The Neurobiology of Depression

Juan F. Lopez, M.D.

Dr. Lopez is a faculty member of the Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor.

Being clinically depressed is very different from just feeling down or blue.

Depressive episodes (there are several kinds) can last months, sometimes years, and can interfere with your social and work functioning. Unfortunately, depressive episodes also tend to recur and, if left untreated, will become more frequent and/or more severe as the disease progresses.41

According to the official professional reference guide, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), to be considered depressed, you have at least five of the following symptoms and they represent a change in your life:
1.Depressed mood most of the day, nearly every day
2.Markedly diminished interest or pleasure in all, or almost all, activities
3.Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day
4.Insomnia or sleeping too much (hypersomnia) nearly every day
5.Psychomotor agitation or retardation nearly every day
6.Fatigue or loss of energy nearly every day
7.Feelings of worthlessness or excessive or inappropriate guilt
8.Diminished ability to think or concentrate, or indecisiveness
9.Recurrent thoughts of death, recurrent suicidal ideation, or a suicide attempt or a specific plan for committing suicide
All Too Common
Depression is very common. Seventeen per cent of people will experience depression sometime during their life. To add insult to injury, if you are acutely or chronically ill, you are even more likely to suffer from it, with rates ranging from 30% to 50%, depending on your specific medical condition.

Though the picture sounds grim, (and will seem especially so if you are depressed, for thinking nothing will get better is often a symptom of depression) we are starting to learn more about the biochemical and other factors that may be involved. Hopefully, with this knowledge, will, eventually, come effective treatment strategies.

Do We Know What Causes Depression?
The actual basis of depression is unknown but it is widely accepted that it is influenced by genetic, environmental and neurobiological factors. Depression does run in families26 but whether this is genetic or simply reflects the kind of parenting a depressed person is able to offer their child is difficult to determine. In addition there are many environmental factors, such as loss of a loved one, unemployment, an unexpected medical illness, that appear to increase the likelihood of depression.

Many brain chemicals ("neurochemicals") and hormones have been linked to the development of depression (e.g., norepinephrine, dopamine, thyroid hormones). However, research studies have implicated disturbances in the serotonin (5-HT) system and the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis as two of the neurobiological alterations most consistently associated with mood-altering illness.18,36,24,39 Recent work, in fact, has strongly suggested that the interaction between these two biochemical systems may play a significant role.

Adrenal glucocorticoid (the "stress" hormone), which helps regulate your metabolism and is produced by the adrenal gland, a tiny gland that sits on top of the kidneys, interacts with serotonin 5-HT receptors in the brain during conditions of chronic stress or severe allostatic load." This is not surprising, as we have known from studies on animals that the two systems are linked in a variety of ways.33,7,30 One of these linked regions, the limbic HPA axis (LHPA), regulates arousal, sleep, appetite and the capacity to experience and enjoy pleasure, as well as the control of mood. As the list of symptoms at the beginning of this article indicates, the functioning of each of these areas can be disturbed in a depressive episode.

LHPA Axis: The Link Between Stress and Depression
Imagine that you're crossing the street and a car suddenly swerves toward you. Instinctively, you jump out of harm's way. Your rapid and automatic response is triggered by, among other things, the LHPA axis. Its response to stress is critical for adaptation and survival. The perception of stress provokes, ultimately, the release of the glucocorticoid "stress" hormones (cortisol in humans, corticosterone in rats) from the adrenal gland and this is regulated by the LHPA axis.11 A very delicate and effective feedback mechanism is set in motion through nerve connections that link the hippocampus, an important area of the brain that's also affected by these biochemicals, to the LHPA. This feedback allows receptors in the hippocampus to control both your hormonal and higher thinking response to stress.34 In other words, thanks to the hippocampal receptors, you are better able to decide how you should handle the stress -- should you let it go or stand your ground? Should you leave your stressful job and confront your boss, or continue working without saying anything?

Pioneer work by one of our contributors, Dr. Bruce McEwen from the Rockefeller University, demonstrated two types of receptors in the hippocampus. We believe these two receptors -- "MR" (also known as Mineralocorticoid Receptors) and "GR" (also known as Glucocorticoid Receptors) -- work together to control metabolism, blood cortisol levels and the LHPA axis.15 Investigators have found, for example, that the MR and GR receptors are able to decrease your stress hormone levels and help defend your body against the effects of stress.14

