Biological theories of depression and implications for current and new treatments

Abstract

Unipolar major depressive disorder is a common condition that has both emotional (mood and anxiety) and physical aspects (1). The physical manifestations are common features of depression present in up to 80% of depressed patients (2). These physical symptoms occur in nearly all body systems and are often the presenting features in the nonpsychiatric setting. The most common physical symptoms are sleep disruption, fatigue, pain and discomfort, and appetite disturbance. Thus, because depression impacts all body systems (3, 4), it is no surprise that investigations attempting to determine the effects of depression on hormones, neurotransmission, brain imaging, sleep architecture, immune function, etc. have tended to identify differences between depressed patients and normal subjects. However, many of these investigations have not been replicated, or show significant overlap between depressed and nondepressed groups, leading to subsequent investigations of subgroups. Such investigations are further complicated by the temporal adaptation that occurs in many biological systems. For example, the hormonal effects of acute stress are different from those of chronic stress. A few studies have attempted to account for such temporal influences. Genetic studies have shown high heritability for depression, although much stronger for the bipolar than the unipolar form. The heritability of depression has been estimated at 0.33 (5), although slightly greater in individuals exposed to stressful life events or parental maltreatment (6). Most studies have focused on the gene coding for the serotonin transporter, a candidate gene emerging from a focus on serotonin following the introduction of selective serotonin uptake inhibitors (SSRIs). A repeat length polymorphism in the promoter region for the 5-HT transporter gene (SCL6A4) regulates gene expression (7). A series of studies showed that individuals carrying one or two copies of the short (S) allele of the serotonin transporter had high levels of neuroticism, a trait linked to depression vulnerability (8). Other studies found that S-carriers in experimental paradigms showed elevated amygdala activity assessed by functional MRI when they were exposed to threateningstimuli. These findings are consistent with other studies indicating that S-carriers who experienced stressful life events or childhood abuse were prone to depression and suicide (9). This line of research has been important in supporting the concept of genetic-environmental interactions, leading to the development of depression and other psychiatric disorders (7, 10). S-carriers are believed to have impaired transporter function resulting in decreased synaptic reuptake of serotonin - an effect that would at first appear to mimic the effects of SSRI. It has been suggested that the lifelong impairment of the serotonin transporter alters the sensitivity of serotonin receptors, increasing vulnerability to stress, although the exact mechanism has not been established. Interestingly, the presence or absence of the S allele has not been proven to predict response to SSRIs. Many investigators in the field believe that the core action of antidepressants is to normalize the HPA axis by reversing impaired activity of the glucocorticoid receptor. The candidate gene focus emerging from this theory has been on FKBP5 which decreases binding affinity of the glucocorticoid receptor for cortisol. On the other hand, when FKBP4 replaces FKBP5, the receptor complex has high affinity for cortisol. Three polymorphisms in FKBP5 (rs1360780, rs4713916, and rs3800373) have been associated with response to antidepressants (11). Homozygotes for the rare allele had a more rapid response to antidepressants (10 days earlier) than the other two genotypes. Perhaps most importantly, it was not limited to treatment with any specific antidepressant (12). Other studies have examined other genes regulating neurotransmitter synthesis and function, including the serotonin 2A receptor gene, tyrosine hydroxylase gene (dopamine synthesis), tryptophan hydroxylase 1 (serotonin synthesis), and COMT (dopamine metabolism) although the importance of these genes in the development of depression is not established (13). To date, however, no genetic finding has been widely enough replicated to serve as a basis for identifying a depression subgroup and/or predicting response to one or another class of treatment. Given that the concordance of depression even in identical twins is considerably less than 100%, it is likely that environmental events such as psychosocial and physiological stress play a substantial role. With unipolar depression, our focus here, a positive family history of depression predisposes individuals to earlier onset, longer time to recovery, greater severity, and more chronicity (14, 15). Thus, there are significant genetic factors, probably including both susceptibility and resistance genes, that modify the risk of developing depression. For example, downregulation of the expression of substance P, upregulation of voltage gated calcium channels, which moderate BDNF signaling in the NAcc, and the release of neuropeptide Y onto amygdala neurons have all been proposed as resilience mechanisms that reduce vulnerability to stress and depression (16). Another study reports that patients with high genetic risk for affective disorders are more vulnerable for developing depression following stressful events than patients who have a low genetic risk (17). There may be a genetic contribution to the association of early childhood maltreatment with elevated rates of depression, anxiety, and other psychiatric disturbance (18). Although early stress can alter the hypothalamic-pituitary axis, cortisol-releasing hormone, monoamines, γ-aminobutyric acid, and glutamate systems, the subsequent caretaking environment or pharmacologic interventions, such as serotonin reuptake inhibitors, benzodiazepine agonists, adrenal steroid inhibitors, tricyclic antidepressants, and electroconvulsant therapy (ECT), can moderate, prevent, or reverse these effects (19-21). Before leaving the area of genetics of depression, it is important to understand the concept of epigenetics. Another explanation of the low concordance of depression in identical twins has been attributed to epigenetic phenomena. Environmental factors may influence gene function without altering DNA sequence changes. One example of this is increased methylation of the glucocorticoid receptor gene promoter, which has the effect of inhibiting gene expression. Interestingly, this can be reversed by a class of agents called histone deacetylase inhibitors, which have demonstrated antidepressant activity in animal models. Up until the 1990s, most attempts to evaluate the neurobiology of major depression were based directly or indirectly upon research into the mechanisms of known antidepressant medications. The inherent circularity of exploring a mechanism already shown to be related to antidepressant activity has limited the discovery of novel treatments that have activity at sites other than the one of the previously known mechanism. In the last decade, there have been more attempts to understand manifestations of depression that are not based upon known antidepressant mechanisms and to present rationales for novel therapeutic agents. A major theme emerging from recent studies is that structural and functional changes in the hippocampus and/or prefrontal cortex produced by stress in genetically susceptible individuals are part of the pathophysiology of depression (20, 22-26). Functional neuroimaging studies have shown that MDD is associated with hyperactivity of the amygdala and subgenual anterior cingulate gyrus (ACC), whereas the DLPFC and supragenual ACC are hypoactive in depressed individuals (27-29). Altered functional connectivity between these structures has also been reported in MDD (30). Electrical stimulation of the white tracks surrounding Cg25, which is located in the prefrontal cortex, has resulted in successful treatment of depression (31) as has stimulation of the nucleus accumbens (32). For a detailed review of the brain structural and functional abnormalities in depression, the reader is referred to the review of Drevets et al. (33). For the purposes of this chapter, it is important to recognize that brain imaging findings have supported other studies that have provided a rational strategy for investigating novel antidepressant therapies that go beyond the monoamine theories and suggest roles for corticosteroid receptor antagonists, GABA agonists, NMDA agonists, and other agents that differ from existing therapeutic agents. Current research does not support a unified theory of the neurobiological basis of depression. Substantial clinical and experimental evidence suggests that there are a number of mechanisms that may lead to major depressive disorders, and it is likely that as these are elucidated through additional research, they will yield therapeutically relevant subtypes. In the review that follows, we will highlight the leading biological theories of unipolar depression and the implications for medication development for mood disorders. The areas of focus are neuroendocrine disturbances, neural degeneration, neurotrophic factors, and neurotransmitter and neuromodulator alterations (see Table 1). © 2011 Springer Science+Business Media, LLC.