OR WAIT null SECS
As we begin this brief review of the neurobiology of major depressive disorder (MDD), we face these fundamental questions
As we begin this brief review of the neurobiology of major depressive disorder (MDD), we face these fundamental questions:
• Will the provided information be clinically relevant?
• Can current scientific research provide us with a coherent, comprehensive, and relatively accurate description of the underlying neurobiology of MDD?
Major depression, bipolar disorder (BD),1 and generalized anxiety disorder (GAD)2 are all characterized by a significant genetic contribution to their etiopathogenesis. Heritability estimates for MDD have exceeded 70%3 in some studies, and BD may be even more genetically based, with estimates reaching the 80% to 90% range.4 Interestingly, MDD is more frequently reported in the families of bipolar patients than is BD itself; this finding suggests a partially shared diathesis and likely a “correlated liability,” if not an affiliation with the same continuum.5 Similarly, the genetic and clinical overlap between MDD and GAD is so extensive that some authors have gone so far as to suggest that they are dual manifestations of the same underlying pathophysiology.6
It is becoming increasingly clear that relationships between MDD, GAD, and BD run deeper than symptomatic similarities shared by these conditions. Although not always consistent, studies point to shared genetic underpinnings for these disorders, emphasizing genes involved in the regulation of monoaminergic and peptide transmission, inflammatory responses, diurnal rhythms, and neurotrophic signaling.4,7 All of these are important modulators of anxiety, mood, and stress responses. Furthermore, symptoms of anger, depression, and anxiety are strongly correlated with one another.8 Stress, in turn, is a major precipitant, perpetuant, and aggravating factor of all 3 conditions. However, one must temper any rampant “clumping” enthusiasm with the recognition that-as with similarities-differences between symptom presentations have also frequently been found. Simple links between genes and symptom–based disorders are complicated by a number of factors, including:
• The most common “vulnerability genes” for mood and anxiety disorders account for relatively little variance.
• A gene for 1 product may produce an array of behavioral outcomes, given that its product is typically ensconced in larger circuits that tend to demonstrate final common pathway–type phenomena.
• Symptom presentations in any given person are likely to result from intricate interactions between multiple genes and environmental factors.7,9
Examples of these types of interactions include epistasis (interactions between the genes) and epigenetic modulation (influences of life experience on gene expression).10 Acknowledging these important distinctions takes us a step closer to more effective personalized care.
It is no surprise that brain circuits involved in the regulation of mood, anxiety, and the stress response overlap to a significant degree with components of a “pain matrix” (areas mediating emotional and cognitive aspects of pain processing) as well as with structures involved in sleep regulation.11–13 From an evolutionary perspective, it is apparent that sleep deprivation, negative emotion, and physical pain all play key adaptive roles. All these apparently disparate phenomena provide a clear signal that current conditions are a threat to an organism’s survival.
Before we further elaborate on the roles and interactions between “danger, reward, and executive circuitries and pathways” in mood disorders, it is important to define these constructs more precisely. Reference to “circuitry and pathways” denotes discrete dynamic functional states of neural network rather than specific neuroanatomic entities. For example, depending on the pattern of “inputs,” nucleus accumbens, amygdala, hippocampus, anterior cingulate cortex [ACC], and paralimbic prefrontal cortex can be alternatively considered as components of either “reward/opportunity” or “danger/threat” pathways.14,15 Their cumulative interactions generate corresponding “outputs” or symptoms (much as one set of musical instruments can be used to produce a joyous or a mournful tune). Given the constant flow of internal and external information, there is a continuous flux of functional states, perpetuating the neural network’s adaptive and homeostatic roles.
In keeping with their shared role in alerting an organism to danger in the external or internal environment (ie, infection/tissue damage), peripheral and central “pathways” of anxiety, depression, and pain overlap significantly.16–18 They are all woven into the mammalian stress and immune response systems. While there are important differences in the sensory processing of anxiety, stress, and pain signals at the cortical and subcortical levels, (eg, dorsal column, thalamus, and primary and secondary somatosensory cortices [SI, and SII]), striking similarities are apparent in the involvement of limbic areas and paralimbic prefrontal cortex, amygdala, hippocampus, insula, ACC, ventromedial prefrontal cortex, as well as more “cognitive” and integrative brain areas, such as rostral ACC, dorsal ACC, dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex.12 Imaging studies of persons experiencing depression, anxiety, spontaneous pain, social isolation, or sleep deprivation, bear more than little resemblance.
