5a:  Depression in Primary Care: Detection and Diagnosis, Volume 1: Clinical Guideline Number 5

Background

At least five reports suggest that primary care practitioners underdiagnose and/or undertreat depressive conditions (Gullick and King, 1979; Johnson, 1974; Ketai, 1976; Magruder-Habib, Zung, Feussner, et al., 1989; Popkin and Callies, 1987). In fact, only one-third to one-half of patients with major depressive disorder are properly recognized by primary care and other practitioners. Only about one-third of patients with bipolar disorder are in treatment. The problem of underrecognition is important enough to warrant special attention.

Other psychiatric disorders are often accompanied by mood symptoms or formal mood syndromes. That is, patients may suffer concurrently from two psychiatric syndromes. In addition, substance abuse or withdrawal may cause mood symptoms/syndromes -- so-called substance-induced mood disorders.

Depressive symptoms or full syndromes commonly accompany a variety of other general medical disorders. For example, diabetes, cancer, heart attacks, and stroke are often accompanied by depressive symptoms of sufficient duration and intensity to meet the criteria for specific mood syndromes. Recognized general medical conditions, such as neurologic, metabolic, oncologic, and other illnesses, can biologically cause mood symptoms or formal mood syndromes (i.e., organic or secondary mood disorders). In other cases, mood syndromes may be psychological reactions to the disability or prognosis associated with nonpsychiatric medical conditions. Some prescription medicines used to treat general medical conditions, such as antihypertensive drugs, may also precipitate or maintain depressive symptoms or syndromes, especially in persons with a personal or family history of mood disorders.

For these reasons, the Depression Guideline Panel has provided Clinical Practice Guideline: Depression in Primary Care to introduce practitioners to the key features of depressive conditions and, thus, to improve early diagnosis. This guideline, an abbreviated version of a far larger document, is divided into two volumes: this one, Volume 1. Detection and Diagnosis, and its companion, Volume 2. Treatment of Major Depression. The nearly 40 literature reviews conducted for these guidelines identified more than 3,500 relevant references, which are cited in the Guideline Report (roughly 1,200 pages). Only recent reviews and highly salient references are cited here.

Definition of Depression

The panel defined depression according to the current U.S. standard diagnostic system in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) (American Psychiatric Association, 1987). Given the need to complete this report in a timely fashion, the panel focused on major depressive disorder with some consideration of DNOS. The DSM-III-R system is closely aligned with and easily translated to the International Classification of Diseases, Ninth Edition (ICD-9) system of the World Health Organization (WHO). Both the DSM-III-R and the ICD-9 are undergoing revisions, which are to be completed by the end of 1993. In choosing to use the DSM-III-R, the panel acknowledges the availability of other clinical taxonomies pertinent to the diagnosis of depression in primary care practice and recognizes that the selection of a particular taxonomy can add bias to the guideline. The panel recognizes this limitation, but believes the DSM-III-R to be the best taxonomy available at this time.

The panel also recognizes that a variety of clinical conditions may be viewed as mood disorder "equivalents." These include masked depression, chronic pain, chronic fatigue syndrome, somatization disorder, fibromyalgia, and others. The panel commissioned reviews of the literature on these conditions to provide a scientific basis for recognizing and differentiating these conditions from mood disorders.

Literature Reviews and Guideline Development

Practitioners often confront clinical situations for which direct research data are limited, but for which indirectly relevant data are available. The translation of what is scientifically confirmed or suspected into what is clinically required or recommended requires training, professional judgment, and experience.

These guidelines are based on systematic literature reviews conducted by experts in diverse substantive areas relevant to depression, with special attention to the clinical issues most pertinent to the diagnosis and treatment of depression in primary care. To develop principles for diagnosis and treatment of mood syndromes in association with other illnesses, the panel also commissioned reviews of the literature on depression and selected general medical conditions. Where evidence is either lacking or incomplete, this is noted; in these cases, either no guideline has been derived or options are provided, based on logical inference, available data, and panel consensus. When the evidence is reasonably clear, though modest in amount, these findings are noted, and a tentative recommendation is offered. Thus, the guidelines that follow are coded according to the strength of the available evidence as interpreted by the panel:

• A. Good research-based evidence, with some panel opinion, to support the guideline statement.

• B. Fair research-based evidence, with substantial panel opinion, to support the guideline statement.

• C. Guideline statement based primarily on panel opinion, with minimal research-based evidence, but significant clinical experience.

This synopsis of diagnostic issues is not based on reviews of the evidence for or against the validity of specific diagnostic entities. (For such reviews, see DSM-IV Sourcebook [Frances and Widiger, in press].) Rather, the panel reviewed the epidemiology of major depressive disorder in community samples and primary care settings and the course, co-occurrence, and co-morbidity of depressive and other medical conditions. The panel also reviewed literature on the role of self-reports and clinician ratings as tools for detecting or differentially diagnosing depression. Therole of laboratory tests in differential diagnosis of the medical causes of depression was illustrated by using the example of thyroid function testing.

This synopsis describes the various forms of depression; their course, epidemiology, and common clinical expression in different age groups; the co-occurrence of depressive symptoms or formal syndromes with other psychiatric or nonpsychiatric medical conditions; the role of medications in causing depression; and the role of clinical and laboratory procedures in the detection and differential diagnosis of depression.

The depression guidelines were drafted in four different formats: (1)the full Depression Guideline Report; (2) the Clinical Practice Guideline, which condenses pertinent information from the report into two volumes for easy use by practitioners; (3) the summary Quick Reference Guide for Clinicians; and (4) A Patient's Guide. The literature reviews, drafts of the full Depression Guideline Report, and all four shorter versions were sent to 14 scientific reviewers, who critiqued them. The guidelines were revised and sent to the original 14 reviewers, plus 14 new scientific reviewers for further critique and subsequent revision.

Additional revisions to these guidelines are anticipated, based on further comments from practitioners, new scientific evidence, studies of the impact of these guidelines on primary care practice, and new reviews to address areas not yet discussed. For example, the panel has not reviewed treatment of certain conditions, such as bipolar disorder; certain treatments, such as use of lithium alone; or certain patient groups, such as children and adolescents. These topics were deferred to subsequent years either because they are less common in primary care or because logistic constraints made deferral necessary. The panel invites correspondence from users to help in these future revisions.

Interpretation of the Scientific Literature

Several limitations to the available scientific literature made the development of guidelines for primary care providers difficult:

• Most studies on diagnosis and treatment of depression come from non-primary care settings (usually psychiatric or psychological practice settings).

• Only modest data are available on the usefulness of DSM-III-R in patients with depression and concurrent medical disorders.

• Only a few randomized controlled treatment trials have been conducted in patients with depression and concurrent significant medical disorders.

• The long-term outcomes of treated and untreated mood disorders seen in primary care settings are relatively unstudied.

• While a moderate number of randomized controlled acute treatment trials using medication and some trials using psychotherapy have been conducted in geriatric patients, only seven trials were conducted in primary care settings, though geriatric patients are common in primary care.

