We propose that reduced BDNF production, arising from several potential causes, may be one of the neurobiological contributors to the onset or maintenance of both illnesses within the same person.
Although the genetic association studies reviewed here do not suggest the met variant of the BDNF val66met SNP is associated with BD or PTSD, these studies did not control for the effects of early trauma. Early trauma is commonly reported by psychiatric patients,15
and this early stress can lead to epigenetic changes with large effects in expression of gene products important to psychiatric illnesses.156
A G×E interaction may exist for BD, whereby people with a family history of BD and who also carry the met variant become more likely to develop BD after early life trauma. The met allele is associated with the development of major depressive disorder among women with two or more childhood stressors, suggesting a similar G×E interaction may occur in other mood disorders as well.157
None of the reviewed studies specifically evaluated BD-PTSD samples, leaving an association between BD-PTSD and the met variant undetermined. The risk for comorbid BD-PTSD may be mediated by impairments in new learning arising from the met-allele carrier status, as suggested by the cognitive, fear extinction, neuroanatomical and neurochemical associations reviewed here. Comorbidity risk may be further increased by other genetic and environmental factors that alter functional BDNF levels, such as epigenetic changes, treatment effects and ongoing stress.
depicts a model proposing a putative link between BDNF and developing comorbid BD-PTSD. BD patients often have experienced significant amounts of early childhood trauma,9
which might act both as a trigger for unmasking BD mood episodes and as a priming experience for later-onset PTSD arising in response to a trauma experienced in adulthood. Building on the animal studies discussed above, a BD patient with early life stress experiencing a trauma in adulthood could have lower BDNF function as a result of: (1) carrying the met-allele variant; (2) early life stress-induced epigenetic modifications of the BDNF
gene; and (3) stress from the adulthood trauma itself. This reduction in BDNF activity may then impair the brain’s ability to engage the amygdala-prefrontal-hippocampal circuits required for fear extinction34
and to modulate other aberrant neural circuits driving BD mood episodes. Such impairments would then set the stage for a patient to develop both PTSD and a greater recurrence of BD mood episodes.
Figure 2 A putative model linking trauma and brainderived neurotrophic factor (BDNF) function to the development of bipolar disorder and post-traumatic stress disorder. Patients may carry genetic risk factors, including BDNF val66met single-nucleotide polymorphism (more ...)
Interactions between early childhood trauma and met-allele carrier status have been identified and are associated with poorer memory among bipolar patients, 142
and with more depression, anxiety and neuroticism among healthy volunteers.155
High neuroticism may contribute to future mood episode relapses in the face of stress,158
and the combination of high neuroticism and impaired episodic memory may contribute to recalcitrant, memory-based, PTSD symptoms such as intrusive recollections and trauma-related amnesia.159,160
Low hippocampal BDNF secretion may be the consequence of similar met-allele–early childhood trauma interactions. Lower BDNF levels could lead to reduced synaptic plasticity in the hippocampus and mPFC, resulting in poorer episodic and extinction memory,66,87
and could lead to impaired modulation of the serotonin system, potentially contributing to higher levels of neuroticism.161
If the animal models implicating the role of BDNF and the met allele in mediating fear extinction translate to humans, this would further support reduced BDNF function as a link between PTSD and BD. The brain regions active in fear inhibition (ACC, anterior hippocampus and mPFC)34,35
are either hypoactive or reduced volumetrically in patients with PTSD44,162,163
and are reduced volumetrically in BD patients with the met allele.143,144
Fear inhibition in BD patients has not been extensively studied; however, pediatric and adult BD patients have a reversal learning deficit on probabilistic response reversal tasks.164,165
Both reversal learning and fear extinction require learning to associate new emotional valences with reward-contingent or previously threatening objects. Impairment in both of these functions may derive from low BDNF states that hinder synaptic formation and new learning.
Alterations in HPA axis activity associated with mood disorders may be another source of reduced BDNF for BD-PTSD patients. BD patients demonstrate hyper-cortisol states during the dexamethasone suppression test and the dexamethasone/corticotropin- releasing hormone test, which persist during mood-episode remission.166,167
These data suggest that BD patients have an ongoing risk for reduced BDNF function, even when euthymic.