It is important to recognize that “stress circuitry,” “reward circuitry” (including nucleus accumbens, amygdala, hippocampus, ventral tegmental area, and orbital prefrontal cortex), and “executive circuitry” are not independent and mutually exclusive entities; they are better conceived of as intersecting and overlapping components of a common 3–dimensional neural network.17,19,20 Disruption in their dynamic balance may give rise to excessive negative emotions, combined with cognitive impairment and withdrawal of hedonic tone. Moreover, anxiety, pain, and depressed mood appear to have a shared capacity to engage autonomic, neuroendocrine, and neuroimmune components of the stress response.21 MDD, GAD,22,23 BD, chronic insomnia,24 and chronic pain25 are all associated with altered sympathetic/parasympathetic balance; neuroendocrine disturbance, manifested by insufficient HPA regulation; and altered immune function, characterized by inhibition of acquired immunity and enhancement of innate inflammatory signaling.1,12,26 In turn, these peripheral responses signal back to neural structures to further drive CNS danger pathway activation; this leads to a maladaptive feed–forward circuit that increasingly appears to be implicated in the production and maintenance of symptoms.
Within the CNS, microglia seem to be the principal recipients of bodily distress/pain signals. Microglia are increasingly implicated in the development of mood (depression and mania)1 and pain symptoms and disorders.27 Indeed, increasing evidence suggests that different patterns of interaction between microglia, astroglia, and neurons may engender diverse symptomatic manifestations (eg, pain, depression). Peripheral distress signals are “amplified” via reverberating communication between microglia, astrocytes, oligodendroglia, and neurons.12,28 The result is suppression of neurotrophic trafficking and an increase in the production and release of proinflammatory cytokines and reactive oxygen and nitrogen species.26 The combined effect of this inflammatory and oxidative “surge” may damage astrocytes and oligodendroglia, thus contributing to demyelination and consequent disruption of CNS regulatory circuits required to restrain peripheral stress/inflammatory responses.12 Thus, the vicious circle closes.
Excessive excitatory glutamatergic transmission and compromised GABA–mediated inhibition (with ensuing excitotoxicity) appear to be common features of anxiety,22 mood,29 sleep,30 and pain disorders.31 Dysregulation in monoamine, substance P, galanin, and opiate–signaling also characterizes GAD, pain syndromes, and MDD. On the other hand, anxiety and mood and pain disorders are characterized by different patterns in the production of neurotrophic factors: depression and mania are characterized by reduced serum levels of brain–derived neurotrophic factor (BDNF), fibromyalgia is associated with increased BDNF,12 while fear and anxiety appear to be accompanied by elevated levels of nerve growth factor.32 Nonetheless, anxiety, pain, stress, and depression have a similar, possibly even synergistic, effect on neurotrophic signaling in the hippocampus, given that all of them are associated with reduced BDNF synthesis in this critical limbic region.33,34 This finding is of particular interest, given that the hippocampus represents a veritable “intersection” of pathways involved in emotional regulation, reward, memory, and coordination of neuroendocrine response.33
MDD, BD, and chronic pain are all associated with neuroplastic changes in the CNS. In pathological pain states, facilitation of pain signaling, presumably on the basis of neuroplastic changes in pain pathways, is often designated as “central sensitization.”35,36 Similarly, the recurrent and progressive nature of MDD and BD is often attributed to “kindling,” which-like central sensitization-reflects neuroplastic changes.37 Given this, MDD, BD,38 and chronic pain39 may all be characterized by adaptive processes gone awry as a result of complex interactions between genetic vulnerabilities and environmental factors. In this scenario, persistent aberrant processing of emotional, painful, and stressful signals eventually becomes “hard–wired,” presumably from ensuing neuroplastic alterations.
In some ways, chronic pain and disorders of sleep, mood, and anxiety share dysfunctional psychosomatic and somatopsychiatric communication patterns-indeed they can be seen as behavioral read–outs for these dysfunctional communication patterns.12 Their synergistic and simultaneous occurrence may give rise to a “symphony” of misery. If we assume that a shared biological underpinning gives origin to the clinical symptoms of MDD, BD, GAD, and chronic pain, it is clear that a full understanding of this “synergy” has critical diagnostic and treatment implications.
Despite these powerful commonalities, however, it is important to realize that diverse underlying biological processes may generate similar symptoms and vice versa; that is, similar pathophysiology may drive diverse clinical manifestations. A synthesis of these dialectical perspectives suggests that understanding shared etiopathogenesis may provide an opportunity for the development of new preventive and treatment strategies that transcend diagnostic boundaries. A full appreciation of each person’s symptoms-as the unique result of interactions between genetic vulnerability, adversity, positive life experiences, individual coping skills, and overall health-offers the clearest way forward in our field’s attempt to develop personalized treatment approaches.