• Even fewer randomized controlled trials with depressed children and adolescents are available, and none have been conducted in primary care settings.

• While many patients with mood disorders seen in primary care settings have DNOS or "minor" forms of depression, very few randomized controlled trials on these patients have been undertaken.

Although several authors have questioned the generalizability of research findings from psychiatric to primary care settings, many difficulties encountered in primary care are also found in psychiatric settings. These include distinguishing depressions from underlying medical disorders, identifying medical disorders that present with depressive symptoms, treating mood disorders in patients with other general medical illnesses, and identifying and treating depressive psychological reactions to nonpsychiatric medical disorders.

The panel believes it essential to highlight the impact of current social and cultural forces, as well as current reimbursement policies, on timely diagnosis and treatment of depressive and other psychiatric conditions.Social stigma contributes to:

• Resistance of patients to seek treatment.

• Reluctance of practitioners to look for and formally diagnose depressions.

• Poor adherence by patients during long-term treatment of more chronic forms of depression.

• Low reimbursement rates by third-party payors for these conditions.

• Inappropriate emphasis on depression and other psychiatric disorders on applications for driver's license,employment, security clearance, and other "routine" purposes (a situation that may be improved with the recent enactment of the Americans with Disabilities Act).

Because of the current discrimination against persons with depressive and other psychiatric conditions, appropriate diagnosis and treatment may carry a far greater personal cost for patients with depression than for those with other medical conditions. In some cases, acknowledgment of diagnosis and treatment of depression can actually worsen an individual's social, occupational, and economic status. The ultimate long-term consequences of this stigma must be addressed to ensure accurate, early diagnosis and effective, early treatment.

The implementation of these guidelines may require one or more of the following:

• Increased reimbursement for those time-intensive tasks recommended in these guidelines.

• Educational efforts aimed at primary care practitioners.

• Patient/family education.

On the other hand, use of these guidelines may reduce overall medical costs, since patients with clinical depression may be identified and treated earlier in the course of the illness, thus reducing the need for multiple physician visits for various somatic symptoms of depression (e.g., tension headaches, abdominal pain, joint pain, insomnia) and the need for eventual, more complex and expensive treatments for more chronic depressions. Indirect cost savings, such as fewer days lost from work, less disability, and less pain and suffering, are additional benefits of effective treatment.

Major Depressive Disorder

Epidemiology

Guideline: The point prevalence for major depressive disorder in the Western industrialized nations is 2.3 to 3.2 percent for men and 4.5 to 9.3 percent for women. The lifetime risk for major depressive disorder is 7 to 12 percent for men and 20 to 25 percent for women. Risk factors for major depressive disorder include female gender (especially during the postpartum period), a history of depressive illness in first-degree relatives, and prior episodes of major depression. (Strength of Evidence = A.)

The above gender difference is found in community samples and, thus, is not due to increased female help-seeking behavior. Prevalence rates for major depressive disorder are unrelated to race, education, income, or civil status. Recent epidemiologic data clearly indicate that the age at onset of major depressive disorder has decreased for the more recently born (the "birth cohort" effect) in many westernized cultures.

A recent review of available studies strongly suggests that psychosocial events or stresses may play a significant role in precipitating the first or second episodes of major depressive disorder, but they may play little or no role in the onset of subsequent episodes (Post, 1992). That is, for the recurrent forms of major depressive disorder, new episodes are less likely to involve a specific precipitant as the disorder becomes more firmly established.

Individuals with major depressive disorder, as well as those with dysthymic disorder and DNOS, are high users of medical services and are as functionally impaired as are patients with severe chronic medical disorders (Katon, von Korff, Lin, et al., 1990; von Korff, Ormel, Katon, et al., 1992; Weissman, Leaf, Tischler, et al., 1988; Weissman and Myers, 1978).

The lifetime psychiatric co-morbidity rate for major depressive disorder can be as high as 43 percent (Sargeant, Bruce, Florio, et al., 1990). That is, up to 43 percent of patients with major depressive disorder have histories of one or more nonmood psychiatric disorders. The 1-month point prevalence for concurrent in contrast to lifetime psychiatric co-morbidity is 8 percent.

Table 2. Prevalence of major depressive and other mood (more...)

Table 2. Prevalence of major depressive and other mood disorders in primary care settings

Study	Number of Subjects	Interview	Major Depression	Other Mood Disorders
Barrett, Barrett, Oxman, et al., 1988	1,055 screened with SCL depression subscale; 260 interviewed	SADS-RDC	2.2% (6.4% masked major depression)	3.6% episodic minor depression; 2.1% chronic depression
Blacker and Clare, 1988	2,308 screened with GHQ; 1,019 interviewed	SADS & PSE RDC	4.8%	5.0% intermittent depression; 3.4% minor depression
Burnam, Wells, Rogers, et al., 1989	RAND Medical Outcome Study; Los Angeles, Chicago	DIS & DSM-III	4.1-5.4%	Not reported
Coulehan, Schulberg, Block, et al., 1990	University general internal medicine clinic; 618 patients	DIS & DSM-III	6.6%	Not reported
Hoeper, Nycz, Cleary, et al., 1979	1,072 screened with GHQ; 247 completed SADS-L	SADS-L & RDC	5.6%	5.0% intermittent depression; 3.4% minor depression
Hoppe, Leon, and Realini, 1989	Family health center, San Antonio; 165 patients	DIS & DSM-III	F = 9.8% MDD or dysthymia; M = 11.1% MDD or dysthymia	Not reported separately
Kessler, Cleary, and Burke, 1985	ECA users of health care	DIS & DSM-III	F = 6.9-9.3% M = 3.3-6.5%	Not reported
Ormel, Van Den Brink, Koeter, et al., 1990	2,237 screened with GHQ	PSE & PSE-10 Bedford College Criteria	5.6%	4.7% borderline depression (similar to minor depression)
Schulberg, Saul, McClelland, et al., 1985	1,554 screened with CES-D; 294 completed DIS	DIS & DSM-III	6.2%	3.0% dysthymic and adjustment disorder
von Korff, Shapiro, Burke, et al., 1987	1,242 screened with GHQ; 730 patients interviewed	DIS & DSM-III	5%	3.7% dysthymic disorder
Zich, Attkisson, and Greenfield, 1990	University general internal medicine: 65 patients	DIS & DSM-III	7.7%	Not reported

Note: SCL = Symptom Checklist. SADS-RDC = Schedule for Affective Disorders and Schizophrenia Research Diagnostic Criteria. GHQ = General Health Questionnaire. PSE = Present State Examination. DIS = Diagnostic Interview Schedule. SADS-L = Schedule for Affective Disorders and SchizophreniaQLifetime Version. MDD = major depressive disorder. ECA = Epidemiologic Catchment Area. CES-D = Center for Epidemiological Studies Depression Scale.

