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Original Investigation |

Positron Emission Tomographic Imaging of the Serotonergic System and Prediction of Risk and Lethality of Future Suicidal Behavior ONLINE FIRST

Maria A. Oquendo, MD1,2; Hanga Galfalvy, PhD1,2; Gregory M. Sullivan, MD3; Jeffrey M. Miller, MD1,2; Matthew M. Milak, MD1,2; M. Elizabeth Sublette, MD, PhD1,2; Sebastian Cisneros-Trujillo, MD1,2; Ainsley K. Burke, PhD1,2; Ramin V. Parsey, MD, PhD4; J. John Mann, MD1,5
[+] Author Affiliations
1New York State Psychiatric Institute, New York
2Department of Psychiatry, Columbia University, New York, New York
3Tonix Pharmaceuticals, LLC, New York, New York
4Department of Psychiatry and Behavioral Science, Stony Brook University School of Medicine, Stony Brook, New York
5Department of Radiology, Columbia University, New York, New York
JAMA Psychiatry. Published online July 27, 2016. doi:10.1001/jamapsychiatry.2016.1478
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Importance  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 serotonin1A binding potential in the raphe nuclei (RN) is associated with greater lethality of past suicide attempts and suicidal intent and ideation.

Objectives  To determine whether serotonin transporter binding potential in the lower midbrain predicts future suicide attempts and whether higher RN serotonin1A binding potential predicts future suicidal ideation and intent and lethality of future suicide attempts.

Design, Setting, and Participants  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 N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide ([11C]WAY-100635), a serotonin1A antagonist; a subset of 50 patients also underwent imaging with carbon 11–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- benzonitrile ([11C]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.

Exposures  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.

Main Outcomes and Measures  Suicide attempt or suicide.

Results  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 serotonin1A binding potential predicted more suicidal ideation at 3 (b = 0.02; t = 3.45; P = .001) and 12 (b = 0.02; t = 3.63; P = .001) months and greater lethality of subsequent suicidal behavior (b = 0.08; t = 2.89; P = .01). Exploratory analyses suggest that the serotonin1A binding potential of the insula (t = 2.41; P = .04), anterior cingulate (t = 2.27; P = .04), and dorsolateral prefrontal cortex (t = 2.44; P = .03) were also predictive of lethality. Contrary to our hypotheses, suicidal intent was not predicted by serotonin1A binding potential in any brain region (F1,10 = 0.83; P = .38), and midbrain serotonin transporter binding potential did not predict future attempts (log-rank χ21 = 0.4; P = .54), possibly owing to low power.

Conclusions and Relevance  Greater RN serotonin1A 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.

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Figure 1.
Correlation Between Maximal Lethality of Suicide Attempts During Follow-up and Serotonin1A Binding Potential (BPF) in the Raphe Nuclei (RN)

Each data point represents the mean RN BPF for a single suicide attempter; error bars indicate SEs. Lethality is scored from 0 to 8, with 0 indicating no injury and 8 indicating fatal injury, using the Beck Suicide Intent Scale20 and Medical Lethality Scale.26

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Figure 2.
Serotonin1A Binding Potential (BPF) in Raphe Nuclei (RN) by Suicide Ideation Severity

Serotonin1A BPF was measured at baseline; suicide ideation severity was measured at 3, 12, and 24 months using the Beck Scale for Suicide Ideation.20 Scores ranged from 0 to 30, with higher scores indicating more severe ideation. Standard errors of the BP estimates were adjusted for in the calculation of the regression estimates.

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