1. Maletic V. Neurobiological aspects of lateâlife mood disorders. In: Ellison JM, Kyomen HA, Verma S, eds. Mood Disorders in Later Life.2nd ed. New York, London: Informa Healthcare; 2009:133â149.
2. Smoller JW, GardnerâSchuster E, Misiaszek M. Genetics of anxiety: would the genome recognize the DSM? Depress Anxiety.2008;25:368â377.
3. Thapar A, McGuffin P. A twin study of depressive symptoms in childhood. Br J Psychiatry.1994;165: 259â265.
4. Craddock N, Forty L. Genetics of affective (mood) disorders. Eur J Hum Genet.2006;14:660â668.
5. McGuffin P, Rijsdijk F, Andrew M, et al. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry. 2003;60:497â502.
6. Kendler KS, Gardner CO, Gatz M, Pedersen NL. The sources of coâmorbidity between major depression and generalized anxiety disorder in a Swedish national twin sample. Psychol Med. 2007;37:453â462.
7. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004;29:1765â1781.
8. Watson D, O’Hara MW, Stuart S. Hierarchical structures of affect and psychopathology and their implications for the classification of emotional disorders. Depress Anxiety. 2008;25:282â288.
9. Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry. 2008;13:131â146.
10. Mill J, Petronis A. Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry. 2007;12:799â814.
11. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161:2126â2128.
12. Maletic V, Raison CL. Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci. 2009;14:5291â5338.
13. Maletic V, Robinson M, Oakes T, et al. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract. 2007;61:2030â2040.
14. Frewen PA, Dozois DJ, Joanisse MF, Neufeld RW. Selective attention to threat versus reward: metaâanalysis and neuralânetwork modeling of the dotâprobe task. Clin Psychol Rev. 2008;28:307â337.
15. Pessoa L. On the relationship between emotion and cognition. Nat Rev Neurosci. 2008;9:148â158.
16. Engel K, Bandelow B, Gruber O, Wedekind D. Neuroimaging in anxiety disorders. J Neural Transm. 2009;116:703â716.
17. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213:93â118.
18. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron. 2007;55:377â391.
19. Heinz A, Grace AA, Beck A. The intricacies of dopamine neuron modulation. Biol Psychiatry. 2009;65: 101â102.
20. Goto Y, Grace AA. Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goalâdirected behavior. Nat Neurosci. 2005;8:805â812.
21. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24â31.
22. Millan MJ. The neurobiology and control of anxious states. Prog Neurobiol. 2003;70:83â244.
23. Grillon C. Models and mechanisms of anxiety: evidence from startle studies. Psychopharmacology (Berl). 2008;199:421â437.
24. Vgontzas AN, Liao D, Bixler EO, et al. Insomnia with objective short sleep duration is associated with a high risk for hypertension. Sleep. 2009;32:491â497.
25. Chapman CR, Tuckett RP, Song CW. Pain and stress in a systems perspective: reciprocal neural, endocrine, and immune interactions. J Pain. 2008;9: 122â145.
26. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732â741.
27. Ren K, Dubner R. Neuronâglia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol. 2008;21:570â579.
28. McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr. 2008;13:501â510.
29. Sanacora G, Rothman DL, Mason G, Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci. 2003;1003:292â308.
30. Winkelman JW, Buxton OM, Jensen JE, et al. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1HâMRS). Sleep. 2008;31:1499â1506.
31. Zhuo M. Cortical excitation and chronic pain. Trends Neurosci. 2008;31:199â207.
32. Alleva E, Francia N. Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neurosci Biobehav Rev. 2009;33:525â536.
33. Duman RS, Monteggia LM. A neurotrophic model for stressârelated mood disorders. Biol Psychiatry. 2006;59:1116â1127.
34. Duric V, McCarson KE. Persistent pain produces stressâlike alterations in hippocampal neurogenesis and gene expression. J Pain. 2006;7:544â555.
35. Yunus MB. Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain. Best Pract Res Clin Rheumatol. 2007;21:481â497.
36. Miller L. Neurosensitization: a model for persistent disability in chronic pain, depression, and posttraumatic stress disorder following injury. NeuroRehabilitation. 2000;14:25â32.
37. Post RM. Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev. 2007;31:858â873.
38. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry. 2000;157:1243â1251.
39. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet.1999;353:1959â1964.