Depressive conditions are highly prevalent in primary care settings (Johnson and Weissman, unpublished manuscript). Prevalence rates of depression based on chart notations by primary care physicians vary from 1.5 to 4.5 percent. Structured psychiatric interviews based on standard diagnostic systems (DSM-III-R or ICD-9) provide the best prevalence data because they identify all who have the conditions and differentiate them from those with depressive symptoms from other causes. (However, even many of the studies in which the investigators used structured interviews may not fully exclude patients whose depression was caused by concurrent nonpsychiatric medical disorders, medications, or substances of abuse.) Eleven studies have used structured psychiatric interviews and specific diagnostic criteria to determine the prevalence of major depressive disorder in primary care settings ( Table 2). The point prevalence of major depressive disorder in primary care outpatient settings ranged from 4.8 to 8.6 percent; 14.6 percent of adult medical inpatients studied met ICD-9 criteria for major depressive disorder (Feldman, Mayou, Hawton, et al., 1987).

Subgroups of Major Depressive Disorder

Table 3. Major depressive disorder subgroups

Table 3. Major depressive disorder subgroups

Subgroup	Essential Features	Diagnostic Implications	Treatment Implications	Prognostic Implications
Psychotic	Hallucinations, Delusions	More likely to become bipolar than nonpsychotic types. May be misdiagnosed as schizophrenia.	Antidepressant medication plus a neuroleptic is more effective than are antidepressants alone. ECT is very effective.	Usually a recurrent illness. Subsequent episodes are usually psychotic. Psychotic subtypes run in families. Mood-incongruent features have a poorer prognosis.
Melancholic	Anhedonia, Unreactive mood, Severe vegetative symptoms	May be misdiagnosed as dementia. More likely in older patients.	Antidepressant medication is essential. ECT is 90% effective.	If recurrent consider maintenance medication.
Atypical	Reactive mood Overeating/weight gain, Oversleeping, Rejection sensitivity, Heavy limb sensation, Fewer episodes	Common in younger patients. May be misdiagnosed as personality disorder.	TCAs may be less effective. MAOIs are preferred. SSRIs preferred.	Unclear.
Seasonal	Onset, fall Offset, spring Recurrent	More frequent in non-equatorial latitudes. Pattern occurs in major depressive and bipolar disorders.	Medications have ? efficacy. Psychotherapy has ? efficacy. Phototherapy is an option.	Recurs.
Postpartum psychosis/ depression	Acute onset (<30 days) in postpartum period. Severe, labile mood symptoms. 1/1,000 is psychotic form.	Often heralds a bipolar disorder.	Hospitalize. Treat medically.	50% chance of recurring in next postpartum period.

Note: ECT = electroconvulsive therapy. TCA = tricyclic antidepressant. MAOIs = monoamine oxidase inhibitors. SSRIs = selective serotonin reuptake inhibitors.

Studies of major depressive disorder reveal heterogeneity with regard to the biology, family history, pharmacologic response, genetics, and course of illness. Several schemes have been proposed to subdivide major depressive conditions. The common subgroups and possible clinical relevance of each are shown in Table 3. These subtypes are not all-inclusive. For example, a large number of patients who have major depressive disorder without melancholic, psychotic, or atypical features have episodes that are not seasonally related and do not have a postpartum onset.

Three subgroups based on cross-sectional symptom features psychotic, melancholic, and atypical may have implications for treatment selection. Two based on course features seasonal pattern and postpartum onset have prognostic utility; the seasonal type may also suggest the specific therapeutic option of light therapy. However, these subgroups may not be etiologically distinct. Rather, they may represent varying clinical expressions of the same condition over time, in different age groups, or in the context of particular provoking stimuli.

Psychotic Features

Guideline: Psychotic features refer to the presence of delusions or hallucinations. They occur in 15 percent of patients with major depressive disorders. (Strength of Evidence = A.)

In psychotic depressions, psychotic features are never present without concurrent mood symptoms. Psychotic depressions must be distinguished from schizoaffective disorder. In the latter only, there are periods of at least 2 weeks during which delusions or hallucinations are present without mood disturbances.

The content of the hallucinations or delusions in psychotic depressions is usually logically consistent with the predominant sad mood (mood-congruent). For example, there may be a delusion that the patient has sinned in an unforgivable way. Less commonly, the hallucinations or delusions have no obvious relationship to sadness (mood-incongruent); for example, there may be persecutory delusions, for which the person has no explanation. Studies to date suggest that mood-incongruent symptoms are associated with a worse prognosis; evolve into schizophreniform or schizo-affective disorders; involve a less episodic, more chronic course; and require more assiduous, longer maintenance treatment(s). (See Lalive-Aubert and Rush, 1992; Lalive-Aubert and Rush, in press, for reviews.)

The psychotic features of psychotic major depressive disorder usually recur in subsequent episodes, should such episodes occur. Some studies suggest that psychotic depressive episodes are familial (Schatzberg and Rothschild, in press; Weissman and Johnson, 1990).

For psychotic depressions, TCAs plus a neuroleptic or electroconvulsive therapy (ECT) are each superior to TCAs alone in treating the illness (Depression Guideline Panel, forthcoming). Given the markedly disabling nature of psychotic depression, maintenance treatments are strongly indicated when the disorder is recurrent. However, the relative efficacy of maintenance treatment compared to placebo; the value of including both a neuroleptic and an antidepressant in maintenance treatment; and the acute and maintenance phase efficacy of non-TCA medications, lithium, or selected anticonvulsants have not been studied in randomized controlled trials (Schatzberg and Rothschild, 1992).

Melancholic Features

Guideline: The key melancholic features of major depressive disorder are:

• Psychomotor retardation or agitation.

• Loss of interest or pleasure.

• Lack of reactivity to usually pleasant stimuli.

• Worse depression in the morning.

• Early morning awakening.

(Strength of Evidence = A.)

Melancholic symptom features appear to repeat from episode to episode in individuals with recurrent, severe major depressive disorder. They are more commonly present in older depressed patients (see Rush and Weissenburger, in press, for a review). Melancholic features are not uniquely associated with a family history of depression. They are associated with reduced rapid eye movement latency and/or dexamethasone nonsuppression (Rush, Cain, Raese, et al., 1991).

Severely symptomatic patients whose depression has melancholic features are likely to respond to treatment with TCAs or to ECT. Melancholic features do not predict which antidepressants will be effective, though their presence indicates that anxiolytics will not be effective (Depression Guideline Panel, forthcoming). The presence of melancholic symptom features, especially in the severely ill, should sharply increase the practitioner's tendency to treat with antidepressants and should provoke a thorough questioning for the presence of psychotic symptom features. If medications fail, ECT should be strongly considered for these patients.

Atypical Features

The groups studying atypical features define the features differently. Two types, vegetative and anxious, have been proposed in the literature. Vegetative features include:

• Overeating.

• Oversleeping.

• Weight gain.

• A mood that still responds to events (reactive mood).

• Extreme sensitivity to interpersonal rejection.

