Positron Emission Tomographic Imaging of the Serotonergic System and Prediction of Risk and Lethality of Future Suicidal Behavior
Authors: Maria A. Oquendo, Hanga Galfalvy, Gregory M. Sullivan, Jeffrey M. Miller, Matthew M. Milak, M. Elizabeth Sublette, Sebastian Cisneros-Trujillo, Ainsley K. Burke, Ramin V. Parsey, J. John Mann
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> Biomarkers that predict suicidal behavior, especially highly lethal behavior, are urgently needed. In cross-sectional studies, individuals with depression who attempt suicide have lower midbrain serotonin transporter binding potential compared with those who do not attempt suicide, and higher serotonin<sub>1A</sub>binding potential in the raphe nuclei (RN) is associated with greater lethality of past suicide attempts and suicidal intent and ideation. <h3>Objectives</h3> To determine whether serotonin transporter binding potential in the lower midbrain predicts future suicide attempts and whether higher RN serotonin<sub>1A</sub>binding potential predicts future suicidal ideation and intent and lethality of future suicide attempts. <h3>Design, Setting, and Participants</h3> In this prospective 2-year observational study, a well-characterized cohort of 100 patients presenting for treatment of a major depressive episode of at least moderate severity underwent positron emission tomography using carbon 11–labeled<i>N</i>-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-<i>N</i>-(2-pyridyl)-cyclohexanecarboxamide ([<sup>11</sup>C]WAY-100635), a serotonin<sub>1A</sub>antagonist; a subset of 50 patients also underwent imaging with carbon 11–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- benzonitrile ([<sup>11</sup>C]DASB), a serotonin transporter radioligand. Imaging was performed at Columbia University Medical Center from May 3, 1999, to March 11, 2008. Follow-up was completed on May 28, 2010, and data were analyzed from August 1, 2013, to March 1, 2016. <h3>Exposures</h3> Patients were treated naturalistically in the community and followed up for 2 years with documentation of suicidal behavior, its lethality, and suicidal ideation and intent. <h3>Main Outcomes and Measures</h3> Suicide attempt or suicide. <h3>Results</h3> Of the 100 patients undergoing follow-up for more than 2 years (39 men; 61 women; mean [SD] age, 40.2 [11.2] years), 15 made suicide attempts, including 2 who died by suicide. Higher RN serotonin<sub>1A</sub>binding potential predicted more suicidal ideation at 3 (b = 0.02;<i>t</i> = 3.45;<i>P</i> = .001) and 12 (b = 0.02;<i>t</i> = 3.63;<i>P</i> = .001) months and greater lethality of subsequent suicidal behavior (b = 0.08;<i>t</i> = 2.89;<i>P</i> = .01). Exploratory analyses suggest that the serotonin<sub>1A</sub>binding potential of the insula (<i>t</i> = 2.41;<i>P</i> = .04), anterior cingulate (<i>t</i> = 2.27;<i>P</i> = .04), and dorsolateral prefrontal cortex (<i>t</i> = 2.44;<i>P</i> = .03) were also predictive of lethality. Contrary to our hypotheses, suicidal intent was not predicted by serotonin<sub>1A</sub>binding potential in any brain region (F<sub>1,10</sub> = 0.83;<i>P</i> = .38), and midbrain serotonin transporter binding potential did not predict future attempts (log-rank χ<sup>2</sup><sub>1</sub> = 0.4;<i>P</i> = .54), possibly owing to low power. <h3>Conclusions and Relevance</h3> Greater RN serotonin<sub>1A</sub>binding potential predicted higher suicidal ideation and more lethal suicidal behavior during a 2-year period. This effect may be mediated through less serotonin neuron firing and release, which affects mood and suicidal ideation and thereby decision making.