A lifetime of challenges: real-life decision outcomes in early- and late-onset suicide attempters.

BACKGROUND: People who have attempted suicide display suboptimal decision-making in the lab. Yet, it remains unclear whether these difficulties tie in with other detrimental outcomes in their lives besides suicidal behavior. We hypothesize that this is more likely the case for individuals who first attempted suicide earlier than later in life. METHODS: A cross-sectional case-control study of 310 adults aged ≥ 50 years (mean: 63.9), compared early- and late-onset attempters (first attempt < 55 vs. ≥ 55 years of age) to suicide ideators, non-suicidal depressed controls and non-psychiatric healthy controls. Participants reported potentially avoidable negative decision outcomes across their lifetime, using the Decision Outcome Inventory (DOI). We employed multi-level modeling to examine group differences overall, and in three factor-analytically derived domains labeled Acting Out, Lack of Future Planning, and Hassles. RESULTS: Psychopathology predicted worse decision outcomes overall, and in the more serious Acting Out and Lack of Future Planning domains, but not in Hassles. Early-onset attempters experienced more negative outcomes than other groups overall, in Lack of Future Planning, and particularly in Acting Out. Late-onset attempters were similar to depressed controls and experienced fewer Acting out outcomes than ideators. LIMITATIONS: The cross-sectional design precluded prospective prediction of attempts. The assessment of negative outcomes may have lacked precision due to recall bias. CONCLUSIONS: Whereas early-onset suicidal behavior is likely the manifestation of long-lasting decision-making deficits in several serious aspects of life, late-onset cases appear to function similarly to non-suicidal depressed adults, suggesting that their attempt originates from a more isolated crisis.

Naltrexone modulates contextual processing in depression.

Context, the information surrounding an experience, can significantly alter the meaning and the affective responses to events. Yet the biological mechanisms through which context modulate experiences are not entirely understood. Here, we hypothesized that the µ-opioid system-extensively implicated in placebo effects, a clinical phenomenon thought to rely on contextual processing-modulates the effects of contextual information on emotional attributions in patients with depression. To test this hypothesis, 20 unmedicated patients with depression completed a randomized, double-blind, placebo-controlled, crossover study of one dose of 50 mg of naltrexone, or placebo immediately before completing two sessions of the Contextual Framing fMRI task. This task captures effects of valenced contextual cues (pleasant vs. unpleasant) on emotional attribution (the rating of subtle emotional faces: fearful, neutral, or happy). Behaviorally, we found that emotional attribution was significantly moderated by the interaction between contextual cues and subtle emotional faces, such that participants' ratings of valenced faces (fearful and happy), compared to neutral, were more negative during unpleasant, compared to pleasant context cues. At a neural level, context-induced blood-oxygen-level-dependent responses in the ventromedial prefrontal cortex, the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the lateral orbitofrontal cortex, significantly moderated the effects of context on emotional attribution, and were blunted by naltrexone. Furthermore, the effects of naltrexone on emotional attribution were partially abolished in more severely depressed patients. Our results provide insights into the molecular alterations underlying context representation in patients with depression, providing pivotal early data for future treatment studies.

Prefrontal expectancy and reinforcement-driven antidepressant placebo effects.

Placebo responses in depression exemplify how expectancies and appraisals impact mood. Cognitive and neural mechanisms underlying these responses are still poorly understood, partly due to the difficulty of simulating antidepressant effects and manipulating mood experimentally. To address these challenges, we developed an acute antidepressant placebo experiment involving the intravenous administration of a "fast-acting antidepressant" and a trial-by-trial sham fMRI "neurofeedback" manipulation, purporting to reveal mood-relevant neural responses. Twenty volunteers with major depression underwent this experiment while rating their expected and actual mood improvement. Mixed-effects analyses of trial-by-trial ratings revealed that the "drug" infusion cues induced higher expectancies of mood improvement, while both the "drug" infusion cue and the sham neurofeedback induced a reported mood improvement. Neurofeedback of greater magnitude, compared to lower magnitude, recruited the lateral prefrontal cortex (lPFC). Individuals with greater lPFC responses to neurofeedback displayed: (1) greater effect of previous mood improvement on expectancy ratings and (2) greater effect of sham neurofeedback on mood improvement. Behavioral antidepressant placebo effects were additionally moderated by changes in peripheral ß-endorphin plasma levels and depressive symptomatology. These data demonstrate the feasibility of trial-by-trial manipulation of antidepressant placebo-associated expectancies and their reinforcement. We provide initial insights into the role of the lPFC in the interplay between placebo-induced expectancies and mood, as well as preliminary evidence for the role of the opioid system in antidepressant placebo effects.

Paralimbic and lateral prefrontal encoding of reward value during intertemporal choice in attempted suicide.

