Competence in the field of psychiatry requires, at the very least, accepting the idea that understanding neural architecture plays a critical role in how providers interpret symptoms and, more importantly, how prescribers treat those symptoms. Unlike the field of architecture, however, with all of its applicable mathematical algorithms, psychiatry (despite extensive progress in the field) continues to be in a stage of psychopharmacological trial and error. In patients with depression, there have been many studies showing a decreased volumetric capacity in several regions of the brain. Of note, the hippocampus, pre-frontal cortex, cingulate gyrus, and cerebellum have all been found to be reduced in volume (Bijanki et al., 2014; van Tol, 2010). Additionally, post-mortem microscopic examinations show decreases in total cortical thickness as well as diminished size of individual neurons (Higgins & George, 2013). Several theories attempt to address and explain the pathology behind these neural changes, some more promising than others, while simultaneously providing novel ways in which providers can treat the observable signs and symptoms.
In order to understand and implement possible treatments, however, it is important to question what exactly happens at the cellular level. Researches have attempted to explain, with convincing data, the decreases in hippocampal volume in relation to the overactivity of the HPA axis. More specifically, elevated levels of cortisol have been implicated in the variations seen in hippocampal morphology (Wiedenmayer et al., 2006). One possible explanation seems to be that elevated levels of cortisol and an overactive HPA axis can be directly toxic to the brain, so much so that it can potentially disrupt normal neuronal growth, resulting in neurologic and psychiatric diseases (Schiavone et al., 2013).
While the hippocampus and the ventricles of the brain have historically been implicated in depression, a recent study investigated the implications that the changes in cortical structures would have on overall neural anatomy. Maller et al. (2014) investigated the prevalence of occipital lobe asymmetry within psychiatric populations: those with depression in comparison to healthy controls.. More specifically, the researchers wanted to investigate if the enlarged lateral ventricles seen in those with depression would result in a pattern of curvature, wherein one occipital lobe would wrap around the other, something the researchers termed “occipital bending” (Maller et al., 2014). Maller et al. (2014) suggest that “incomplete neural pruning may lead to the cranial space available for brain growth being restricted, or ventricular enlargement may exacerbate the natural occipital curvature patterns, subsequently causing the brain to become squashed and forced to ‘wrap’ around the other occipital lobe” . As is the case with any new study, the clinical implications remain unclear, but the data do provide a new way of looking at anatomical variation in those with major depressive disorder: the effects are not simply localized or seen on a cellular level, but can be observed at a macroscopic level.
At a microscopic level, the effects, or lack thereof, of oxygen have recently been implicated in the signs and symptoms of depression. More specifically, researchers are beginning to look deeply into the effects that hypoxia can have on the synthesis of serotonin. Katz (1982) was one of the first researchers to propose the possibility that hypoxia and symptoms of depression could be interrelated. He proposed that a decrease in biogenic amine synthesis, in other words the synthesis of serotonin, due to low oxygen levels could result in decreased appetite, libido, motivation, and changes in sleep patterns (Katz, 1982). Similarly, various researchers have implicated levels of oxygen and its relation to the suicide rates seen with COPD, asthma, and smokers (Goodwin, 2011; Goodwin et al., 2012; Li et al., 2012). Interestingly, researchers have also shown that the human body doesn’t simply use oxygen for energy, but that many enzymatic pathways in the brain require oxygen and those same pathways can be affected even by mild hypoxia (Vanderkooi et al., 1991). Based on research into suicide rates among those living in high altitudes (Kim et al., 2011; Haws et al., 2009), Young (2014) proposes the idea that because serotonin synthesis, when measured appropriately, is low in individuals with suicidal ideation as well as in those with previous suicide attempts and that because low serotonin levels are associated with lowered mood, impulsivity, and aggression, that perhaps we should be looking at the association between high altitudes (where oxygen levels are low) and depression/suicide rates. Similarly, a recent study by the University of Utah proposed that “a potential cause for depression at [high] altitude might be found in low levels of serotonin [because] hypoxia impairs an enzyme involved in synthesis of serotonin, likely resulting in lower levels of serotonin that could lead to depression” (Study Links Thin Air, Higher Altitudes to Depression in Female Rats, 2015). More importantly, if the decrease in brain serotonin synthesis associated with hypoxia does lead to depression in subsequent suicide and suicidal attempts, a clinically relevant issue that inevitably surfaces is treatment.
Symptoms of major depression, including suicidal behavior and suicidal attempts, are associated with impaired neuronal plasticity. Treatment options for depression have historically relied on the ability of antidepressants to promote neurogenesis, synaptogenesis, neuronal maturation, as well as increases in brain derived neurotrophic factor (BDNF). “BDNF belongs to the family of neurotrophins that are characterized by their ability to regulate diverse neuronal responses, including the type and number of afferent synapses” (Müller et al., 2000). Some studies have found that patients with major depressive disorder (MDD) who had attempted suicide had lower levels of serum BDNF while other studies have shown that plasma BDNF was significantly lower in suicidal compared to nonsuicidal MDD patients (Deveci et al., 2007; Kim et al., 2007). Several classes of antidepressants, MAOIs, SSRIs, TCAs, and SNRIs modulate the expression of BDNF by upregulating gene expression; the implication being that it may be the upregulation of BDNF that plays a critical role in the actions of antidepressant treatment (Duman & Monteggia, 2006). “BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression” (Lee & Kim, 2010).
A relatively recent and important clinical finding has been the effectiveness of ketamine and its potential for treating depression and suicidal behavior. Historically, ketamine, a noncompetitive NMDA receptor antagonist that blocks glutamate, has been used for the induction and maintenance of general anesthesia. Recently, however, many studies have shown promising results in the treatment of depression and acute suicidality. In some patients with treatment-resistant major depressive disorder, ketamine was shown to rapidly reduce suicidal thinking (Price et al., 2014). After infusion of ketamine, suicidal ideation scores decreased significantly, as measured through various suicide subscales and rating instruments, within 40 minutes of administration; the decreases remained significant through four hours post-infusion (Diaz Granados et al., 2010). The implication here is that ketamine may be an antidepressant treatment option in emergency clinical settings, with special implications in acute situations of suicide.
Despite the promise that ketamine may have as an option for depressed patients at imminent risk of suicide, providers need to remain vigilant of its potential consequences. As with many treatments for depression, practitioners in the field of psychiatry are still not sure how those treatments work exactly or what consequences they may have in the future. Whatever the cause of depression or suicidal ideation may be and while these treatments may be restoring functional cognitive capacity, resolving conflict in micro-architecture, and restoring the appropriate curvature of the brain, the question always remains: what are the unintended consequences of implementing treatment longterm?
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