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Differential Diagnosis of Depression

Differential diagnosis of depressive disorders rests largely on clinical phenomenological grounds. The practitioner is advised to proceed according to the following steps:

1. Conduct a clinical interview to assess the patient for the nine specific signs/symptoms of major depressive disorder according to DSM-III-R. This step is essential, since the evidence for the efficacy of various treatments for major depressive disorder is very strong, but is relatively unstudied for nonmajor forms of depression or for dysthymic disorder without a history of major depressive disorder.

2. Interview the patient to investigate the possibility of concurrent substance or alcohol abuse and current use of medications that may cause depressive symptomatology (see Figure 2).

3. Conduct a medical review of systems to detect the existence of medical disorders that may biologically cause or be commonly associated with depressive symptoms.

4. Interview the patient further to detect the presence of another concurrent nonmood psychiatric condition that may be associated with and be responsible for the depressive symptoms.

5. Exclude alternative causes (1 through 4, above) for depressive symptoms or syndromes to diagnose a primary mood disorder. This process is summarized in Table 8.

Laboratory Tests

Guideline: The descriptive diagnosis of depression is based entirely on the patient's signs, symptoms, and personal history. Therefore, the practitioner should spend substantial time carefully interviewing the patient and, where appropriate, other informants (i.e., close relatives or friends) before embarking on extensive biologic, neuropsychological, or psychological testing. The main principle is to conduct only a limited number of basic laboratory tests to detect potential general medical causes for the depression unless specific risk factors, specific positive symptoms on the medical review of systems, unusual symptom profiles, or an atypical course of illness is present, in which case selected additional tests are called for to answer specific diagnostic questions. (Strength of Evidence = B.)

There are two kinds of laboratory tests: (1) those that screen for underlying medical causes for the depression and (2) those that identify biologic abnormalities characteristic of depression.

At the point at which a differential diagnosis is framed, with specific alternative conditions being relatively likely based on history, physical examination, or other risk factors, the primary care provider may use selected tests to determine whether these associated conditions are indeed

Table 8. Steps in detecting and treating depressive conditions (1) Maintain high index of suspicion and evaluate risk factors.

(2) Detect depressive symptoms with clinical interview and/or self-report questionnaire.

(3) Define mood syndrome (clinical history, interview, report by spouse or significant other).

(4) Define potential known causes of mood syndrome (medical, medications, substance abuse, other causal nonmood psychiatric disorders)."

(5) Treat potential causes.

(6) Reevaluate for mood syndromes.

(7) If mood syndrome is still present, treat as primary mood disorder.

'In some cases, the mood syndrome itself and the underlying cause must each be specifically treated.

present. In addition, various laboratory tests, such as the thyrotropinreleasing hormone stimulation test, the dexamethasone suppression test, and the sleep electroencephalogram, identify biologic abnormalities characteristic of the depressed state (see Rush, Cain, Raese, et al., 1991; Goodwin and Jamison, 1990 for reviews). These tests are not recommended for routine use in primary care outpatients. They lack sufficient specificity and sensitivity to be useful as screening tools.

The general principle of laboratory testing is that the likelihood of the disorder for which the test is being conducted should be relatively high in the patient being tested because virtually all tests have certain falsepositive as well as false-negative rates. If the false-positive rate of the test is 5 percent and the incidence of the condition in the population is 1 percent, 5 of 100 patients will test positive when only 1 in 100 really has the condition. The clinician should have a rational basis, independent of the laboratory test per se, for selecting and conducting the test. For example, if a depressed patient shows significant symptoms suggesting a dementing process or a clinical history suggestive of higher cortical impairment, further neuropsychological or neurologic laboratory tests, such as the electroencephalogram or magnetic resonance imaging, may be useful either to establish or exclude the diagnosis, or to identify the causes of the dementia. If, on the other hand, the patient simply complains of concentration problems that are not out of the ordinary for a person with a typical major depressive disorder, the use of such tests is both inappropriate and likely in at least some patients to lead to false-positive findings, thereby requiring additional testing, unnecessary specialized consultation, delay in appropriate treatment, and unnecessary worry to patients and family members.

Large epidemiologic studies in the general population suggest that previously unrecognized laboratory abnormalities occur in between 0.8 and 4.0 percent of the population (Korvin, Pearce, and Stanley, 1975). A

significant portion of these abnormalities, however, either are predictable based on clinical assessment (Dolan and Mushlin, 1985) or represent falsepositive test findings for the reasons cited previously. Those populations at highest clinical risk for meaningful abnormalities on these screening laboratory examinations include those who cannot care for themselves entirely, those who currently abuse alcohol or other substances, and those who merit a more thorough evaluation because of age or clinical circumstances (Ferguson and Dudleston, 1986; Koran, Sox, Marton, et al., 1989; Roca, Breakey, and Fischer, 1987; Sox, Koran, Sox, et al., 1989). These general population findings are supported by three studies in which a psychiatric population was prospectively investigated for identification of previously unrecognized illness (Ferguson and Dudleston, 1986; Kolman, 1985; Willett and King, 1977). The principal findings in these studies, which involved more than 1,300 adult psychiatric inpatients, suggest an abnormality rate of 6 to 17 percent in this psychiatric population. Most of these abnormal findings, however, were predictable based on history and physical examination or were false-positives. A side finding was that many test results were never reviewed by the ordering physician.

Laboratory tests should be tailored to the population served and should be specifically based on patient findings. Reliance on laboratory tests in general evaluation of the condition of depressed patients should be greater if:

The medical review of systems reveals signs or symptoms that are rarely encountered in depression.

The patient is older.

The depressive episode first occurs after the age of 40 to 45. ■The depression does not respond fully to routine treatment.