Hyperactivity of the LHPA axis is a well-documented event in depression. Not only is too much of the stress hormone, cortisol, produced6,22,27,17,23 but we have also found, in a group of suicide victims with a history of depression, lowered levels of MR and GR other in the hippocampus29 and the prefrontal cortex, an area of the brain which is associated with higher thinking and executive function. We don't know whether these changes represent a genetic or developmental vulnerability "marker" for suicide or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress.20,21

There is little doubt among scientists that glucocorticoids, the final products of the LHPA axis, have profound effects on mood and behavior.32 For example, those afflicted with Cushing's syndrome, a disease where excess cortisol (the "stress" hormone) is produced, have a high incidence of depression. Most interestingly, their depression disappears when cortisol levels return to normal with treatment.23,38

The precise mechanism by which glucocorticoids exert this influence on mood is not well understood. We do know that in depression the LHPA axis is very often hyperactive. We suspect that the mechanism likely involves interactions with brain neurotransmitters, since we know that the brain's central control of your mood is intimately associated with the actions of serotonin, norepinephrine and dopamine, the neurotransmitters affected by the most common antidepressant medications.

Serotonin Receptors and Depression
The serotonin 5-HT system has been widely investigated as a key element in the development of depression36 and of suicide,32 and the means by which many antidepressants provide relief.1 Although the 5-HT system has many components, there are two serotonin molecules closely associated with the neurobiology of mood: the serotonin 1a receptor (5-HT1a) and the serotonin 2a receptor (5-HT2a).

Most newer (as well as older) antidepressants inhibit the re-uptake of serotonin from the communicating space between nerves (synapse), hence their name: selective serotonin reuptake inhibitors (SSRIs).28,40 Animal studies have demonstrated that chronic antidepressant administration affects the function and number of these two receptors. Other studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a receptors in the hippocampus, while at the same time "down-regulating" or "desensitizing" 5-HT2a receptors elsewhere in the brain.3 We have found that suicide victims, with a history of depression, have fewer 5-HT1a receptors in the hippocampus.29

These research findings have led several scientists to theorize that a disturbed balance of these receptors may be contributing to the development of depression2 and that restoring this balance is necessary for antidepressant action.4

Stress and Serotonin
Stress and depression have been linked in a variety of ways. Both physical and psychological stressors, such as physical illness or financial problems, have been shown to have a cause and effect relation to the onset of depressive episodes.41

We are not saying that stress "causes" depression in people. Rather, stress is very likely interacting with an inborn genetic predisposition, such that, in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e., vulnerability + stress = depression). Studies in twins have shown a clear interaction between genetic predisposition and a recent stressful life event in the precipitation of a depressive episode.26 There are even cases in which the genetic predisposition is so high that an episode of depression can occur in the absence of any apparent precipitating factors.

The study of chronic unpredictable stress in animals has given us important clues about depression. In our research, we expose rats to different, mild to moderate stressors every day, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity and increases in peripheral glucocorticoids, very similar to those found in depression.9 Other changes in brain chemicals occur which we have also found in suicide victims with a history of depression.32 This suggests that a chronic or severe stress (e.g., loss of a spouse, serious illness or injury, history of abuse) may cause similar neurochemical changes in vulnerable people, therefore triggering episodes of depression.

How Different Antidepressant Medications Work...and Don't Work
The LHPA overactivity observed with chronic unpredictable stress can be prevented by the daily chronic administration of either imipramine or desipramine, two tricyclic antidepressants.29 Both desipramine and imipramine (key ingredients in Norpramine® and Tofranil®) also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in brain cortex. On the other hand, zimelidine (Zelmid®, an antidepressant formerly used in Europe) and fluoxetine (Prozac®), two specific serotonin reuptake inhibitors are unable to prevent the stress-induced elevation in corticosterone levels and correct LHPA overactivity. Although it is not clear if this also occurs in humans, these research findings may explain why some patients with severe depression exhibit "treatment resistance."

There is, in fact, some clinical evidence that the various depressive disorders might have differing physiological explanations. These differences may explain why some patients benefit from one antidepressant and not another. Continued persistence, for example, of high levels of stress hormones (hypercortisolemia) after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome.19,42 Some clinical studies have found that tricyclic antidepressants are more effective than SSRIs in the treatment of melancholia.12,13,43 Melancholia is a severe form of depression characterized by complete loss of the capacity for pleasure, psychomotor slowing or "retardation" and worse symptoms in the morning. Patients with melancholia also tend to have high cortisol levels.24,35 Venlafaxine (Effexor®), an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported in one study to be more effective than fluoxetine in treating melancholic depression10 and in patients with both depression and anxiety.44 In spite of this, we cannot predict accurately which specific antidepressant will be the "right one" for a particular individual, and it often requires a process of trial and error.

