This is the first study to examine the role of serotoninergic neurotransmission and its association with personality factors in modulating the risk of developing a future depressive episode in healthy individuals. We found novel evidence that neocortical 5-HT2AR binding interacts with the inward-directed facets of neuroticism to amplify the risk of developing depression later in life. In particular, healthy individuals with the greatest probability of developing depression were those with high 5-HT2AR binding and high neuroticisminward scores. Thus, the present study provides a novel risk model for first-episode depression which suggests that the interaction between neocortical 5HT2AR binding and neuroticisminward is involved in the etiology of depression.
Despite the abundance of studies examining serotonin neurotransmission in MDD, its exact role in the pathophysiology of depression is unclear. Studies from both post-mortem and in vivo neuroimaging studies have largely shown high 5-HT2AR levels in patients relative to healthy individuals,9–11 however, there have also been mixed reports with evidence for lower and no significant differences in 5-HT2AR binding between patients with MDD and healthy individuals.12, 14, 15 This may in part be due to differences in sample characteristics or due to methodological differences, such as tracer or quantification methods. Another confounding factor is that treatment with selective serotonin reuptake inhibitors may also reduce 5-HT2AR binding.17 The apparent lack of consensus also highlights the importance of considering additional factors, such as personality, environmental stressors, and genetic risk factors for depression that could interact with serotoninergic function44 to moderate the risk of developing depression. For instance, a previous study showed that 5-HT2AR binding was significantly increased relative to individuals only in those patients who had extremely high dysfunctional attitudes.12
Cross-sectional studies performed in depressed and healthy individuals point to a well-established association between the 5-HT2AR system and personality. These studies have shown a positive association between cortical 5-HT2AR binding and personality factors that are associated with an increased risk of developing depression such as harm avoidance and dysfunctional attitudes.12, 24 Neuroticism is yet another personality trait that is shown to be a risk factor for depression, and our cross-sectional investigations revealed that the positive association between cortico-limbic 5-HT2AR binding and neuroticism found in healthy individuals20 is stronger in individuals who have a familial risk of developing depression relative to those who are at low risk of depression.21 The present finding from the examination of up to 19 years of longitudinal data in healthy individuals confirms our earlier hypothesis that the interaction between 5-HT2AR binding neuroticisminward is involved in the etiology of depression.20 Importantly, it provides a risk model for first-episode depression, indicating that healthy individuals who have the behavioral phenotype that is characterized by high neuroticisminward along with the serotonergic phenotype of high 5-HT2AR binding may be at the greatest risk for developing depression in the future.
Binding potential (BPP) may reflect changes in receptor density (Bavail) and/or changes in receptor affinity (Kd). Evidence from post-mortem studies indicates that the high 5-HT2AR binding is likely to represent the up-regulation of 5-HT2AR binding sites.10 Thus, in context, our results suggest that in a subgroup of healthy individuals who have a serotonergic phenotype of increased 5-HT2AR availability, perhaps genetically determined45 and/or reflecting a maladaptive homeostatic response to low serotonin levels, there is a greater susceptibility to having a personality phenotype characterized by higher neuroticism. Together, this combination of personality and serotonergic phenotypes puts individuals at a higher risk of developing depression. We speculate that this could reflect a partly shared biological mechanism such that a genetic predisposition to 5-HT2AR availability may contribute to increased neuroticisminward even in the absence of environmental stressors, thereby accentuating the risk for depression. Alternatively, it could reflect two independent mechanisms that accentuate the risk for depression significantly when coupled.
Intriguingly, our data raise the question of whether interventions that simultaneously target the 5-HT2AR agonism and address personality-based maladaptive responses could help alleviate depression. An example is psilocybin-assisted psychotherapy which combines the pharmacological effects of psilocybin (a 5-HT2AR agonist) administered in conjunction with psychotherapy and psychological support. A single dose of psilocybin has shown to be associated with decreases in neuroticism for up to three months,46 and a down-regulation of cerebral 5-HT2AR was proportional to increased mindfulness and openness.47 We speculate whether such interventions could be applied in a precision medicine approach and might work particularly efficiently in specific strata, for instance, individuals with high 5-HT2AR binding and high neuroticisminward scores.
As expected, the present study additionally found that women were significantly more likely than men to develop depression, a finding that is consistent with clinical and epidemiological observations.48 The study also found that the 19-year probability of developing depression in the present sample of healthy participants was approximately 13%. We expected the risk of developing depression in the current cohort to be lower given a selection bias, as the individuals were without a lifetime history of neurological and psychiatric disorders and were healthy enough to take part in a neuroimaging study. Nevertheless, our result is consistent with epidemiological survey findings that show a 10%-15% of lifetime prevalence risk of depression in the general population.49
The findings of the study must be considered in the context of its limitations. We did not have cross-sectional or longitudinal data on clinical or psychosocial factors such as premorbid anxiety, childhood adversity, and other environmental stressors that may have a role to play in the risk of developing depression, and in its association with 5-HT2AR binding. The NEO-PI-R scale which was used to assess neuroticisminward in this study also can be used to measure other aspects of personality such as openness to experience, extraversion, conscientiousness, and agreeableness. However, we restricted our investigations to neuroticism as it is less clear whether these other trait factors are associated with depression.50 Neuroticism, on the other hand, has shown to be associated with the presence of depression and with treatment outcomes.50 Furthermore, it is an important predictor of late-onset depression.50 This is of significance given that the median age of the sample was 34 years and past the most common age of onset of depression. The 5-HT2A R is most abundantly found in the neocortex where the signal with the applied PET method is also best captured, and therefore we limited our investigation to neocortical 5HT2AR binding and its association with neuroticisminward. Whether there is a region-specific difference in the interaction with neuroticisminward is unclear. The present study leverages a large and unique dataset which includes molecular imaging and personality assessments. However, events such as death were rare (n = 8) in this dataset and replication of our current findings related to death need to be ascertained using larger datasets in order to make meaningful interpretations and conclusions. Lastly, there is some evidence that neocortical 5-HT2AR binding may be associated with estradiol,51 however, we could not control for this in our study.
In conclusion, we present a risk model for the development of the first depressive episode in healthy individuals using serotonergic and personality-based biomarkers. Healthy individuals with the greatest risk of developing depression were those with a serotonergic phenotype of high 5-HT2AR binding with an associated behavioral phenotype characterized by high neuroticisminward levels. Evidence-based interventions such as cognitive behavioral therapy or mindfulness training to reduce neuroticism,52–54 particularly the inward-directed facets may help in mitigating the risk of developing depression in healthy individuals who have the risk-phenotype of high neuroticism and high 5HT2AR availability.