• A feeling of heaviness in the arms and legs.

Anxious features include:

• Marked anxiety.

• Difficulty in falling asleep.

• Phobic symptoms.

• Symptoms of sympathetic arousal.

Atypical features of either type are associated with a younger age at onset of illness. Whether these symptoms run in families, repeat across episodes, or are associated with an identifiable or unique biology is not known. However, rapid eye movement latency is not characteristically reduced in this type of mood disorder. The relationship between atypical and melancholic symptom features remains to be clarified. Some data suggest that atypical symptoms may be more likely earlier in the course of major depressive disorder, while melancholic features are more likely to appear later.

Several randomized controlled trials indicate that, when atypical features (those in the vegetative group above) are present, monoamine oxidase inhibitors (MAOIs) are more effective than TCAs, although the latter are still more effective than placebo. Case reports and clinical experience suggest that those depressions with atypical features may respond better to selective serotonin reuptake inhibitors (SSRIs) than to TCAs.

Seasonal Pattern

Guideline: DSM-III-R indicates that a seasonal pattern for major depressive disorder can be diagnosed only if:

• Episodes are recurrent (at least two episodes by some criteria, three by other criteria).

• There has been a regular temporal relationship between the onset of the major depressive episodes and a particular period of the year (such as regular onset of depression in fall and offset in spring).

• Seasonal episodes substantially outnumber nonseasonal episodes.

Most often, depressive symptoms remit fully between seasonal episodes. (Strength of Evidence = A.)

The first systematic evidence of the prevalence of seasonal affective disorder was an estimate of 6 percent from a study in the New York area. Subsequently extended to various east coast latitudes, this study showed less than 2 percent prevalence in Florida and nearly 10 percent prevalence in New Hampshire (Rosenthal, Levendosky, Skwerer, et al., 1990; Terman, 1988). There are two to three times as many people personally troubled by the winter recurrence of seasonal mood symptoms than there are those with manifestations severe enough to warrant clinical diagnosis (Kasper, Wehr, Bartko, et al., 1989; Rosen, Targum, Terman, et al., 1990; Terman, Botticelli, Link, et al., 1989).

Preliminary evidence suggests that light therapy is effective in the short-term treatment of outpatients with mild to moderate seasonal major depressive disorder. Further research is required before such a claim can be made for subsyndromal seasonal affective disorder. To date, no hazard has been encountered with short-term light therapy using standard fluorescent lighting apparatus (designed to produce 2,500 to 10,000 lux stimulation and low levels of ultraviolet emission). Exposure extending beyond 2 weeks has not been fully evaluated. Clinical reports suggest that medications may also be effective for some seasonal mood disorders.

Postpartum Onset

Postpartum mood symptoms are divided into three categories, based on severity: blues, psychosis, and depression (Kendell, 1985; for a review, see Purdy and Frank, in press). Postpartum blues are brief episodes (1 to 4 days) of labile mood/tearfulness that normally occur in 50 to 80 percent of women within 1 to 5 days of delivery. Treatment consists of reassurance and time to resolve this normal response.

Postpartum psychoses can be divided into depressed and manic types. Patients with the depressed type show more psychotic, disoriented, agitated, and emotionally labile features, as well as more psychomotor retardation, than do nonpostpartum matched depressed controls (Dean and Kendell, 1981). Most of these cases are associated with signs of organic impairment. Features of the manic type are similar to features of a classic mania. The incidence of postpartum psychosis is low (0.5 to 2.0 per 1,000 deliveries), as shown in eight studies (Grundy and Roberts, 1975; Hemphill, 1952; Kendell, Rennie, Clarke, et al., 1981; Meltzer and Kumar, 1985; Nott, 1982; Paffenbarger, 1964; Paffenbarger and McCabe, 1966; Paffenbarger, Steinmetz, Pooler, et al., 1961). Many early cases were mistaken for toxic/infectious states.

The symptoms of postpartum psychosis develop rapidly (over 24 to 72 hours), typically beginning 2 to 3 days after delivery. The period of risk for developing postpartum psychosis is within the first month following delivery. For acute postpartum psychosis, the prognosis is generally good. However, many patients have previously had or subsequently develop a bipolar disorder. The risk of postpartum psychosis is higher for those with episodes at prior deliveries. The recurrence rate is from 33 to 51 percent.

Nonpsychotic postpartum depressions (major or minor depressive disorders) have also been identified (O'Hara, Neunaber, and Zekoski, 1984). These conditions may occur from 2 weeks to 12 months postpartum, but typically occur within 6 months. The prevalence of nonpsychotic depressions is 10 to 15 percent within the first 3 to 6 months after childbirth, which is somewhat higher than are the rates (5 to 7 percent) in nonchildbearing matched controls. However, the risk for nonpsychotic postpartum depression is higher for persons with a psychiatric history.

No randomized controlled treatment trials for any of the postpartum mood conditions are available. Logic and clinical experience suggest that prophylactic lithium be given as soon as possible after delivery to prevent a postpartum precipitation in patients with a history of bipolar disorder. Likewise, given the high likelihood of recurrence, other previously effective psychotropic medications should be considered in those with a history of psychotic postpartum mood episodes immediately after giving birth.

Dysthymic Disorder

Clinical Features and Course

Guideline: The essential feature of dysthymic disorder is a chronic mood disturbance (sadness in adults; sadness and, possibly, irritability in children and adolescents) present most of the time for at least 2 consecutive years (1 year for children and adolescents). (Strength of Evidence = A.)

Table 4. DSM-III-R criteria for dysthymic disorder

Table 4. DSM-III-R criteria for dysthymic disorder

A. Depressed mood for most of the day, more days than not, for at least 2 years B. While depressed, presence of at least two of the following: Poor appetite/overeating. Insomnia/hypersomnia. Low energy/fatigue. Low self-esteem. Poor concentration or difficulty making decisions. Feelings of hopelessness. C. During a 2-year period of the disturbance, never without the symptoms in A and B for more than 2 months at a time. D. No evidence of a major depressive episode during the first 2 years. E. Never had a manic or hypomanic episode. F. Not superimposed on a chronic psychotic disorder, such as schizophrenia or delusional disorder. G. Cannot be established that an organic factor initiated and maintained the disturbance.

Source: American Psychiatric Association, 1987.

Patients with dysthymic disorder exhibit at least two of the associated symptoms noted in Table 4. The associated features of dysthymic disorder are similar to those of major depressive disorder, except that, by definition, delusions or hallucinations are absent. Dysthymic disorder usually begins in childhood or adolescence without a clear onset and with a chronic course.