BACKGROUND: Alongside impulsive suicide attempts, clinicians encounter highly premeditated suicidal acts, particularly in older adults. We have previously found that in contrast to the more impulsive suicide attempters' inability to delay gratification, serious and highly planned suicide attempts were associated with greater willingness to wait for larger rewards. This study examined neural underpinnings of intertemporal preference in suicide attempters. We expected that impulsivity and suicide attempts, particularly poorly planned ones, would predict altered paralimbic subjective value representations. We also examined lateral prefrontal and paralimbic correlates of premeditation in suicidal behavior. METHOD: A total of 48 participants aged 46-90 years underwent extensive clinical and cognitive characterization and completed the delay discounting task in the scanner: 26 individuals with major depression (13 with and 13 without history of suicide attempts) and 22 healthy controls. RESULTS: More impulsive individuals displayed greater activation in the precuneus/posterior cingulate cortex (PCC) to value difference favoring the delayed option. Suicide attempts, particularly better-planned ones, were associated with deactivation of the lateral prefrontal cortex (lPFC) in response to value difference favoring the immediate option. Findings were robust to medication exposure, depression severity and possible brain damage from suicide attempts, among other confounders. Finally, in suicide attempters longer reward delays were associated with diminished parahippocampal responses. CONCLUSIONS: Impulsivity was associated with an altered paralimbic (precuneus/PCC) encoding of value difference during intertemporal choice. By contrast, better-planned suicidal acts were associated with altered lPFC representations of value difference. The study provides preliminary evidence of impaired decision processes in both impulsive and premeditated suicidal behavior.

Corticostriatothalamic reward prediction error signals and executive control in late-life depression.

BACKGROUND: Altered corticostriatothalamic encoding of reinforcement is a core feature of depression. Here we examine reinforcement learning in late-life depression in the theoretical framework of the vascular depression hypothesis. This hypothesis attributes the co-occurrence of late-life depression and poor executive control to prefrontal/cingulate disconnection by vascular lesions. METHOD: Our fMRI study compared 31 patients aged ⩾60 years with major depression to 16 controls. Using a computational model, we estimated neural and behavioral responses to reinforcement in an uncertain, changing environment (probabilistic reversal learning). RESULTS: Poor executive control and depression each explained distinct variance in corticostriatothalamic response to unexpected rewards. Depression, but not poor executive control, predicted disrupted functional connectivity between the striatum and prefrontal cortex. White-matter hyperintensities predicted diminished corticostriatothalamic responses to reinforcement, but did not mediate effects of depression or executive control. In two independent samples, poor executive control predicted a failure to persist with rewarded actions, an effect distinct from depressive oversensitivity to punishment. The findings were unchanged in a subsample of participants with vascular disease. Results were robust to effects of confounders including psychiatric comorbidities, physical illness, depressive severity, and psychotropic exposure. CONCLUSIONS: Contrary to the predictions of the vascular depression hypothesis, altered encoding of rewards in late-life depression is dissociable from impaired contingency learning associated with poor executive control. Functional connectivity and behavioral analyses point to a disruption of ascending mesostriatocortical reward signals in late-life depression and a failure of cortical contingency encoding in elderly with poor executive control.

The temptation of suicide: striatal gray matter, discounting of delayed rewards, and suicide attempts in late-life depression.

BACKGROUND: Converging evidence implicates basal ganglia alterations in impulsivity and suicidal behavior. For example, D2/D3 agonists and subthalamic nucleus stimulation in Parkinson's disease (PD) trigger impulse control disorders and possibly suicidal behavior. Furthermore, suicidal behavior has been associated with structural basal ganglia abnormalities. Finally, low-lethality, unplanned suicide attempts are associated with increased discounting of delayed rewards, a behavior dependent upon the striatum. Thus, we tested whether, in late-life depression, changes in the basal ganglia were associated with suicide attempts and with increased delay discounting. METHOD: Fifty-two persons aged ≥ 60 years underwent extensive clinical and cognitive characterization: 33 with major depression [13 suicide attempters (SA), 20 non-suicidal depressed elderly] and 19 non-depressed controls. Participants had high-resolution T1-weighted magnetization prepared rapid acquisition gradient-echo (MPRAGE) magnetic resonance imaging (MRI) scans. Basal ganglia gray matter voxel counts were estimated using atlas-based segmentation, with a highly deformable automated algorithm. Discounting of delayed rewards was assessed using the Monetary Choice Questionnaire (MCQ) and delay aversion with the Cambridge Gamble Task (CGT). RESULTS: SA had lower putamen but not caudate or pallidum gray matter voxel counts, compared to the control groups. This difference persisted after accounting for substance use disorders and possible brain injury from suicide attempts. SA with lower putamen gray matter voxel counts displayed higher delay discounting but not delay aversion. Secondary analyses revealed that SA had lower voxel counts in associative and ventral but not sensorimotor striatum. CONCLUSIONS: Our findings, although limited by small sample size and the case-control design, suggest that striatal lesions could contribute to suicidal behavior by increasing impulsivity.