Examination of pain threshold and neuropeptides in patients with acute suicide risk
Introduction
A growing and persistent epidemic, suicide is the 2nd leading cause of death among young adults. Almost 800,000 individuals die by suicide annually (2018). There are approximately 25 suicide attempts for every suicide (Drapeau and McIntosh, 2015; Maris, 2002). The complexities of suicidal behavior are highlighted by the multiple factors and potential mechanisms that underlie suicide risk.
Although risk for suicide is multifactorial, there is a growing literature regarding abnormalities in pain processing in suicidal individuals. A strong association is observed between psychological pain and suicidal behaviors (Ducasse et al., 2018). A recent meta-analysis showed a significant link between physical pain and suicidal thoughts and behaviors (Calati et al., 2015). Further, chronic pain is associated with increased suicidal ideation and attempts (Fishbain et al., 2014; Jimenez-Rodriguez et al., 2014). Previous studies have described higher suicide rates in patients with autoimmune disorders, which are characterized by persistent pain (Timonen et al., 2003). Additionally, higher pain tolerance and threshold, defined as the highest level an individual tolerates a given pain and the lowest level an individual feels pain, respectively, are found in individuals after recent suicidal behavior (Caceda et al., 2017; Orbach et al., 1997; Orbach et al., 1996a; Orbach et al., 1996b). This decrease in pain sensitivity seems to be transient (Caceda et al., 2017). We have previously shown that the elevated pressure pain threshold in recent suicide attempters returned within a week to levels comparable with those of non-suciidal patients and depressed patients with only suicidal ideation but no suicidal behavior (Caceda et al., 2017). Elucidating the biological mechanisms associated with pain processing abnormalities may provide insight into the underlying risk factors for suicide.
Reports indicate a pro-inflammatory state associated with suicidal behavior (Brundin et al., 2017). Treatment with interferon alpha has been shown to induce suicidal ideation in patients with hepatitis C (Dieperink et al., 2004). Moreover, increased C-reactive protein (CRP), a marker of systemic inflammation, and pro-inflammatory cytokines have been described in individuals following recent (Gibbs et al., 2016) and remote (Courtet et al., 2015) suicide attempts, (for review see (Black and Miller, 2015)). Recent suicide attempters show the most inflammation among suicidal patients (Gananca et al., 2016).
Peptides, in addition to modulating physiological processes (e.g. pain, immune function and endocrine regulation), are known to powerfully regulate an array of complex behaviors including social bonding, mating, parenting, aggression, and even self-harm (Macdonald and Macdonald, 2010; Panksepp et al., 2007; Stanley et al., 2010; van Anders et al., 2011). Alterations in pain modulating peptides such as β-endorphin are found in individuals endorsing chronic pain (Bruehl et al., 2012) and in patients diagnosed with psychiatric disorders (Colasanti et al., 2011; Merenlender-Wagner et al., 2009). It stands to reason that specific peptides may underlie changes in the pain processing and inflammatory pathways that influence the progression to suicidal behavior.
The first goal of the current study was to shed light into the biological underpinnings of suicidal behavior by examining plasma levels of peptides involved in regulation of pain and inflammatory responses. Specifically, we aimed to evaluate whether plasma peptides associated with inflammation and pain regulation were linked to suicidal ideation and behavior. The second goal of the study was to examine the relationship between these peptides with different components of the pain experience in suicidal patients, namely psychological and physical pain, and threshold for experimental pain. We chose markers related to analgesic and inflammatory responses for analyses: β-endorphin, neurotensin, agouti-related protein (AgRP), C-reactive protein (CRP), adrenocorticotropic hormone (ACTH), and brain-derived neurotrophic factor (BDNF). We hypothesized that a) recent suicide attempters (patients currently hospitalized for suicide attempt) as compared to recent suicidal ideators (patients currently hospitalized for suicidal ideation) have increased pain threshold and elevated plasma levels of pain regulatory and inflammatory markers; b) the number of lifetime suicide attempts, current/lifetime suicidal ideation severity, and lifetime suicide attempt lethality are correlated with elevated plasma levels of pain regulatory and inflammatory markers; and c) pain processing abnormalities (psychological and physical pain, and higher pain threshold) are correlated with elevated plasma levels of pain regulatory and inflammatory markers.
Section snippets
Participants
Depressed adult patients of both sexes, ages 18–62 years with current suicidal ideation or after a recent suicide attempt were recruited between September 2016 and June 2017 from the inpatient units of the Psychiatric Research Institute at the University of Arkansas for Medical Sciences (UAMS) within 24 h of hospital admission.
Inclusion criteria were the following: a) presence of current suicidal ideation as defined by the suicidal ideation severity subscale of the Columbia Suicide Severity
Results
A total of 37 depressed patients with current suicidal ideation (n = 26) or following a recent suicide attempt (n = 11) were examined. Table 1 presents the demographic and clinical characteristics of the study sample. The mean age was 39 years old, with similar proportion of males and females. Student t-Test revealed that higher pain threshold was measured in the suicide attempt group (p = .028; Hedges' g = 0.89) as compared to the suicidal ideation group. The suicidal ideation group had higher
Discussion
The present study sought to define the association between suicidal thoughts and actions and plasma peptides involved in the regulation of pain and the inflammatory response. Additionally, we examined the relationships between pain experience and levels of plasma peptides. We report: a) higher pain threshold and lower suicidal ideation severity in the suicide attempt group as compared to the suicidal ideation group, b) a positive correlation of number of lifetime suicide attempts with
Financial support
This work was partially funded by the Clinician Scientist Program of the University Arkansas for Medical Sciences, NCATS UL1TR000039, NIGMS P30 GM110702, and NIH/NIA AG12411. No funding source had any role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.
Contributors
DJK participated in the data analysis and preparation of the manuscript. SB participated in the peptide measurement and data analysis. PLD participated in the design, data analysis and preparation of the manuscript. JMC participated in the design, execution and preparation of the manuscript. RC participated in the design, execution, data analysis and preparation of the manuscript. All authors have approved the final version of this manuscript.
Ethical statement
The UAMS Institutional Review Board approved all procedures. The study conformed to the principles of the Declaration of Helsinki. Participants were compensated for their participation in the study.
Declaration of Competing Interest
None.
Acknowledgments
None.
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