Differentiation between dysthymic disorder and major depressive disorder can be difficult. Their symptoms are similar, differing only in duration and severity. Individuals who initially present with dysthymic disorder frequently go on to develop concurrent major depressive disorder. Some develop hypomanic episodes, a situation requiring a revised diagnosis of either bipolar disorder not otherwise specified or bipolar II disorder. If the onset of an apparent dysthymic disorder directly follows a major depressive episode, the correct diagnosis is major depressive disorder in partial remission. By definition, dysthymic disorder cannot follow an episode of major depressive disorder unless the major depressive episode has been in full remission for at least 6 months before the onset of the dysthymic condition. When a major depressive episode immediately follows a preexisting dysthymic disorder that has been present for at least 2 years, the diagnosis is concurrent major depressive disorder and dysthymic disorder.

Dysthymic disorders may be primary (i.e., unrelated to other preexisting disorders), or they may accompany coexisting nonmood psychiatric disorders or other nonpsychiatric medical conditions. In the latter case, they are called secondary dysthymic disorders. The presence of dysthymic disorder with no prior episodes of major depressive disorder should cue the practitioner to search for other nonmood psychiatric disorders, such as substance or alcohol abuse. The reanalysis of the ECA Study data showed that, in patients with dysthymic disorder (with and without major depressive disorder) who were reexamined 1 year later, 7 to 26 percent still had dysthymic disorder, 4 to 10 percent had major depressive disorder, 5 to 20 percent had both, 11 to 23 percent had DNOS, and 41 to 52 percent were well (Johnson and Weissman, unpublished manuscript).

Depression Not Otherwise Specified

Bipolar Disorders

Clinical Features and Course

Guideline: Bipolar disorders classically feature episodes of major depression interspersed with episodes of mania and/or hypomania. (Strength of Evidence = A.)

Table 5. DSM-III-R criteria for a manic episode

Table 5. DSM-III-R criteria for a manic episode

A. A discrete period of abnormal, persistently elevated, expansive, or irritable mood. B. At least three of the following in the same period: Inflated self-esteem/grandiosity. Marked decrease in need for sleep. Much more talkative (pressured speech) than usual. Flight of ideas (rapidly racing thoughts). Marked distractibility. Increased goal-directed activity/psychomotor agitation. Excessive involvement in pleasurable activities without regard for negative consequences (e.g., unrestrained buying sprees, sexual indiscretions, foolish business ventures). Symptoms severe enough to impair function markedly or require hospitalization to prevent harm to self or others. Not caused by schizophrenia, schizoaffective disorder, or substance abuse.

Source: American Psychiatric Association, 1987.

The major depressive episodes of bipolar disorder meet the criteria outlined in Table 1. Manic episodes are distinct periods of persistently elevated, abnormally expansive, or irritable mood associated with at least three of the symptoms noted in Table 5. About 3 percent of all bipolar disorder patients experience only manic episodes (so-called unipolar mania).

Delusions or hallucinations are sometimes present in manic episodes. Their content is usually consistent with the predominant mood (mood-congruent). For example, a patient may hear "God's voice" explaining that the patient has a special mission or special powers. Delusions may be based on the idea that the person is being persecuted because of some special relationship or attribute. Less commonly, hallucinations or delusions have no apparent content relationship to the expansive/irritable mood (mood-incongruent). Disorders with mood-incongruent psychotic features in the manic episode appear to have a poorer prognosis.

Although they are similar to manic episodes, hypomanic episodes are milder. They are usually brief periods (4 days to several weeks) in which patients are often mildly dysfunctional. Sometimes, they actually feel very well and are creative, but others see them as different from their normal selves. By definition, psychotic symptoms are never present in hypomanic episodes. Patients often do not recall hypomanic periods as times of illness, though others recognize the disturbance. Persons with bipolar I disorder may have hypomanic episodes as well as manic episodes.

In the course of classic bipolar disorder (so-called bipolar I disorder) manic, depressive, and/or mixed manic episodes may occur. (Mixed manic episodes refer to the simultaneous presence of both depressive and manic symptoms in the same episode within the same 24- to 48-hour period.) In bipolar I disorder, manic and depressive episodes are equally frequent. Mixed manic episodes occur in one-third of patients with bipolar I disorder, but these episodes represent only 6 percent of all episodes.

The mean age at onset of bipolar disorder is in the early 20s, and the decade for highest risk of onset is 20 to 29 years of age. The sexes do not differ in age at onset. Men are more likely to have initial manic episodes, while women are more likely to experience initial depressive episodes.

The mean duration of untreated manic episodes is 6 months; the mean duration of untreated major depressive episodes is approximately 8 to 10 months. The depressive episodes immediately precede and/or follow manic episodes in more than half of cases. The total number of episodes of illness experienced by a patient with bipolar disorder during a lifetime is variable. On the average, the episode risk is 0.3 to 0.4 episodes each year.

The time between episodes decreases with subsequent episodes. For individuals, the temporal pattern of episodes tends to repeat itself. Therefore, the future course of illness is best predicted by the individual's prior course. There is usually a full recovery between episodes, although roughly 25 percent have less than full recovery.

The morbidity and mortality associated with bipolar I disorder are high. Suicides, "accidental deaths," and intercurrent illnesses contribute to an excessive mortality rate. Ten to 15 percent of untreated patients commit suicide, which is 15 to 20 times the suicide rate in the general population (1 percent over a lifetime of 70 years). Women with bipolar disorder are much more likely than are men to attempt suicide; men are more likely to complete suicide. A large study found that prior to the availability of effective treatment, 23 percent of 4,341 patients with a manic episode admitted between 1912 and 1932 died in the hospital, 60 percent from "exhaustion" (Derby, 1933).

Patients with bipolar disorder experience considerable impairment in social and occupational functioning. While manic, they often need to be protected from the consequences of their poor judgment and overactivity, which often results in involuntary hospitalization. Over time, even with periods of remission, the chronicity and unpredictability of the disorder lead to secondary problems, such as joblessness, legal difficulties, divorce, and death by suicide, as well as medical morbidity.

Mood Disorders in Special Age Populations

Alcohol/Drug Abuse or Dependency

The following conclusions are tentatively applicable to primary care settings since no data were found on depression in alcoholic patients seen in primary care settings or in alcoholics self-referred to self-help groups such as Alcoholics Anonymous. Most studies are of patients seen in psychiatric settings, who may be more likely to have other psychiatric problems in addition to alcoholism. Furthermore, the diagnostic criteria for alcoholism have become more inclusive over the last 15 years.

Nine studies have examined the extent to which patients with primary depression develop alcoholism (Deykin, Levy, and Wells, 1987; Hasin, Grant, and Endicott, 1988; Lewis, Helzer, Cloninger, et al., 1982; Powell, Read, Penick, et al., 1987; Robins, Gentry, Munoz, et al., 1977; Schuckit, 1983, 1985; Winokur, Reich, Rimmer, et al., 1970; Woodruff, Guze, Clayton, et al., 1973). Most revealed that alcoholism is rarely a consequence of depression; it occurs in less than 5 percent of patients. Overall, the prevalence of alcoholism in patients with primary depression is probably no higher than in the general population.

