of healthy controls.^{4, 5} Similarly, we have perceived little evidence for somatoprogression (i.e., the accumulation of somatic comorbidities with every mood episode), in our clinical practice with OABD patients. Cross-sectional data from our clinic showed an even lower chronic physical burden in OABD compared to the general population.⁶ In this study, the observed faster accumulation of chronic physical diseases in OABD that could be explained by differences in psychosocial, lifestyle, and health behavior factors.⁶ What we do encounter in our daily practice is that our patients with OABD suffer from poor psychosocial functioning, polypharmacy, and poor physical health, all of which reduce their quality of life. Our clinical and research findings in OABD urgently call for the use of integrated care in BD. In case of strong collaboration between psychotherapists, medical specialists, family physicians, pharmacists, and social workers, clinical outcome of patients could improve tremendously. Next, we should try to overcome barriers for psychosocial interventions and develop accessible evidence-based psychotherapeutic interventions that focus on improvement of daily functioning and quality of life instead of prevention of recurrence. Moreover, prevention of cardiovascular diseases and interventions to improve lifestyle should be offered to patients with BD of all ages. Such a clinical focus on “daily functioning” is perhaps less appealing than the search for a neurobiological origin of BD, but nevertheless our aim as clinicians and researchers is, and should ultimately be, to improve quality of life of those struggling with BD. If we don't, we should indeed apologize for not making that our focus in BD for the next decade(s).

科学中的问题是：什么时候有足够的证据来改变范式？Strejilevich 及其同事在社论中指出，治疗双相情感障碍 (BD) 的时代已经到来。¹作者认为，我们无法证明双相情感障碍的神经进展，坚持下去会伤害患者。对预防 BD 新发作的（过度）关注可能会导致过度用药，从而增加心血管疾病的风险，而药物和心血管疾病都与 BD 的认知障碍有关。^{2, 3}这种过度关注也可能会阻止临床医生和研究人员超越相对狭隘的 BD 因果治疗方法，仅关注预防情绪症状复发。我们认为，BD 需要采取更加差异化、个性化的方法，同时也考虑到心理社会和认知功能。因此，我们确实应该转移焦点：从预防下一次发作转向通过整合双相情感障碍患者的精神和身体护理来优化发作间的功能。

神经进展假说吸引了许多人。一方面，神经进展假说鼓励临床医生预防新的发作，因为根据该理论，每次情绪发作都可能具有神经毒性。此外，神经进展为患者及其亲属提供了关注点：“当前事件的现实无法改变，但我们可以致力于预防下一次事件的发生。” 它为临床医生提供了明确的目标和治疗方向：减少（未来）情绪症状和临床康复。另一方面，研究人员喜欢这个理论，因为它推动了对双相情感障碍神经生物学起源的探索。迄今为止，尽管全球在众多遗传和影像学研究中做出了努力，但 BD 的病理生理学基础尚未查明，这令人沮丧。作为研究人员，我们假设了一个假设，然后试图证明它，或者最好反驳它，这就是我们所做的。然而，对神经进展假说的持续信念也可能是一种附带现象的结果，即观察到 BD 最严重病程的患者身体健康状况不佳和高剂量使用多种精神药物的风险最高，这两种情况最终可能导致认知障碍。是时候退后一步了吗？

作为老年双相情感障碍（OABD，50 岁及以上）领域的临床医生，我们几乎没有观察到神经进展的迹象。确实，有些患者会患上痴呆症，但总体而言，OABD 患者的认知过程与健康对照组的自然过程相似。^{4, 5}同样，在 OABD 患者的临床实践中，我们几乎没有发现躯体进展的证据（即每次情绪发作时躯体合并症的积累）。我们诊所的横断面数据显示，与一般人群相比，OABD 患者的慢性身体负担甚至更低。⁶在这项研究中，观察到 OABD 中慢性身体疾病的积累速度更快，这可以用社会心理、生活方式和健康行为因素的差异来解释。⁶我们在日常实践中确实遇到的是 OABD 患者心理社会功能较差、需要服用多种药物且身体健康状况不佳，所有这些都会降低他们的生活质量。我们在 OABD 方面的临床和研究结果迫切需要在 BD 中使用综合护理。如果心理治疗师、医学专家、家庭医生、药剂师和社会工作者之间强有力的合作，患者的临床结果可以得到极大的改善。接下来，我们应该努力克服心理社会干预的障碍，开发可行的循证心理治疗干预措施，重点关注改善日常功能和生活质量，而不是预防复发。此外，应向所有年龄段的双相情感障碍患者提供心血管疾病的预防和改善生活方式的干预措施。这种对“日常功能”的临床关注可能不如寻找 BD 的神经生物学起源那么有吸引力，但尽管如此，作为临床医生和研究人员，我们的目标是而且最终应该是改善 BD 患者的生活质量。如果我们不这样做，我们确实应该为没有在未来十年将其作为 BD 的重点而道歉。