Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT_1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT_1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT_1A binding potential BP_ND using [¹¹C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BP_ND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT_1A BP_ND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT_1A BP_ND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT_1A BP_ND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT_1A BP_ND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

情绪障碍和自杀行为具有中等遗传性，并且与皮质边缘血清素 1A 受体 (5-HT _1A ) 脑结合的改变有关。然而，尚不清楚这是否反映了童年逆境的遗传效应或表观遗传效应、补偿机制或疾病应激相关的变化。我们试图通过检查高家族风险个体 (HR) 来区分对 5-HT _1A结合的影响，这些个体已经过了精神病理学发病风险最大的年龄，无论是否出现情绪障碍或自杀行为。使用 [ ¹¹ C]CUMI-101 在健康志愿者（HV， N = 23）和具有一名或多名亲属表现出早发性情绪障碍和自杀企图的三组中使用 [ 11 C]CUMI- _101进行PET 成像量化 5-HT 1A 结合潜力 BP ND： 1. 未受影响人力资源（ N = 23）； 2. HR患有终生情绪障碍且没有自杀企图（HR-MOOD， N = 26）； 3. 既往有自杀企图的 HR-MOOD（HR-MOOD + SA， N = 20）。结果在未选择家族史的独立队列中进行了测试（HV、MOOD 和 MOOD + SA，总N = 185）。我们测试了区域 BP _ND差异以及全脑模式是否能区分各组。低腹侧前额叶 5-HT _1A BP _ND与终生情绪障碍诊断和自杀企图相关，但仅限于有情绪障碍和自杀企图家族史的受试者。全脑 5-HT _1A BP _ND模式（包括低腹侧前额叶和中颞叶皮质结合）将 HR-MOOD + SA 与 HV 区分开来。没有观察到与弹性相关的生物内表型。 低腹侧前额叶 5-HT _1A BP _ND可能反映家族情绪障碍和自杀相关病理。需要进一步的研究来确定较高的腹侧前额叶 5-HT _1A BP _ND是否具有恢复能力，降低家庭风险背景下自杀行为的风险，从而提供潜在的预防目标。