# Psychiatric Disorders/Mood Disorders/Major Depressive Disorder

Major Depressive Disorder (often simply called "Major Depression") is a common and yet very hidden disorder. It can be confusing at times: in normal conversation, we talk about being “depressed.” Major depression is different from the normal blues we might experience in that it is more severe, longer lasting (chronic) and less reactive to positive changes in our environment. It affects every aspect of our functioning: not only our mood, but also our physical functioning and even our thoughts. People who have major depression do not just feel “sad”—they feel truly sick.

## Phenomenology

Major depression affects all areas of functioning. It is classically defined by its effect on mood: patients describe feeling sad or down. Alternately, they may also feel irritable or anxious.
It also affects our physical functioning: patients routinely describe a lack of energy and complain of feeling drained, exhausted, and tired. Others speak of a “nervous energy,” akin to agitation. Libido is often diminished. Other physical functions, as sleep and appetite, (two of what are known as “vegetative symptoms”) are affected. These tend to be decreased, although some patients, especially those who will later develop bipolar disorder, experience hypersomnia and/or an increased appetite.
Finally, it affects our thoughts: persons with major depression often seem overly negative or pessimistic in their thinking. This pessimistic outlook may include suicidal ideation. In the extreme, the thought distortions may be severe enough to be considered psychotic.
As one can imagine, depression can negatively affect all aspects of a person’s life: work performance, relationships. The combination of the effects on attitude and energy can spell disaster in the workplace. One should keep in mind that this disease often strikes people during their most productive years—young to middle adulthood—and it is not surprising that health economists consider this one of the most expensive diseases affecting humans.

## Epidemiology

Major depression is very common. Figures vary, but it seems that about 5% of the general population suffers from this disorder during their lifetime. This disorder affects women twice as frequently as men—and this 2:1 ratio has been seen rather consistently throughout the world. In children, however, the ratio is equal between girls and boys.

## Etiology

Major depression appears to be, in part, an inherited disorder. In dizygotic twins, the concordance rate for major depression is about 20%, and in monozygotic twins, it jumps to about 50%. Among the first-degree relatives of patients with major depression, the risk of major depression is 2 to 3 times higher than for the normal population. Adoption studies also support a genetic link. However, the actual locus has not been identified. It is very unlikely that we will discover a single “depression gene”: the genetics of depression are very complex and heterogeneous.
In addition to inheritance, the environment plays a role in the expression of depression. Early childhood losses, especially significant losses (such as that of a parent), are strong risk factors for future depression. It is interesting that the first episode of depression is more likely to be triggered by a stressful environment; with repeat episodes, the connection with the environment is less obvious.
The fact that antidepressants work leads one to assume that there must be some deficit in the normal functioning of monoamine neurotransmitters, such as norepinephrine and serotonin. In general, research in this area is confusing and inconsistent. Though there are some intriguing findings, it is likely that the relationship between neurotransmitters and mood is complex, and not simply a “chemical imbalance” as is sometimes suggested.
Major depression is likely a heterogeneous disorder. Patients with depression likely have an inherited abnormality that predisposes them to depression, through some effect on normal physiologic processes in the brain. The neurotransmitters serotonin and norepinephrine are likely affected in this process, though in a complicated way. Environmental stresses can trigger this predisposition. However, with time, the disorder becomes more autonomous and less related to stress.

## Pathophysiology

On looking at the pathology of depression, the problem seems to be on of physiology rather than anatomy, and MRIs of depressed patients are usually normal.
A number of physiological abnormalities are associated with depression. Most commonly reported are abnormalities in the hypothalamic-pituitary-adrenal axis. This is most commonly demonstrated by the fact that many patients have an abnormal dexamethasone suppression test—the normal suppression in response to administration of an exogenous corticosteroid is blunted in almost half of patients with major depression. Similarly, one sees blunting of the TSH response to TRH or blunting of the growth hormone response to clonidine.
Other physiologic abnormalities are common. Disturbances of sleep architecture are common, including shortened rapid eye movement latency, or REM latency, and increased REM density.
On direct observation, such imaging technologies as Positron Emission Tomography, or PET and Single Photon Emission Computed Tomography (SPECT) also show abnormalities in major depression. The most common finding is hypofrontality, which is usually bilateral, but sometimes is nondominant.