What's Ahead
Glucocorticoid modulation of 5-HT receptors has important implications for the understanding and treatment of mood disorders and, perhaps, suicide. It may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and/or precipitate suicidal behavior.

An important therapeutic implication of this model is the prediction that agents which can reduce the stress response and/or decrease LHPA activation will be useful in the pharmacological treatment of anxiety, depression and, perhaps, suicidal behavior. In fact, patients with major depression, who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole.37,45

These suppressor agents, unfortunately, have many side effects and are often difficult to tolerate. A new drug class, CRH receptor antagonists, which decrease the release of the stress hormones, currently under development, may provide a therapeutic option.16,8 The CRH antagonist could, theoretically, be used in conjunction with antidepressants to improve the effectiveness of antidepressants, particularly for those patients who have treatment resistance.

Research, now on going, will, hopefully, soon provide new pharmacological treatments for all those who suffer from depression and other disorders of mood. We have made much progress and we will make more.

1. Berendsen, H. H., 1995. Interactions between 5-hydroxytryptamine receptor subtypes: is a disturbed receptor balance contributing to the symptomatology of depression in humans. Pharmacology & Therapeutics 66, 17-37. return

2. Betitto, K., Mitchell, J. B., Rowe, W., Boksa, P., Meany, M. J., 1990. Serotonin (5-HT) regulation of corticosteroid receptor binding in cultured hippocampal cells: The role of 5-HT-induced increases in cAMP levels. Soc. for Neurosci. Abstract 16, 1070.

3. Blier, P., de Montigny, C., 1994. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15: 220-226. return

4. Borsini, F., 1994. Balance between cortical 5-HT1A and 5-HT2 receptor function: hypothesis for a faster antidepressant action. Pharm Res 30, 1-11. return

5. Brown GW, Harris TO, Hepworth C, 1994. Life events and endogenous depression. A puzzle reexamined. Arch Gen Psychiatry 51:525-534.

6. Carroll, B. J., Curtis, G. C.,Mendels, J., 1976. Neuroendocrine regulation in depression I. Limbic system-adrenocortical dysfunction. Arch Gen Psychiatry 33: 1039-1044. return

7. Chalmers, D. T., Lopez, J. F., Akil, H.,Watson, S. J., 1993. Molecular Aspects of the Stress Axis and Serotonergic Function in Depression. Clinical Neuroscience 1: 122-128. return

8. Chalmers, D. T., Lovenberg, T. W., Grigoriadis, D. E., Behan, D. P.,De Souza, E. B., 1996. Corticotrophin-releasing factor receptors: from molecular biology to drug design. Trends Pharmacol Sci 17: 166-172. return

9. Chappell, P. B., Smith, M. A., Kilts, C. D., Bissette, G., Ritchie, J., Anderson, C., Nemeroff, C. B., 1986. Alterations in corticotropin-releasing factor-like immunoreactivity in discreate rat brain regions after acute and chronic stress. Journal of Neuroscience 6: 2908-2914. return

10. Clerc, G. E., Ruimy, P.,Verdeau-Palles, J., 1994. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol 9: 139-143. return

11. Dallman, M. F., Akana, S. F., Cascio, C. S., Darlington, D. N., Jacobson, L.,Levin, N., 1987. Regulation of ACTH secretion: Variations on a theme of B. Recent Prog Horm Res 43: 113-173. return

12. Danish University Antidepressant Group., 1986. Citalopram: clinical effect profile in comparison with imipramine: a controlled multicenter study. Psychopharmacology (Berl) 90: 131-138. return

13. Danish University Antidepressant Group., 1990. Paroxetine: a sel;ective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. J Affect Disord 18: 289-299. return

14. De Kloet, E. R., Rosenfel, P., Van Eekelen, J. A. M., Sutanto, W.,Levine, S., Eds. (1988) Stress, glucocorticoids and development. Progress in Brain Research. Amsterdam, Elsevier. return

15. De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S.,M., J., 1998. Brain corticosteroid receptor balance in health and disease. Endocrine Rev 19: 269-301. return

16. De Souza, E., 1995. Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology. 20: 789-819. return

17.Frank E, Anderson B, Reynolds CFr, Ritenour A, Kupfer DJ, 1994. Life events and the research diagnostic criteria endogenous subtype. A confirmation of the distinction using the Bedford College methods. Arch Gen Psychiatry 51:519-524.