On the other hand, most studies have found that alcoholics do become depressed over time. Of the 24 studies reviewed, most found that between 10 and 30 percent of patients with alcoholism also suffered from depression at the time of evaluation (see Petty, 1992, and Depression Guideline Panel, forthcoming).

The ECA Study found the prevalence of alcoholism to be approximately 5 percent (Helzer and Pryzbeck, 1988). This study also found the odds ratio for the coexistence of depression and alcoholism to be 1.7. That is, persons in the community who met the diagnostic criteria for alcoholism were nearly twice as likely as those without alcoholism to meet the criteria for major depressive disorder.

Based on the ECA data reanalysis commissioned by the panel, 10 percent of those with major depressive disorder and a concurrent psychiatric condition (n = 31) had alcohol abuse as the second condition. For those with dysthymic disorder complicated by another psychiatric condition (n = 46), 30 percent abused alcohol. For those with DNOS and another psychiatric condition (n = 167), 67 percent abused alcohol. Thus, practitioners should always inquire about co-morbid alcohol and drug abuse or withdrawal in those with mood syndromes and symptoms.

The idea that depressed patients self-medicate with alcohol and, therefore, become alcoholic seems untrue for men, but may be true for some women. The few studies (Depression Guideline Panel, forthcoming) that focused specifically on women suggest that women alcoholics (perhaps as many as one in four) may be more likely to have had a preexisting mood disorder. They may also be more likely to develop depression as a consequence of prolonged heavy drinking, perhaps twice as often as their male alcoholic counterparts. Women reared by alcoholic fathers appear to be at greater risk for depression (Goodwin, Schulsinger, Knopf, et al., 1977).

Although family studies have provided strong evidence that alcoholism and major depressive disorder are independently transmitted, a family history of depression and alcoholism may be associated with a poorer prognosis for the alcoholism. However, there is no evidence for familial aggregation between alcoholism and depression. Adoption studies confirm the independent transmission of depression and alcoholism. Goodwin and colleagues (Goodwin, Schulsinger, Hermansen, et al., 1973; Goodwin, Schulsinger, Knopf, et al., 1977) found an increased incidence of alcoholism in both the adopted sons and daughters of alcohol abusers, but no increase in the incidence of depression. They also found that daughters of alcoholics reared by their biologic parents were more likely to experience depression as adults. This suggests that the environment can contribute to the development of depression, particularly in women. Two studies suggest an important additive interaction between alcoholism and depression (von Knorring, Bohman, von Knorring, et al., 1985; Zisook and Schuckit, 1987). It may be that the familial contribution of mood disorder to alcoholism indicates a poorer prognosis for the alcoholism.

The clinical course of depression with alcoholism has not been extensively studied. Available data from four studies suggest that most patients admitted to alcoholism treatment programs who also have clinical depression experience spontaneous remission of their depressive symptoms during the first 2 to 4 weeks of sobriety (Brown and Schuckit, 1988; Dorus, Kennedy, Gibbons, et al., 1987; Schuckit, 1983, in press; Willenbring, 1986). Depressive symptoms and syndromes seen in very recently detoxified alcoholics likely reflect the toxic effects of alcohol consumption.

The longer term course of illness for depression with alcoholism is more difficult to assess. Two studies that followed patients for more than a year determined that the existence of depression and alcoholism at initial assessment predicted a poorer outcome for the alcoholism, at least in men, 1 year later (Loosen, Dew, and Prange, 1990; Rounsaville, Dolinsky, Babor, et al., 1987). One 2-year followup study found no difference in alcoholic symptoms in patients with major depressive disorder plus alcoholism versus those with alcoholism alone at initial assessment (O'Sullivan, Rynne, Miller, et al., 1988). No lengthier followup studies are available.

For logistical reasons, the panel did not formally review the area of depression with drug abuse or dependency. However, depressive symptoms or major depressive episodes can occur concurrently with drug abuse. Intoxication with brain depressants is known to cause dysphoric mood and even suicidal ideation. Withdrawal from stimulants, such as cocaine or amphetamines, produces sadness, insomnia, apathy, and other depressive symptoms. The course and response to treatment of depressive disorders in patients who abuse drugs may differ from those of depressive disorders in patients who do not have substance dependency. In the ECA data reanalysis, drug abuse was the second condition in 19 percent of the 31 individuals with major depressive disorder and another psychiatric condition, in 30 percent of the 46 with dysthymic disorder and another condition, and in 26 percent of the 167 with DNOS and another psychiatric condition. Substance abuse is common in those with depressive syndromes and symptoms.

Anxiety Disorders

Concurrent panic disorder is present in 10 to 20 percent of patients with major depressive disorder seen in ambulatory treatment settings. In possibly half of these, the panic disorder preceded the major depressive disorder. About 30 percent of outpatients with major depressive disorder may also have met the criteria for generalized anxiety disorder sometime during the course of their illness. In about half of these, the generalized anxiety disorder preceded the major depressive disorder.

Four community studies (Angst and Dobler-Mikola, 1985; Boyd, Burke, Gruenberg, et al., 1984; Hecht, von Zerssen, and Wittchen, 1990; Vollrath, Koch, and Angst, 1990) and one conducted in a primary care setting (Katon, Vitaliano, Russo, et al., 1986) have reported current co-morbidity of anxiety and mood disorders using DSM-III or DSM-III-R. In the ECA data reanalysis (Johnson and Weissman, unpublished manuscript), panic disorder was found in 19 percent of the 31 people with major depressive disorder and another psychiatric condition, in 7 percent of the 46 people with dysthymic disorder and another condition, and in 21 percent of the 167 people with DNOS and another psychiatric condition.

Most longitudinal studies of patients with anxiety disorders have found an increased incidence of depressive disorders over time. In one study, 91 percent of patients with agoraphobia developed a mood disorder over the 3-year followup (Munjack and Moss, 1981). Eighty-four percent of these patients had a family history of probable mood disorder. One study found that two-thirds of a group with agoraphobia or panic disorder developed major depressive disorder, 85 percent of which was of the melancholic type (Breier, Charney, and Heninger, 1985). Approximately half of those who developed major depressive disorder had experienced at least one prior major depressive episode that was separate from the onset of panic attacks. In a comparative family study of individuals with panic disorder with agoraphobia, limited phobic avoidance, or social phobia, a significantly higher percentage of agoraphobic patients had family histories of mood disorders compared to those with limited and social phobias (Munjack and Moss, 1981).

Available data are consistent with the idea that many persons with concurrent major depressive disorder and panic, social phobic, or generalized anxiety disorders may actually have only a single disorder that presents with both anxiety and depressive symptoms. The decision about which disorder to treat may in some cases be determined by one of the following:

• The patient's family history.

• The symptom complex that began first in this episode of illness.

• The symptom complex that is currently most incapacitating.

Given that followup studies of those with panic or other anxiety disorders reveal that many will subsequently develop major depressive disorder and that they often have had a prior major depressive disorder or have a family history of major depressive disorder, the depression is the appropriate main target of treatment in many cases. Sometimes, however, only a treatment trial and observation will answer this complex diagnostic question.