## Differential Diagnosis
### Normal Emotional Reactions

The question usually comes up, how does one differentiate major depression from “normal reactions” such as appropriate sadness or grief. Admittedly, this can be hard, especially on a cross sectional evaluation, however there are a number of things you should consider when deciding whether to make the diagnosis of major depression:
One would want to consider whether the severity of symptoms is out of proportion to the event. This is subjective, but if one thinks that the patient is greatly “overreacting” to a minor or moderate stress, one would be more inclined to diagnose major depression.
One should also consider the duration of symptoms. Do the depressive symptoms remain strong even after the crisis has passed? This would again suggest major depression, particularly if the symptoms last 6 months to a year.
One should look for unusual symptoms. Some symptoms are more common with major depression than with other forms of sadness or grief. Examples include self-deprecation or severe unwarranted guilty feelings. Other suspicious symptoms would include physical symptoms, such as psychomotor agitation retardation, or early morning awakening.
Finally, a personal or family history of depression is also suggestive that a person is more than just sad or grieving.

### Other Mood Disorders

Major Depression can resemble a number of other illnesses. Of other mood disorders that may include depressive symptoms. Most differ in their course of illness. For example, dysthymia is a chronic depressive disorder, often lasting years, which consists of milder but unrelenting symptoms of depression. Post partum depression and premenstrual dysphoric disorder are all depressive episodes linked to certain times or events.
Depressive episodes of bipolar disorder can appear very similar to those occurring on the basis of major depression; a history of mania, however, rules out a diagnosis of major depression. Should this history be unavailable, then four ways are used to ascertain whether the depressed patient has bipolar disorder. A history of five or more depressive episodes, or a duration of a decade from the onset of the first to the onset of the current depressive episode, makes the future probability of mania very low. Secondly, a family history of mania is far more common in patients with bipolar disorder compared to major depression. Furthermore, patients with bipolar depression tend to be younger when presenting with their first depressive episode (teens or early twenties or, in some cases, even as children). Finally, bipolar depressions tend to come on acutely and be characterized by psychomotor retardation, hypersomnia, and hyperphagia, whereas major depressions come on insidiously and be characterized by agitation, insomnia, and anorexia with weight loss. Psychotic features (aka delusions and hallucinations) are also far more common in bipolar depression.

### Other Psychiatric Disorders

Other psychiatric disorders can include depressive symptoms as part of a larger syndrome—one has to be careful to recognize the “big picture” for these disorders, and not get stuck just on the first symptoms that may present. For example, a number of anxiety disorders, including Obsessive Compulsive Disorder, or Generalized Anxiety Disorder can include symptoms that overlap with depression, such as dysphoria, irritability, poor sleep and appetite. Posttraumatic Stress Disorder may include significant depressive symptoms as part of the overall syndrome. Schizoaffective disorder often includes full-blown depressive episodes. However, unlike psychotic depression, where the psychosis improves with the mood, the psychosis of schizoaffective disorder persists beyond the improvement in depression.

### Other Disorders

Finally, a number of disorders may cause a secondary depression. The term “secondary depression” implies that, although the depression is real, it is directly due to some other disease, and is best treated by treating the primary problem. Examples include the depression seen with alcoholism and drug abuse, depression secondary to anorexia nervosa, and depression secondary to medical syndromes, such as hypothyroidism or Cushing’ disease. In each case, antidepressant treatment is often used. However, antidepressants often do not work well as they do in uncomplicated major depression until the primary problem is also treated.

