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MRI scans of patients with depression have reported a number of differences in brain structure compared to those without the illness. Although there is some inconsistency in the results, meta-analyses have shown there is strong evidence for smaller hippocampal[1] volumes and increased numbers of hyperintensive lesions.[2] Hyperintensities have been associated with patients with a late age of onset, and have led to the development of the theory of vascular depression.[3]

There may be a link between depression and neurogenesis of the hippocampus,[4] a center for both mood and memory. Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood. Drugs may increase serotonin levels in the brain, stimulating neurogenesis and thus increasing the total mass of the hippocampus. This increase may help to restore mood and memory.[5][6] Similar relationships have been observed between depression and an area of the anterior cingulate cortex implicated in the modulation of emotional behavior.[7] One of the neurotrophins responsible for neurogenesis is the brain-derived neurotrophic factor (BDNF). The level of BDNF in the blood plasma of depressed subjects is drastically reduced (more than threefold) as compared to the norm. Antidepressant treatment increases the blood level of BDNF. Although decreased plasma BDNF levels have been found in many other disorders, there is some evidence that BDNF is involved in the cause of depression and the mechanism of action of antidepressants.[8]

It has not been possible to pin down the cause of depression to a single specific flaw in a single part of the brain. Instead it seems likely that depression usually involves a disturbed pattern of interaction between multiple parts of the brain. Here are the areas that are most strongly affected:

Raphe nuclei

The raphe nuclei are a group of small nuclei in the upper brain stem, located directly at the midline of the brain. They are the sole source of serotonin in the brain. Despite their small size, they project very widely, and are involved in a very diverse set of functions. Most antidepressants are agonists for serotonin. Serotonin system dysfunction cannot be the sole cause of depression, though: antidepressants usually bring serotonin levels up to normal very quickly, but it often takes at least two to four weeks before mood improves significantly.

The functions of serotonin are difficult to describe in a simple way. In some circumstances serotonin seems to act as a signal of "repletion" or "satisfaction". Thus, satiation after eating, and orgasm following sex, both produce release of serotonin. In animals that have hierarchical social structures, dominant individuals show higher levels of serotonin metabolites than lower-status individuals. In the brain, serotonin exerts a suppressive effect on both the reward and punishment systems, and therefore is likely to reduce the intensity of motivation whether aversive or appetitive. (One of the most common but least-discussed side effects of antidepressants is to reduce sex drive.)

Suprachiasmatic nucleus (SCN)

The Suprachiasmatic nucleus (SCN) is the control center for the body's "biological clock". It contains neurons whose activity waxes and wanes throughout the day. The output from the SCN controls the sleep/wake cycle as well as a number of other biological rhythms, such as fluctuations in body temperature. Disturbances of these cycles are a consistent symptom of depression, especially of the melancholic type. The "classic" pattern is for depressed people to have great difficulty falling asleep at night, and then to wake bolt upright at around 3 AM. The waking is usually preceded by a rise in body temperature, which in non-depressed people does not usually occur until several hours later. It is a common observation that antidepressants produce a return to normal sleep patterns before they produce an improvement in mood: if good sleep does not return, it is a strong sign that the treatment is not going to be effective. Conversely, disruptions to sleep are often the first indication of impending relapse.

There is a powerful interaction between the Raphe nuclei and the SCN. On one hand, the Raphe nuclei send a strong serotonergic projection to the SCN. In animal studies, this input has been shown to modulate the ability of light to reset the timing of the biological clock: the more serotonin, the stronger the effects of light. On the other hand, the biological clock exerts a strong influence on the Raphe nuclei: serotonin levels drop during sleep, and fall almost to nothing during REM (dreaming) sleep. It is worth noting that one of the characteristics of sleep in depressed people is that REM tends to appear very soon after sleep onset, whereas in non-depressed people it does not usually dominate sleep until the last hours, in the early morning. Antidepressants are powerful suppressors of REM.

Hypothalamic-Pituitary-Adrenal (HPA) axis

The Hypothalamic-pituitary-adrenal axis is a chain of structures that are activated during the body's response to stressors of various sorts. It often shows increased activation in depressed people, and drugs that reduce its activate are sometimes effective in reducing symptoms. The HPA influences many parts of the brain, including the Raphe nuclei.

Ventral tegmental area (VTA)

The Ventral tegmentum or Ventral tegmental area is a small area in the basal forebrain which is a critical part of the brain's reward system. It sends projections to the nucleus accumbens that use the neurotransmitter dopamine. Addictive drugs universally increase the effects of dopamine in this system, whereas drugs that oppose dopamine produce anhedonia of the sort seen in depressed people. Dopamine-enhancers such as cocaine often relieve the lack-of-pleasure in dopamine, but the effects only last as long as a drug is present in the body: that is, they temporarily alleviate one of the main symptoms, but do not help to cure the disease.

Anterior cingulate cortex (ACC)

The anterior cingulate cortex is activated by negative experiences of many types, and consistently shows higher levels of activity in depressed people than in non-depressed people. The functions of the ACC are controversial, but one proposal is that it mediates the conscious experience of suffering. Several decades ago, trials were made of ablating parts of the ACC in an attempt to relieve intolerable pain in patients who were terminally ill. These patients reported that after the surgery, they could still perceive the physical sensations of pain, but they no longer found them distressing. (The effects of heroin and morphine are sometimes described in the same way.) Very recently, clinical experiments were made in using deep brain stimulation to temporarily inactivate the ACC in severely depressed patients. This was not effective in all cases, but in some patients very striking results were achieved, with a perceptible lifting of mood immediately apparent to the patient as soon as the stimulus was applied.

Default mode network (BMN)

Studies have reported a hyper-connectivity of task negative (TN) brain regions in depression during rest.[9][10]

Monoamine theories

File:Synapse Illustration2 tweaked.svg

Illustration of the major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells.