Whichever disorder is primary, the data are clear that the combination of panic and major depressive disorders results in a more severe disorder with greater impairment than does either disorder alone. For example, depressed patients with associated panic attacks have a more severe depressive illness and are less likely to recover during a 2-year followup than are those without panic attacks (Coryell, Endicott, Andreasen, et al., 1988). The lifetime suicide attempt rate for persons with both panic and major depressive disorders is more than twice that of those with panic disorder, but without major depressive disorder (19.5 versus 7.0 per 100) (Johnson, Weissman, and Klerman, 1990). In two separate studies, panic disorder and primary major depressive disorder were each associated with high suicide rates (Coryell, Noyes, and Clancy, 1982, 1983). These data strongly suggest the importance of inquiring about, and even expecting to find, a concurrent mood disorder (especially major depressive disorder) in patients with anxiety complaints. If an individual presents with both conditions and if they are equally impairing, the practitioner should consider treatment with medications for which efficacy has been demonstrated for both conditions. These include MAOIs, SSRIs, TCAs, or in selected cases alprazolam.

Eating Disorders

The eating disorders include anorexia nervosa and bulimia nervosa (American Psychiatric Association, 1987). Anorexia is a refusal to maintain body weight over a minimal normal weight, accompanied by intense fear of becoming fat, disturbance in body image, and amenorrhea. Anorexia occurs in 0.2 to 0.8 percent of adolescent girls in school cohort studies and in 0.05 to 0.1 percent of adults in community samples (Robins, Helzer, Weissman, et al., 1984).

Bulimia is characterized by recurrent episodes of rapid consumption of large amounts of food, accompanied by a feeling of loss of control; regular use of vomiting, laxatives, or other means to attempt to control weight; and overconcern with body shape and weight. The prevalence of bulimia is approximately 1 percent among adolescent and young adult women. Prevalence rates of 1.8 to 1.9 percent have been found in populations at family planning clinics, and rates ranging from 1 to 22 percent have been found in primary care settings.

No large studies of the prevalence of eating disorders among patients with major depressive disorder have been conducted. On the other hand, it is well established that one-third to one-half of patients with eating disorders (either anorexia or bulimia) suffer concurrently from a major depressive syndrome. Approximately 50 to 75 percent of eating disorder patients have a lifetime history of major depressive disorder. Dysthymic disorder and DNOS occur less frequently among patients with eating disorders by most reports.

Assuming a 1 percent prevalence of eating disorders and an 8 percent prevalence of major depressive disorder, and assuming that one-half of eating disorder patients also suffer from concurrent major depressive disorder, the likelihood of an eating disorder may be as high as 1/16 (6 percent) in women between the ages of 15 and 35 who suffer from a major depressive disorder.

Patients with undernutrition from various etiologies often exhibit depressive symptoms, including depressed mood, irritability, poor concentration, indecisiveness, loss of sexual interest, and sleep disturbance, all of which usually improve with weight gain. Thus, when significant depressive symptoms are found with anorexia nervosa, treatment is first aimed at the eating disorder. If mood symptoms persist after the malnourished state has been reversed, treatment is as for a primary mood disorder. A number of studies indicate that some antidepressant medications (e.g., imipramine, desipramine, fluoxetine, MAOIs) and formal cognitive behavioral psychotherapies may help treat the bulimia with or without associated depressive symptoms. (For examples, see Hughes, Wells, Cunningham, et al., 1986; Mitchell and Groat, 1984; Pope, Hudson, Jonas, et al., 1983; Walsh, Stewart, Wright, et al., 1982.) Such treatments, if successful, usually result in remission of the depressive symptoms.

Obsessive-Compulsive Disorders

The ECA survey revealed some overlap between OCD, major depressive disorder, and schizophrenic disorder. Most studies agree that the lifetime occurrence of depressive symptoms is high (80 to 100 percent) among OCD patients, even though only about 10 to 30 percent of them meet the criteria for major depressive disorder at the time of admission to study. The major depressive disorder usually follows the onset of OCD, while schizophreniform symptoms are equally likely to precede or to follow OCD onset. A review of 13 followup studies found that OCD patients were at increased risk for major depressive disorder, but not for schizophrenia (Goodwin and Jamison, 1990). Whether currently or ever depressed, OCD patients are likely to have a family history of depression.

The ECA data reanalysis showed that OCD is relatively common among those with a mood disorder complicated by the presence of another psychiatric condition (Johnson and Weissman, unpublished manuscript). Specifically, OCD was found in 35 percent of the 31 subjects with major depressive disorder, in 15 percent of the 46 with dysthymic disorder, and in 40 percent of the 167 with DNOS, when the mood disorder was associated with another psychiatric condition.

The practitioner must differentiate severe depression, which may present with obsessive features, from true OCD. Severely depressed patients have recurrent ruminations, but rarely have compulsions. The content of their ruminations is usually consistent with a negative sad mood (e.g., guilty preoccupations). These patients often do not meet the formal criteria for OCD and often have had prior episodes of severe depression. The onset of these obsessive symptoms in the severely depressed occurs at the same time as the onset of the major depressive episode.

Somatization Disorder

Somatization may well be the main reason for the misdiagnosis of mental illness by primary care physicians (Bridges and Goldberg, 1985). In primary care settings, many depressed and nondepressed patients present with medically unexplained symptoms. Most patients with such complaints do not meet the formal criteria for somatization disorder, which in DSM-III-R require the presence of 13 or more medically unexplained symptoms. Most patients with diffuse unexplained somatic symptoms in primary care and community samples either have a treatable psychiatric illness (e.g., anxiety or depressive disorders) or are responding to stressful life events. Accurate differential diagnosis and treatment of the acute psychiatric illness often decrease the tendency toward somatization.

Twelve studies of a total of 976 primary care and medical specialty (e.g., gynecology) patients with clinically significant depressive symptoms revealed that 30 to 87 percent also had clinically significant pain complaints (Fishbain, Goldberg, Meagher, et al., 1986; Haley, Turner, and Romano, 1985; Katon, 1988; Katon, Ries, and Kleinman, 1984; Kramlinger, Swanson, and Maruta, 1983; Large, 1986; Lindsay and Wyckoff, 1981; Maruta, Vatterott, and McHardy, 1989; Schaffer, Donlon, and Bittle, 1980; Turner and Romano, 1984; Walker and Greene, 1989; Walker, Katon, Harrop-Griffiths, et al., 1988). A highly significant 30 to 50 percent met the formal criteria for major depressive disorder. Two additional studies found that 50 to 70 percent of primary care patients with psychiatric illness (mainly mood disorders) presented with somatic complaints (Katon, 1987; Katon, Kleinman, and Rosen, 1982).

