The article ‘‘Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study,’’ by Nery et al., highlights important concerns about the risk of future diagnostic conversion among offspring of bipolar parents. At the time of inclusion in the study, the offspring did not meet criteria for a mood disorder, but over an 8-year follow-up period, 20% of the participants were found to develop a full-blown mood episode (depressive, manic, hypomanic, or mixed). Logistic regression identified baseline variables associated with increased risk of conversion, including the presence of an anxiety disorder and subthreshold mood symptomatology. Of notice, use of antidepressants was found to be associated with a higher risk of conversion, independently of the presence of subsyndromal mood symptoms. The ability to predict (and potentially prevent) the development of full-threshold psychiatric disorders among high-risk populations has been regarded by many as the ‘‘Holy Grail’’ of psychiatry. In that sense, over the last decades, several cohorts of individuals at high genetic risk for bipolar disorder (BD) have been established. While there seems to be a consensus as to the association between prodromal features (e.g., anxiety and subsyndromal mood symptoms) and future development of BD, results are much less consistent with regards to the possible predictive power of neuroimaging findings and other biological measures at baseline. To date, a brain signature allowing the early identification of those offspring who will later develop BD has not yet been described. On the other hand, the association between treatment with antidepressants and increased risk for the development of BD among offspring of parents with BD has important clinical implications. Antidepressants are commonly regarded as first-choice agents in the treatment of anxiety, and may be considered the default option for patients with depressive symptoms, even in the absence of full criteria for a major depressive episode. While the potential role of antidepressants in triggering manic or hypomanic symptoms and inducing mood deregulation in patients with BD is well established, the mechanism through which these medications have the potential to impact the maturing brain among individuals at high genetic load for BD and catalyze the development of a major mood disorder is not yet clear. A meta-analysis focusing on functional neuroimaging findings among highrisk adolescents, pediatric patients with BD, and controls revealed greater activity in the right dorsolateral prefrontal cortex (DLPFC), insula, and left cerebellum among the non-bipolar offspring compared to patients with BD, who, in turn, seemed to display higher activation in limbic areas, such as the amygdala, but lower activation in the right ventrolateral prefrontal cortex and in the DLPFC when compared to controls. These findings are in consonance with pathophysiological models proposing that the mood deregulation observed in BD is a result of a combination of increased limbic activity and decreased compensatory activities from frontoparietal areas. Still according to this model, the increased prefrontal activity observed in unaffected offspring would be responsible for counterbalancing the increased limbic activity related to the genetic diathesis for BD, therefore preventing the development of full clinical symptoms of the disorder. Since, as pointed out by the authors, antidepressants may induce hyperactivation of limbic structures such as the amygdala, it can be hypothesized that the use of these medications in highly susceptible individuals could disturb this delicate balance and tip the scale towards the development of BD. While there is not yet enough clinical evidence to support the routine use of mood stabilizers or antipsychotics in the treatment of offspring of bipolar parents presenting with prodromal symptoms, the decision to starting such patients on antidepressants (as well as stimulants) needs to be made with caution. There is an urgent need for research focusing on possible pharmacological alternatives to the management of subsyndromal symptoms in offspring of parents with BD. Similarly, research on the

中文翻译：

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抗抑郁药、遗传风险和双相情感障碍的预防

Nery 等人的文章“药物暴露和双相情感障碍父母后代首次情绪发作的预测因素：一项前瞻性研究”强调了对双相情感父母后代未来诊断转换风险的重要担忧。在纳入研究时，后代不符合情绪障碍的标准，但在 8 年的随访期间，发现 20% 的参与者出现了全面的情绪发作（抑郁、躁狂、轻躁狂或混合）。Logistic 回归确定了与转换风险增加相关的基线变量，包括焦虑症的存在和阈下情绪症状。值得注意的是，发现使用抗抑郁药与较高的转换风险相关，与亚综合征情绪症状的存在无关。在高危人群中预测（并可能预防）全阈值精神疾病发展的能力已被许多人视为精神病学的“圣杯”。从这个意义上说，在过去的几十年里，已经建立了几个具有双相情感障碍 (BD) 高遗传风险的个体队列。虽然对于前驱特征（例如，焦虑和亚综合征情绪症状）与 BD 未来发展之间的关联似乎存在共识，但结果与基线神经影像学发现和其他生物学测量结果的可能预测能力不一致. 迄今为止，尚未描述允许早期识别那些后来发展为 BD 的后代的大脑特征。另一方面，抗抑郁药治疗与 BD 父母的后代患 BD 风险增加之间的关联具有重要的临床意义。抗抑郁药通常被认为是治疗焦虑症的首选药物，即使没有重度抑郁发作的完整标准，也可能被认为是有抑郁症状的患者的默认选择。虽然抗抑郁药在触发 BD 患者的躁狂或轻躁狂症状和诱导情绪失调方面的潜在作用已得到充分证实，但这些药物有可能影响 BD 高遗传负荷个体的成熟大脑并催化发展的机制主要情绪障碍的分类尚不清楚。一项针对高危青少年、患有 BD 的儿科患者和对照组的功能性神经影像学发现的荟萃分析显示，与 BD 患者相比，非双相性后代的右侧背外侧前额叶皮层 (DLPFC)、岛叶和左小脑活动更大，反过来，与对照组相比，他们似乎在边缘区域（例如杏仁核）中表现出更高的激活，但在右腹外侧前额叶皮层和 DLPFC 中的激活较低。这些发现与病理生理学模型一致，该模型提出在 BD 中观察到的情绪失调是边缘活动增加和额顶区域代偿活动减少的组合的结果。还是按照这个模型，在未受影响的后代中观察到的前额叶活动增加将负责抵消与 BD 遗传素质相关的边缘活动增加，从而防止该疾病的全部临床症状的发展。正如作者所指出的那样，由于抗抑郁药可能会导致杏仁核等边缘结构的过度激活，因此可以假设，在高度易感的个体中使用这些药物可能会扰乱这种微妙的平衡，并导致 BD 的发展。虽然目前还没有足够的临床证据支持常规使用情绪稳定剂或抗精神病药治疗出现前驱症状的双相父母的后代，需要谨慎做出让此类患者开始服用抗抑郁药（以及兴奋剂）的决定。迫切需要研究可能的药理学替代方法来管理患有 BD 的父母的后代的亚综合征症状。同样，研究