Identifying Neurobiological Correlates of Suicide Risk in Depression

Patients suffering from depressive disorders, particularly those with a history of suicide attempt, are at increased risk for future suicidal acts. Neurobiological studies of suicidal behavior have investigated anomalies that distinguish suicide attempters and completers from individuals who are depressed but do not engage in any suicidal behavior. To aid in the development of a predictive model in which both biological measures and clinical instruments are used to identify those at risk for future suicidal acts, studies have focused on biological correlates of behavioral and other factors identified by clinical studies as indicative of higher risk for suicidal behavior, such as aggression/impulsivity.

Neuroendocrine challenge and cerebrospinal fluid (CSF) studies suggest that suicide attempters have decreased function in the serotonin system (Malone et al., 1996; Siever et al., 1984; Virkkunen et al., 1989). Among individuals with depression, high-lethality suicide attempts are associated with even lower serotonergic function (Malone et al., 1996; Mann and Malone, 1997). Neuroendocrine challenges and CSF measures are, however, unable to provide specific information about the anatomical location of abnormality. So far, it is known from studies mapping postmortem serotonin receptor binding that cortical serotonergic abnormalities associated with suicide are localized to the ventral prefrontal cortex (PFC) region of the brain (Arango et al., 1997). Positron emission tomography (PET) studies offer a distinct advantage over previous methodologies, allowing for more precise in vivo identification and study of the activity of brain regions that differ in those who have survived a suicide attempt of high lethality, compared to those surviving a low-lethality attempt. Given the findings of CSF and neuroendocrine studies with respect to differences in serotonin levels between high- and low-lethality attempters, PET studies of high-lethality attempters would be expected to reveal pronounced differences.

In a recent study, my colleagues and I examined regional brain glucose metabolism with placebo and after administration of fenfluramine (Pondimin), a serotonin-releasing drug, in order to discern regional differences in glucose metabolism associated with serotonergic activity between high- and low-lethality depressed suicide attempters (Oquendo et al., 2003). Changes in metabolism, which include both increases and decreases, reflect changes in neuronal activity, owing to the surge of serotonergic activity caused by fenfluramine. The changes can occur in both directions because serotonin has both inhibitory and indirect excitatory effects in different brain regions. These differences in response by different brain regions due to serotonergic activity can be visualized with PET.

Our PET study of the regional serotonergic function in patients who are depressed and have a history of high-lethality suicide attempts compared to patients who are depressed and have a history of low-lethality suicide attempts revealed differences in brain activity between the two groups (Oquendo et al., 2003). High-lethality suicide attempters showed less activity in the ventral, medial and lateral PFC, compared to low-lethality suicide attempters, indicating a relative hypofunction in the PFC in high-lethality attempters. There were two specific regions of interest (ROIs) where differences were identified between low- and high-lethality attempters. One was in the anterior cingulate and the medial frontal gyri (ROI #1) and the second in the anterior cingulate and right superior frontal gyri (ROI #2). The first ROI was located bilaterally in the anterior cingulate and medial frontal gyrus (BA 32 and 8). The second ROI was located in the right midcingulate and superior frontal gyri (BA 24 and 6).

PET and Clinical Measures

One way to further understand the meaning of these neurobiological differences between the two groups is to assess the relationship between the regions showing differences in glucose metabolism and clinical measures. In our study, more impulsive depressed patients who made low-lethality attempts showed higher activity in the two ROIs of the PFC compared to the less impulsive high-lethality attempters (Figure 1 and Figure 2) (Oquendo et al., 2003). (Due to copyright concerns, these figures cannot be reproduced online. Please see p50 of the print edition--Ed.) This higher activity was also associated with greater impulsivity and lower age. Age and impulsivity were negatively correlated, suggesting possibly that age influences suicide lethality via an age-related decrease in PFC activity that reduced impulsivity. In contrast, suicide intent correlated inversely with ROI #1, but not ROI #2 or age, suggesting that the effect of suicidal intent on lethality may be mediated by a more restricted area of the PFC and be independent of age and impulsivity.

Lower activity in the PFC was associated with lower lifetime impulsivity, higher suicidal intent (planning) and high-lethality attempts. Further, we found that high-lethality attempters had later onset of depression and suicidal behavior but not a different number of episodes. This suggests that these people may have different biological and clinical characteristics (such as less impulsivity and more intent) and, consequently, a higher risk for high-lethality suicide behavior than patients with an earlier onset. In our study, suicide intent and impulsivity correlated independently with suicide-attempt lethality (Oquendo et al., 2003). It has been reported that low-lethality attempters are more impulsive than high-lethality attempters (Baca-Garcia et al., 2001; Mann and Malone, 1997). In addition, impulsivity declines with age and more planful suicidal acts occur with increasing age (Conwell et al., 1998).

A negative correlation between lethality and serotonin receptor activity PFC is consistent with our hypothesis that PFC function has a role in suicidal behavior (Mann et al., 1999). Postmortem studies have shown that alterations in serotonin transporter (SERT) binding and 5-HT1A binding in suicide victims compared with psychiatric controls are localized to Brodmann areas 11, 12, 45, 46 for SERT and more ventrolateral PFC areas for 5-HT1A, respectively, in the ventral PFC (Arango et al., 2002, 1997). Lesion studies have linked the ventral and medial PFC to behavioral inhibition, which may be partly mediated by serotonin input into these brain regions (Godefroy et al., 1999).

Our in vivo PET study found abnormalities in PFC (Brodmann areas 6, 8, 9, 24, 32) that are close, but not identical, to the regions with reported postmortem receptor changes. Further in vivo studies measuring specific serotonin receptor binding in PFC are needed to determine whether the serotonergic hypofunction we have described in high-lethality attempters is associated with the same receptor changes as those found in suicide victims.

Summary

Positron emission tomography studies may eventually offer a means to measure neurobiological correlates of different types of suicidal behavior, thereby allowing the identification of individuals at more acute risk of suicide completion. The differences we found in the PFC of high- and low-lethality attempters were associated with differences in impulsivity. It may be that the presence of impulsivity and/or decision-making difficulties, well-documented functions of the PFC, affect planning of suicidal behavior and explain the tendency toward high- or low-lethality attempts. Positron emission tomography studies, undertaken in conjunction with clinical studies, can thus offer a more comprehensive picture of the traits and states that precipitate suicidal activity of differing levels of lethality and can help scientists elaborate the meaning of neurobiological findings.

References:

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