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.

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 families 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. 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. 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. 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 TheDoctorWillSeeYouNow.com 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. 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.

Hyperactivity of the LHPA axis is a well-documented event in depression. Not only is too much of the stress hormone, cortisol, produced 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 hippocampus 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.

There is little doubt among scientists that glucocorticoids, the final products of the LHPA axis, have profound effects on mood and behavior. 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.

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 depression and of suicide, and the means by which many antidepressants provide relief. 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). 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. We have found that suicide victims, with a history of depression, have fewer 5-HT1a receptors in the hippocampus.

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

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.

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. 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. Other changes in brain chemicals occur which we have also found in suicide victims with a history of depression. 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. 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. Some clinical studies have found that tricyclic antidepressants are more effective than SSRIs in the treatment of melancholia., 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. Venlafaxine (Effexor&ref;), an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported in one study to be more effective than fluoxetine in treating melancholic depression and in patients with both depression and anxiety. 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.

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. 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.

The research reviewed in this paper was supported by a NARSAD Young Investigator Award, a Scientist Development Award (MH 01164) and by MH42251.