18. Gold PW, Goodwin FK, Chrousos GP, 1988. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (second of two parts). N. Eng. J. Med. 319:413-420. return

19. Greden, J. F., Gardner, R., King, D., Grunhaus, L., Carroll, B. J.,Kronfol, Z., 1983. Dexamethasone suppression tets in antidepressant treatment of melancholia. Arch Gen Psychiatry 40: 493-500. return

20. Herman, J. P.,Watson, S. J., 1994. Glucocorticoid regulation of stress-induced mineralocorticoid receptor gene transcription in vivo. Ann NY Acad Sci 746: 485-488. return

21. Herman, J. P.,Watson, S. J., 1995. Stress regulation of mineralocorticoid receptor heteronuclear RNA in rat hippocampus. Brain Res 677: 243-249. return

22. Kalin, N. H., Dawson, G., Tariot, P., Shelton, S., Barksdale, C., Weiler, S.,Thienemann, M., 1987. Function of the adrenal cortex in patients with major depression. Psy Res 22: 117-125. return

23. Kathol RG, 1985. Etiologic implications of corticosteroid changes in affective disorder. Psychiatr Med 3:135-155. return

24. Kathol RG, Jaeckel RS, Lopez JF, Meller WH, 1989. Pathophysiology of HPA axis abnormalities in patients with major depression: an update. Am J Psychiatry 146:311-317. return

25. Katz, R. J.,Sibel, M., 1982. Further analysis of the specificity of a novel animal model of depression-- effects of an antihistaminic, antipsychotic and anxiolytic compound. Pharmacology of Biochemical Behavior 16: 979-982.

26. Kendler KS, 1998. Major depression and the environment: a psychiatric genetic perspective Pharmacopsychiatry 31(1):5-9. return

27. Lopez, J. F., Kathol, R. G., Jaeckle, R. S.,Meller, W. M., 1987. The HPA response to insulin hypoglycemia in depression. Biol Psychiatry 22: 153-166. return

28. Lopez, J. F., Chalmers, D. T., Vazquez, D. M., Watson, S. J.,Akil, H., 1994. Serotonin transporter mRNA in rat brain is regulated by classical antidepressants. Biol. Psychiatry 35: 287-290. return

29. Lopez, J. F., Chalmers, D., Little, K. Y.,Watson, S. J., 1998. Regulation of 5HT1a receptor, glucocorticoid and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression. Biol Psychiatry 43: 547-573. return

30. Lopez, J. F., Liberzon, I., Vazquez, D. M., Young, E. A.,Watson, S. J., 1999a. Serotonin 1a receptor mRNA regulation in the hippocampus after acute stress. Biological Psychiatry 45: 943-947. return

31. Lopez, J. F., Akil, H.,Watson, S. J., 1999b. Neural circuits mediating stress and anxiety. Biological Psychiatry (In press).

32. Mann JJ, Arango V, Marzuk PM, Theccanat S, Reis DJ, 1989. Evidence for the 5-HT hypothesis of suicide: A review of post-mortem studies. Br J Psychiatry 155:7-14. return

33. McEwen BS, 1987. Glucocorticoid-biogenic amine interactions in relation to mood and behavior. Biochemical Pharmacology 36:1755-1763. return

34. McEwen BS, 1991. Stress and hippocampus. An update on current knowledge. Presse Med. 20:1801-1806. return

35. Meador-Woodruff, J., Greden, J. F., Grunhaus, L.,Haskett, R. F., 1990. Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors. Acta Psychiatrica Scandinavica 81: 364-371. return

36. Melzter H, 1989. Serotonergic dysfunction in depression. Br J Psychiatry 155:25-31. return

37. Murphy BEP, Dhar V, Ghadirian AM, Chouinard G, Keller R, 1991. Response to steroid suppression in major depression resistant to antidepressant therapy. J Clinl Psychopharmacol 11:121-126. return

38. Murphy BEP, 1991. Steroids and Depression. J Steroid Biochem 38:537-559. return

39. Nemeroff, C. B., 1998. The neurobiology of depression. Sci Am 278: 42-49. return

40. Owens, M. J.,Nemeroff, C. B., 1998. The serotonin transporter and depression. Depression & Anxiety 8 Suppl 1: 5-12. return

41. Post RM. 1992. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999-1010. return

42. Ribeiro, S. C., Tandon, R., Grunhaus, L.,Greden, J. F., 1995. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry 152: 1618-1629. return

43. Roose, S. P., Glassman, A. H., Attia, E.,Woodring, S., 1994. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151: 1735-1739. return

44. Silverstone, P. H.,Ravindran, A., 1999. Once-daily venlafaxine extended release compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 60: 22-28. return

45. Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L, Weingartner H, 1993. Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150:810-812.