## Course

Major depression tends to be a relapsing and remitting illness.
It can begin at any age. Most often, it begins in young to middle adulthood, though childhood and geriatric onsets do occur. The depression usually begins gradually. It may be triggered by a stressful life event, such as the loss of a loved one, though it can also seemingly begin for no reason.
An episode of untreated depression can last anywhere from 6 to 12 months. After that time, most persons return to their normal state. However, about 1/10 of people develop a more chronic disorder.
Most persons who recover from an episode of depression will have another episode during their lifetime. It is difficult to say just when it will recur. On average, the interval between episodes is about 5 years; however there is a wide variability in this.
The course is worsened in the presence of comorbid disorders. Such disorders as alcoholism and other drug abuse and anxiety disorders are common in persons with major depression. Suicide is also common—the overall suicide rate is about 4% in patients with major depression and in those severe enough to be hospitalized, the rate jumps to about 9% (the suicide rate in the normal population is only about 0.012%--so this represents a 1000-fold increase in risk).

## Treatment

There are three phases of treatment for depression: the acute phase, the continuation phase and the maintenance phase. The goals of each phase are different.

### Acute Treatment

The goal of the acute phase is to bring about a remission of symptoms, meaning to eradicate, or at least decrease the number and intensity of current depressive symptoms.
In the acute phase of treatment, a number of options are available for treating the current symptoms. One may use a medication, specifically an antidepressant to treat the symptoms. Alternately, a number of psychotherapies have been shown to be effective in treating depressive symptoms. As a general rule, medications are usually preferred for more severe episodes, including psychotic ones, whereas both medications and talk therapies may be equally effective for mild to moderate depression.
The details of medication and psychotherapy treatments will be covered elsewhere in more detail. For now, some generalities:

#### Medication Treatment

There are a number of classes of medications that are effective for depression. Classes of drug include first generation agents, such as tricyclic medications and monoamine oxidase inhibitors, or MAOIs. These were the original medications used for depression, and were discovered largely through serendipity. Examples of tricyclic antidepressants include amitriptyline and nortriptyline. They appear to work through the inhibition of norepinephrine reuptake into the neuronal synapse. Conversely, monoamine oxidase inhibitors, as the name implies, inhibit the enzyme most responsible for the catabolism of norepinephrine and other monoamines. An example of an MAOI is phenelzine.
Both the tricyclic antidepressants and the MAOIs are very effective antidepressants. However, they suffer from a number of unwanted effects, due to their lack of selectivity. For example, amitriptyline, in addition to inhibiting the reuptake of norepinephrine, is also a potent inbitor of acetyl choline in the brain. The result of these anticholinergic effects include dry mouth, dizziness and constipation. In addition, the tricyclics have an antiarrhythmic effect similar to quinidine, and cause cardiac arrhythmias in patients with preexisting conduction defects. For that reason, they are usually avoided in patients with cardiac disorder. The MAOIs, in addition to sharing significant anticholingic and other unwanted effects, inhibit the metabolism of tyramine, an amino acid which is common in cured, fermented or aged foods. The result of a tyramine build up is a syndrome called the “tyramine-cheese”reaction.
Newer agents include the second generation selective serotonin reuptake inhibitors, or SSRIS. These are "second generation" agents as an attempt was made to develop agents that were more specific in their actions. As they are selective, they tended to cause less side effects, and certainly less serious ones, and for that reason largely supplanted the first generation agents as first line treatments for depression. Example of an SSRI includes fluoxetine, sertraline, paroxetine, citalopram and escitalopram. Side effects of these include jitteriness, nausea and insomnia. More serious reactions can occur if they are concurrently given with another serotoninergic agent, causing the “Serotonin syndrome.”
The 3rd generation of agents often combine multiple effects in an attempt to improve efficacy. If they offer an advantage in efficacy at all, it is mild at best, however they are effective agents. Such agents include venlafaxine and duloxetine, which selectively inhibit both norepinephrine and serotonin reuptake and mirtazapine.
In general, all antidepressants have approximately equal efficacy. In choosing an antidepressant, one considers the patient’s history as well as side effects. A history of good response to an agent, or a family history of such response, is predictive of a good response for the patient. In addition, as many side effects can be predicted, one usually chooses agents that will be tolerant to a patient. For example, a patient who is troubled by insomnia might not tolerate an SSRI as well as another antidepressant less likely to cause insomnia.
Two particularly troubling side effects are weight gain and sexual side effects. Most antidepressants cause these side effects, at least in some degree. A notable exception is bupropion.
All antidepressants take about the same amount of time to work – anywhere from 2 to 6 weeks until one sees an effect, and sometimes longer. The average time to effect is perhaps 3 to 4 weeks, and one should wait that long after starting a medication before considering a treatment change, if the medication is already at a proper dose.
Adherence is a big problem. The major reason for a lack of response is that the medication is often not taken long enough and at a proper dose to allow for an effect.
There are several barriers to adherence. One is side effects. On average, newer agents are better tolerated than older ones, but all antidepressants have some measure of side effects. For example, the SSRIs can cause nausea, jitteriness and insomnia. Patients should be prepared for these side effects, and it is important to know the side effects of a particular drug in deciding whether a patient is going to be able to tolerate the drug.
Another barrier is a lingering bias against using medications for mood. The physician should both reassure and educate the patient that major depression is a real disease, and like all real diseases, it needs medical treatment.