In contrast to patients with BD, PTSD patients demonstrate hypo-cortisol states as assessed by the dexamethasone suppression test and dexamethasone/corticotropin-releasing hormone test.168
For some PTSD patients, this may be the result of early life trauma-induced, epigenetic modification of the glucocorticoid receptor, making it hyper-responsive to cortisol feedback.168
Although cortisol levels impact BDNF production, the relationship between HPA axis suppressor status and BDNF function is unclear. Whether such non-suppressors are more or less sensitive than suppressors or super-suppressors to developing PTSD in the wake of a traumatic event, and whether these effects are mediated by BDNF function, is worthy of further study. HPA axis activity in comorbid BD-PTSD patients has not been characterized. Hence, it is unclear how the effect of early life trauma and PTSD, both common among BD patients, affects the long-term functioning of their HPA axis.
The proposed model may also apply to other anxiety disorders that occur comorbidly with BD, including panic disorder, specific phobias or social anxiety disorder.11
Similar to PTSD, patients with these other anxiety disorders often experience early life trauma169
and may be unable to extinguish fear memories.170
The role of BDNF in these illnesses has yet to be determined. Although it is outside the scope of this review focused on BD, this model may equally apply to PTSD comorbidity with major depressive disorder, as there is substantial data demonstrating BDNF deficits63
and the impact of early childhood trauma171
among these patients.
Antidepressants increase BDNF levels in patients with major depression,63
suggesting that according to our model, antidepressants should be efficacious for those with PTSD. However, influential reviews have concluded that antidepressants lack convincing evidence of efficacy for PTSD,172
although other reviews challenge that conclusion.173
The weakness of antidepressant efficacy for PTSD is not in conflict with our model, because the evaluated trials studied only antidepressant monotherapy, specifically excluding concomitant exposure therapy treatment for trial participants. For the BDNF elevating effects of antidepressants to improve core PTSD symptoms, we propose the patient must be engaging in a form of exposure to permit the new synaptic formations required to extinguish fear responding.174
This hypothesis could be tested in clinical trials in which PTSD patients receive standard exposure-based psychotherapy along with concomitant, randomized, blinded treatment with either an antidepressant or placebo.
Limitations to this model are that the associations between the met variant of the val66met SNP and the findings reported above may have been the result of linkage disequilibrium between val66met and another gene loci, such as the BDNF-LCPR. In addition, low BDNF levels may be a state marker of illness and not necessarily a pathophysiological agent in either BD or PTSD. If this were the case, then perhaps the increased PTSD comorbidity rate among BD patients might be due to more trauma experienced as a result of risky-impulsive manic behaviors rather than underlying BDNF dysfunction occurring during manic episodes. Studies could be designed to control for the effects of intrinsic BDNF activity and mood state at the time of trauma. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients.
If the val66met SNP, patterns of BDNF transcription silencing or lower BDNF levels are more often associated with the PTSD-comorbid subgroup of BD patients, then treatments aimed at combining exposure therapy with medications that could enhance fear extinction would be worthy of further study. These medications could include: (1) replacement BDNF or a BDNF receptor agonist with effects as described above;88,175
(2) D-cycloserine, a partial NMDA receptor agonist that facilitates extinction in patients with phobias,176
social anxiety disorder,177,178
and obsessive-compulsive disorder, 180,181
and was found to rescue the extinction deficit in mice with the human BDNF met allele;83
or (3) histone deacetylase inhibitors, like valproate, which increase histone acetylation resulting in increased BDNF mRNA expression and enhanced fear extinction in mice.89
These approaches could potentially improve the patient’s impaired extinction learning capacity while avoiding the potentially destabilizing effect of antidepressants on BD illness.32
In addition, if impaired fear extinction and the emotional dysregulation characteristic of BD were subserved by the same neural networks, then medication treatments aimed at enhancing fear extinction could also provide mood stabilization, as already demonstrated in BD prophylactic studies using valproate.182,183