Most antidepressants increase synaptic levels of the monoamine neurotransmitter serotonin. They may also enhance the levels of two other neurotransmitters, norepinephrine and dopamine. This observation gave rise to the monoamine theory of depression. In its contemporary formulation, the monoamine theory postulates that the deficit of certain neurotransmitters is responsible for the corresponding features of depression: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." The proponents of this theory recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. The anxious and irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy and enjoyment of life—with norepinephrine and dopamine enhancing drugs.[11]

Consistent with the monoamine theory, a longitudinal study uncovered a moderating effect of the serotonin transporter (5-HTT) gene on stressful life events in predicting depression. Specifically, depression seems especially likely to follow stressful life events, but even more so for people with one or two short alleles of the 5-HTT gene.[12] Serotonin may help to regulate other neurotransmitter systems, and decreased serotonin activity may "permit" these systems to act in unusual and erratic ways. Facets of depression may be emergent properties of this dysregulation.[13]

In the past two decades, research has uncovered multiple limitations of the monoamine theory, and its inadequacy has been criticized within the psychiatric community.[14] Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people nor does it worsen the symptoms in depressed patients.[15][16] Already limited, the monoamine theory has been further oversimplified when presented to the general public.[17]

An offshoot of the monoamine theory suggests that monoamine oxidase A (MAO-A), an enzyme which metabolizes monoamines, may be overly active in depressed people. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people.[18] In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression.[19][20] Contrary to the assumptions of the monoamine theory, lowered but not heightened activity of MAO-A was associated with the depressive symptoms in youth. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders.[21] In addition, some evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression.[22]

Brain imaging and depression

In the 1930s, it was realized that stimulating the surgically exposed brain in specific areas could bring about reported mood and emotional changes. At the same time, surgical destruction of these regions could alter negative mood. The results indicated that the orbitofrontal cortex and the frontal, temporal, and basal ganglia played important roles in mood regulation.

The development of additonal techniques have allowed for this picture to be further developed

From these studies a number of anotomical structures have been linked to depression:

See also

References & Bibliography

  1. Videbech, P and Ravnkilde (2004). Hippocampal volume and depression: A meta-analysis of MRI studies. American Journal of Psychiatry 161: 1957–66..
  2. Videbech, P (1997). MRI findings in patients with affective disorder: a meta-analysis. Acta Psychiatrica Scandinavica 96 (3): 157–68.
  3. Herrmann LL, Le Masurier M, Ebmeier KP (2008). White matter hyperintensities in late life depression: a systematic review. Journal of Neurology, Neurosurgery, and Psychiatry 79: 619–24.
  4. Mayberg H (July 6, 2007). Brain pathway may underlie depression. Scientific American 17 (4): 26–31.
  5. Sheline YI, Gado MH, Kraemer HC (2003). Untreated depression and hippocampal volume loss. American Journal of Psychiatry 160: 1516–18.
  6. Duman RS, Heninger GR, Nestler EJ (1997). A molecular and cellular theory of depression. Archives of General Psychiatry 54 (7): 597–606.
  7. Drevets WC, Savitz J, Trimble M (August 2008). The subgenual anterior cingulate cortex in mood disorders. CNS Spectrums 13 (8): 663–81.
  8. Sen S, Duman R, Sanacora G (September 2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications. Biological Psychiatry 64 (6): 527–32.
  9. Zhou, Yuan, Yu, Chunshui; Zheng, Hua; Liu, Yong; Song, Ming; Qin, Wen; Li, Kuncheng; Jiang, Tianzi (2010). Increased neural resources recruitment in the intrinsic organization in major depression. Journal of Affective Disorders 121 (3): 220–230.
  10. Berman, M. G., Peltier, S.; Nee, D. E.; Kross, E.; Deldin, P. J.; Jonides, J. (19 September 2010). Depression, rumination and the default network. Social Cognitive and Affective Neuroscience 6 (5): 548–555.
  11. Nutt DJ (2008). Relationship of neurotransmitters to the symptoms of major depressive disorder. Journal of Clinical Psychiatry 69 Suppl E1: 4–7.
  12. Caspi A, et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301: 386-89.
  13. Mandell AJ, Knapp S (1979). Asymmetry and mood, emergent properties of serotonin regulation: A proposed mechanism of action of lithium. Archives of General Psychiatry 36 (8): 909–16.
  14. Hirschfeld RM (2000). History and evolution of the monoamine hypothesis of depression. Journal of Clinical Psychiatry 61 Suppl 6: 4–6.
  15. Delgado PL, Moreno FA (2000). Role of norepinephrine in depression. J Clin Psychiatry 61 Suppl 1: 5–12.
  16. Delgado PL (2000). Depression: the case for a monoamine deficiency. Journal of Clinical Psychiatry 61 Suppl 6: 7–11.
  17. Lacasse J, Leo J (2005). Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS Med 2 (12): e392. Free full text, open-access source
  18. Meyer JH, Ginovart N, Boovariwala A, et al. (November 2006). Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression. Archives of General Psychiatry 63 (11): 1209–16.
  19. Huang SY, Lin MT, Lin WW; Huang CC; Shy MJ; Lu RB (2007-12-19). Association of monoamine oxidase A (MAOA) polymorphisms and clinical subgroups of major depressive disorders in the Han Chinese population. World Journal of Biological Psychiatry.
  20. Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW (September 2005). Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response. Neuropsychopharmacology 30 (9): 1719–23.
  21. Cicchetti D, Rogosch FA, Sturge-Apple ML (2007). Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds. Dev. Psychopathol. 19 (4): 1161–80.
  22. Castrén, E (2005). Is mood chemistry?. Nature Reviews Neuroscience 6 (3): 241–46.

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