The issue of thyroid disease and depression is a case in point. Studies using thyroid function tests to screen nearly 15,000 general medical patients for either hyper- or hypothyroidism indicate that such a procedure is not cost-effective in identifying patients with the disorder (0.3 percent detection of hyperthyroidism [women/men = 10/1]; 0.5 percent detection of hypothyroidism [women/men = 2/1]).

At least two studies indicate that using fatigue and depression as prescreening symptoms does little to improve the likelihood of identifying hyper- or hypothyroidism with thyroid function tests as a general screen. The first study included 250 patients and found no increase in the identification rate of patients with hyper- or hypothyroidism when mental disorders or tiredness were present compared with the general population (Eden, Sundbeck, Lindstedt, et al., 1988). The second study suggested that, while the likelihood of identifying true cases of disease on laboratory testing improved when the symptoms of hyper- or hypothyroidism were elicited in advance, depression and fatigue were not among the most highly discriminant symptoms (Drake, Miller, and Evans, 1982).

These studies suggest that the optimal means to screen for thyroid disorders are through history and physical examination. The one exception is in the identification of hypothyroidism in women over the age of 50, in whom the identification rate is 10.3 percent in previously unidentified cases (Eden, Sundbeck, Lindstedt, et al., 1988; Hodkinson and Denham, 1977; Taylor, Tomson, and Caird, 1974). Thus, for women over 50 with depressive symptoms, thyroid function tests have a key role in detecting thyroid disease. The prevalence of this illness in women over age 50 is the same in women with major depressive disorder. The same cannot be said of older men, who are far less likely to suffer thyroid disease as a group than are older women.

When symptoms of thyroid disease are present, case finding with thyroid function tests increases to 12 percent for hyperthyroidism (Nuutila, Irjala, Viikari, et al., 1988) and to 3 to 4 percent for hypothyroidism (Goldstein and Mushlin, 1987; Nuutila, Irjala, Viikari, et al., 1988). As the symptoms of thyroid disease increase in number, case finding with such laboratory testing increases (more than five symptoms, 50 percent identification rate) (Drake, Miller, and Evans, 1982). Although fatigue is seen as a symptom of thyroid disease, in isolation it does not increase case finding with laboratory tests over that obtained in the general population (Sugarman and Berg, 1984).

When a treatment trial is conducted, the patient's symptomatic response should be monitored. If the patient does not respond fully, then the diagnostic workup (history, medical review of systems, and physical examination) should be repeated. At that juncture, a differential diagnostic picture may appear that was not obvious at initial evaluation. Appropriate laboratory testing for the differential diagnostic questions raised at the reassessment should then be undertaken.

As noted earlier, some laboratory tests that may be relatively specific to depressive conditions are now under clinical investigation. These include selected sleep electroencephalogram features and failure to suppress cortisol following a dexamethasone challenge, among others (Rush, Cain, Raese, et al., 1991). While many severely depressed patients, especially those with psychotic or melancholic symptoms, display abnormalities on these tests, the tests are not indicated as routine screens for depression because they lack specificity and have lower sensitivity in the less severely ill. However, they can play a role in selected differential diagnostic situations (for example, using the dexamethasone suppression test to differentiate psychotic depression from schizophrenia or using the sleep electroencephalogram to differentiate sleep/wake disorders such as sleep apnea from depression), which are typically managed by specialists rather than primary care providers.

Psychological Tests

Most psychological tests are standardized in the general population (Dobson, 1985). In general, recommendations for the use of psychological and neuropsychological tests in screening for depressive disorders are similar to those for laboratory tests. They are not recommended for routine use in screening for depression. However, in selected cases, psychological and neuropsychological tests may be very useful in differential diagnosis of depression. Neuropsychological tests, such as the modified HalsteadReitan battery, should be considered when it is necessary to distinguish dementia from depression. Depressed patients have been found to show significantly different test profiles on the Minnesota Multiphasic Personality Inventory (MMPI), the Symptom Checklist 90, and the Millon Clinical Multiaxial Inventory than do nondepressed patients with psychiatric diagnoses (Weitzler, Strauman, and Dubro, 1989). While these psychological tests predicted depression at a rate surpassing chance, such instruments were not substitutes for a thorough clinical evaluation. In other words, these tests may confirm, but they do not independently render, the diagnosis.

Perhaps the most commonly faced differential diagnosis in primary care practice is that between depressive and anxiety disorders. Dobson (1985) determined that the self-report symptom ratings for these two disorders have poor divergent (discriminative) validity, which is not surprising, since many depressed patients also have anxiety symptoms or suffer from concurrent, co-morbid anxiety disorders.

With regard to distinguishing subtypes of depression, the MMPI and Rorschach are of limited value in differentiating major depressive from bipolar disorder and melancholic from nonmelancholic major depressive disorder. In one study, patients with major depressive disorder showed elevated scores on most MMPI scales, compared to those with bipolar disorder, depressed phase (Donnelly, Murphy, and Goodwin, 1976), although subsequent studies failed to replicate this finding (Lumry, 1978; Silver, Isaacs, and Mansky, 1981). Another study found Rorschach responses to be of no value in distinguishing melancholic from nonmelancholic depressions (Carney, Roth, and Garside, 1965).

It is not appropriate to use psychological tests, including the MMPI, as the sole means to determine whether a patient with a concurrent symptomatic nonpsychiatric medical illness "really" has a depression, because symptoms from the medical illness itself affect test results. To illustrate, medical patients typically have a depressive/hypochondriacal pattern on the MMPI, because the MMPI somatic symptoms that emanate from the nonpsychiatric medical illness contribute to the depressive/ hypochondriacal symptom scales.

In summary, the available empirical data do not support the routine use of self-report or projective instruments to differentiate depression from anxiety disorders. These tests can distinguish depressive from other

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