#### Psychotherapy

Many types of psychotherapy have been shown to be effective for depression. The two that have the greatest weight of positive data are Cognitive Behavioral Therapy and Interpersonal therapy. However, many other therapies, including psychodynamic psychotherapy, couples therapy, group therapy and behavioral therapy also have some efficacy data.
A critical variable in considering therapy is intensity. When used, therapy should be frequent and of sufficient duration to have maximal effect. Once-weekly, hour-long therapy, lasting the length of the acute period, seems a minimum for patients with moderate depression.
Again, psychotherapy is not the treatment of choice for severe major depression or depression with psychotic features.

#### Other options

Electroconvulsive therapy or ECT has long been thought to be the most effective and rapidly acting treatment. It works through inducing seizures in the brain. It is likely that it is only the general bias against ECT that prevents wider use. For now, it is usually restricted to the most severe, meaning life threatening, or most treatment resistant cases of depression.

### Continuation Treatment

In the continuation phase, the goal is to prevent relapse or a reemergence of symptoms once they have been treated.
Once the symptoms are controlled, the goal of therapy is to prevent the symptoms from coming back, or “relapsing.” In general, treatments that are effective in the acute period are thought to be effective in this continuation period as well, with the proviso that they should be continued at the same dose as was used in the acute period.

### Maintenance Treatment

In the maintenance phase, the goal is prevent recurrence, or the emergence of new episodes of depression.
Generally, treatment of depression is continued for the likely length of a major depressive episode: 6 to 9 months. At that time treatment can often be discontinued. However, there are situations in which longer term, even indefinite treatment is recommended. These cases are as follows:

#### Recurrent Depression

Many patients who recover from an episode of depression will have a later episode. Patients with recurrent depression are those who have had at least 3 clear episodes of depression in their lifetime. Such patients have such a high likelihood of recurrence that ongoing treatment is often recommended.

#### Chronic depression

Some patients do not recover from their acute episode of depression. Some continue to have major depression. Others may recover from the severe episode, but may turn out to also have comorbid dysthymia. In these cases, ongoing treatment is recommended.

#### Severe Depression

There may be cases where, even after one episode of depression, the symptoms are so severe that the patient does not want to risk another episode. As with all treatment, one should always compare risks and benefits, and in some cases the risks of going off medication may just too risky.

##### Maintenance Treatment Options

Although the data is much more skimpy, is seems that most drugs used in the acute period also prevent recurrence. Usually they are continued at the same dose needed to achieve remission.
However, these drugs only work while one takes them. Once stopping, they confer no additional preventive benefit, and the risk of relapse returns.
ECT generally is used only for achieving acute remission of depression and has no longer lasting benefit. In some cases, such as patients who only respond to ECT, or prefer it to medication, maintenance ECT may be given, on a perhaps monthly basis for ongoing treatment.
Psychotherapy may be beneficial in that, even when discontinued; it may confer an ongoing benefit. This make sense when one thinks about it: in effective psychotherapy, one learns something, such as new ways to cope, or new ways to think about stress.