Major depression is one of the most prevalent, serious illnesses in the United States. It affects millions of people of all ages and walks of life. Although this disorder can be devastating, it is now more treatable than ever. There are now twenty-two different antidepressants belonging to one of eight pharmacologically distinct classes. Thus, major depression is to psychiatry as hypertension is to general medicine in that the clinician has a wide array of mechanistically different medications to select from when treating patients suffering from this disorder.

Since depression is a common condition that leads many patients to seek care from the primary-care practitioner, these clinicians are in the frontline of the battle against this disorder.^61,98,121 Over one-half of all patients with major depression are treated in the primary-care setting. Unfortunately, many cases go unrecognized, and those that are identified are frequently inadequately treated.²⁴¹

There are several myths that contribute to this problem. One is the mistaken belief that major depression and other psychiatric disorders are trivial, will go away on their own, or are the result of character weakness. Another is that the treatment of these conditions is somehow mysterious such that primary-care practitioners cannot understand or treat such patients. This book will dispel these myths.

The same principles and approaches that apply to hypertension, diabetes mellitus, and other medical conditions also apply to psychiatric illnesses. Primary-care practitioners will find that the approach they use in their general-medicine practice will also apply to psychiatric illnesses. While the focus of this book is major depression, the principles discussed here are universally applicable to all psychiatric illnesses.

FIGURE 1.1 — Diagnostic Criteria Pyramid

TABLE 1.1 — Critical Variables in Diagnosis Onset (type and age Signs/symptoms Premorbid personality Family history Natural course Response to treatment Laboratory data

All diagnoses in medicine fit into one of the categories shown in Figure 1.1, arranged hierarchically from most (etiologic) to least (symptomatic) sophisticated. Critical variables in diagnosis are listed in Table 1.1.

The fundamental point in diagnosing and understanding major depression is that it is a syndrome. It is not just low mood, but rather a cluster of signs and symptoms termed a depressive episode and consisting of:

• Change in mood:
  - Usually "depressed," "blue," or "sad"
  - Sometimes irritable or anxious
  (Of note, while the syndrome takes it name from the mood symptom, the two are not synonymous. Not everyone who is "blue" has major depression, nor is "depressed mood" necessarily the most prominent symptom for every patient with major depression.)
• Change in sleep patterns
• Change in appetite
• Change in weight
• Change in activity levels
• A sense of fatigue
• Decreased motivation
• Decreased interest
• Decreased sex drive
• Decreased concentration and attention.

A patient suffering from a major depressive episode will have five or more of these signs and symptoms every day for weeks to months, and even years, if not effectively treated. Diagnostic criteria for a major depressive episode as listed in the Diagnostic and Statistical Manual version IV (DSM-IV) of the American Psychiatric Association are shown in Table 1.2.

In classic or melancholic major depression, there is a decrease in:

• Sleep
• Appetite
• Weight
• Activity levels.

However, there is also an "atypical" or "reversed vegetative symptom" syndrome in which these symptoms are increased (Table 1.3):

• Hypersomnolence
• Hyperphagia
• Weight gain
• Lethargy
• Agitation.

This atypical form has an earlier age of onset (late teens to late twenties) compared to the melancholic form (late thirties to late forties). The atypical form also has a unique family pattern: female relatives with atypical major depression and male relatives with alcoholism. In contrast, the family pattern in the melancholic form tends to be more one of pure major depression. These differences suggest that these are different forms of clinical depression. There are also some data to suggest a differential response to different classes of antidepressants in patients with melancholic versus atypical clinical depression (Chapter 8).

The diagnosis of major depression can be compared to the diagnosis of migraine. A patient presents with a symptom, such as low mood in the case of major depression or headache in the case of migraine. The clinician then screens the patient for the syndrome. A pathophysiological cause, perhaps hypothyroidism in the case of a depressive syndrome or increased intracranial pressure in the case of migrainous-like headache, is checked. The clinician then should go on to explore possible etiological causes.

Major depression is currently at the syndromic level of understanding, but research is expanding our knowledge at the levels of pathophysiology and etiology, just as with any medical condition. The clinician, when faced with a patient who may have a depressive syndrome, must do differential diagnosis to confirm the diagnosis or find another explanation.

The most common known etiologies of a depressive episode include:

• Substance abuse and/or dependence involving:
  - Sedatives, especially alcohol
  - Stimulants, especially cocaine
• Other drug therapy, such as antihypertensives, particularly those that antagonize central biogenic amine mechanisms (ie, norepinephrine, serotonin, and dopamine)
• Occult malignancies:
  - Should be thoroughly considered when:
• Patient is in high-risk group (eg, elderly)
• Weight loss is out of proportion to other depressive symptoms
• The depressive episode remains refractory despite adequate trials of several classes of antidepressants and/or electroconvulsive therapy (ECT)
  - A classic scenario is carcinoma of the head or the pancreas.

It is necessary to consider these common medical causes of a depressive episode because they require different treatments.

The bottom line is that clinical or major depression is a syndromic diagnosis made after excluding other medical conditions.

Once the diagnosis has been made, the clinician should endeavor to determine whether the patient has manic-depressive (also called bipolar) disorder or unipolar major depression. In bipolar illness, the patient is susceptible to hypomanic or manic episodes (Table 1.3) as well as depressive episodes, while in the latter the patient only has depressive episodes. The unipolar condition is considerably more common-about 10 times more prevalent-than the bipolar form. Nonetheless, some patients with manic-depressive illness will present for the first time with a depressive episode rather than a manic episode. It is important to make this distinction because bipolar patients are at risk for the development of a manic episode during treatment of their depressive episode (Chapter 11). If the clinician is alert to this possibility, steps can be taken (eg, concomitant treatment with lithium and increased vigilance) to decrease the risk associated with a switch into mania.

TABLE 1.3 — Signs and Symptoms of Different Types of Affective Episodes
Sign/Symptom	Melancholia	Atypical or Nonclassic Depression	Hypomania
Mood	Depressed Anxious Irritable	Irritable Anxious Depressed	Irritable Euphoric
Affect	Reactivity	Reactivity	Reactivity
Energy (subjective)
Activity (objective)
Sleep
Appetite
Sex drive
Concentration/ attention
Interest

The question is how to determine whether the patient has a bipolar rather than a unipolar disorder? That can be more difficult than it may first appear. The problem is not with mania since the psychosis and/or level of functional impairment due to overt mania is such that even a casual observer can detect the condition. The problem is with hypomanic episodes. The symptoms involve the same functions as those found in major depression (Table 1.3) but differ in their expression (eg, increased rather than decreased activity) or are experienced differently (eg, the depressed patient complains of "not being able to sleep" while the hypomanic patient reports "not needing to sleep"). Rarely, if ever, do hypomanic patients present complaining about hypomania (eg, "Gee, Doc, I feel too good."). Hence, the clinician must inquire about such episodes in all patients presenting with a first-time episode of major depression.

The family history can also be helpful. Bipolar disorder has one of the strongest, if not the strongest, familial patterns of any psychiatric illness. If one or more of the patient's first- or second-degree family relatives has bipolar disorder, the clinician should consider the patient to be at increased risk, and may wish either to treat with lithium in addition to an antidepressant (Chapter 11) or instruct the patient to contact the clinician if s/he should begin feeling "too good," "wound up," or having one of the other symptoms listed in Table 1.3.

In summary, to make a diagnosis of a major depression, the clinician must first establish that the patient has a depressive episode and, second, rule out known medical causes of such episodes.