Conversely, pain symptoms occurred in approximately 60 percent of patients with major depressive disorder in three studies with 403 primary care and medical specialty patients, in which pain was documented by self-report (Lindsay and Wyckoff, 1981; Magni, Schifano, and de Leo, 1985; von Knorring, Perris, Eisemann, et al., 1983). Major depressive disorder patients had significantly more symptoms on a medical review of symptoms, even when the investigators controlled for chronic medical illness. In a study using a 1,000-patient sample from a health maintenance organization, patients with one pain complaint were no more depressed than were controls (Dworkin, von Korff, and LeResche, 1990). However, patients with two pain complaints were six times more likely, and patients with three pain complaints were eight times more likely, to have a clinical depression. The Medical Outcomes Study also showed that patients with major depressive disorder perceived their general health as poorer; had more limitations in physical, social, and vocational functioning; and had more pain complaints than did persons with chronic medical illnesses (Wells, Stewart, Hays, et al., 1989).

The majority of patients with major depressive disorder, DNOS, or dysthymic disorder have some pain symptoms. The most common complaints in such patients are joint pain, headaches, backaches, and abdominal pain. Treatment of major depressive disorder with somatic complaints usually results in complete relief of the pain complaints.

Personality Disorders

Studies of depressed patients using structured interviews indicate prevalences of personality disorders ranging from 35 percent in psychiatric outpatients to 72 percent in psychiatric inpatients. Most studies report rates of 45 to 65 percent. However, most of these studies were conducted in specialized research centers, which may attract a greater proportion of mood-disordered patients who also have personality disorders.

The DSM-III-R personality disorders are grouped into three clusters:

• Cluster A (odd/eccentric) paranoid, schizoid, and schizotypal disorders.

• Cluster B (dramatic/emotional/erratic) antisocial, borderline, histrionic, and narcissistic disorders.

• Cluster C (anxious/fearful) avoidant, dependent, obsessive-compulsive, and passive-aggressive disorders.

The presence of these personality disorders may negatively affect the natural course and treatment response of mood disorders. Five studies have examined patients with concurrent major depressive disorder and a personality disorder (Black, Bell, Hulbert, et al., 1988; Charney, Nelson, and Quinlan, 1981; Ionescu and Popescu, 1989; Pfohl, Stangl, and Zimmerman, 1984; Shea, Glass, Pilkonis, et al., 1987). Those with personality diagnoses had an earlier age of onset for their first depressive episode, more severe depressive symptoms, more frequent episodes, longer depressive episodes, poorer short-term recovery with both antidepressant medications and psychotherapy, and more residual symptomatology at later followup. A concurrent personality disorder diagnosis is associated with a more complicated, disturbed social history, especially in patients with Cluster A or B personality disorders. When depression is complicated by personality disorder, most studies find increased rates of suicide attempts and self-harm.

The generally negative effect of personality disorders on the outcome of depression seems largely accounted for by Cluster B, or borderline personality disorder specifically. Depressed patients with co-morbid borderline personality disorder had poorer social outcomes and higher levels of residual symptomatology at both 4- and 7-year followups (Pope, Jonas, Hudson, et al., 1983). Borderline personality disorder seems highly prevalent among depressed psychiatric patients; a sample drawn from a general psychiatric population yielded an estimate of 6 percent. The estimated community prevalence of borderline personality disorder is 0.2 percent (Weissman and Myers, 1980). One study of people who were not psychiatric patients found a 1.6 percent prevalence of borderline personality disorder, but this population included a large sample of first-degree relatives of psychiatric inpatients (Zimmerman and Coryell, 1989). There are insufficient studies of the incidence of personality disorders in primary care settings to make prevalence estimates.

Grief and Adjustment Reactions

Grief reactions are equally common in women and men. Over the course of the first year of bereavement, Clayton (1974) found that 35 percent of 109 widows and widowers met the criteria for a major depressive episode at 1 month, 25 percent at 7 months, 17 percent at 13 months, and 46 percent were depressed some time during the first year following the loss of a spouse.

Zisook and Shuchter (1991) studied 350 widows and widowers 2 and 13 months after their spouses' deaths. Twenty-four percent met the DSM-III-R criteria for a major depressive episode at 2 months. Since the deaths had occurred only recently, the condition of these subjects was diagnosed as uncomplicated bereavement rather than major depressive disorder. Those meeting the criteria for major depressive disorder early in the period of grief were more likely to have personal or family histories of major depressive episodes (not in response to the death of a loved one), current treatment with antidepressant medications, suicidal ideation, poor health, and poor current job satisfaction. Most important, they were likely to be in a major depressive episode 1 year following the loss. Given the anticipated prolonged suffering and disability, it is logical to consider treating these patients for the major depressive disorder, though randomized controlled trials of any treatment are lacking in this population.

A distinct, but poorly studied, segment of primary care patients present serious mood symptoms thought to require clinical management, though they do not fulfill the criteria for major depressive or dysthymic disorders. DSM-III-R classifies such "subthreshold" pathology as either DNOS or an adjustment disorder with depressed mood. Little is known of the presenting symptoms, clinical course, or outcome of an adjustment disorder with depressed mood. However, the clinical utility of the diagnosis is that it allows practitioners to identify mildly distressed patients, some of whom may need followup to determine whether the symptoms remit or whether they evolve into a formal mood syndrome. If such patients develop a major depressive or dysthymic disorder, treatment should be as for the primary mood disorder. There are no randomized controlled trials of treatment for adjustment disorder with depressed mood, but it is logical to consider treatment with psychotherapy or medication for those with substantial pain, suffering, incapacity, or chronicity.

Stroke

The association between cerebral infarction and depression has long been recognized. However, systematic studies (Depression Guideline Panel, forthcoming) have found only a weak relationship between depression severity and physical/cognitive impairment following stroke. Case reports (Ross and Rush, 1981) indicate that post-stroke patients who are also depressed, especially those with major depressive disorder, are less compliant with treatment, are more irritable and demanding, and have an apparent personality change.

Six prospective evaluations of depressive symptoms/syndromes using various criteria revealed the prevalence of major depressive disorder to be between 10 and 27 percent in post-stroke patients, with an additional 15 to 40 percent showing less severe forms of illness within 2 months of the stroke (Eastwood, Rifat, Nobbs, et al., 1989; Ebrahim, Barer, and Nouri, 1987; House, Dennis, Magridge, et al., 1991; Morris, Robinson, and Raphael, 1990; Robinson, Starr, Kubos, et al., 1983; Wade, Leigh-Smith, and Heuer, 1987). In the four studies using DSM-III criteria (total n = 378), the same approximate prevalence rates for major depressive disorder and DNOS were found as in those studies not using such criteria (Eastwood, Rifat, Nobbs, et al., 1989; House, Dennis, Magridge, et al., 1991; Morris, Robinson, and Raphael, 1990; Robinson, Starr, Kubos, et al., 1983).

Two studies have prospectively examined the longitudinal course of depression following stroke (Morris, Robinson, and Raphael, 1990; Robinson, Bolduc, and Price, 1987). Both found the mean duration of major depressive disorder to be just under 1 year. The course of DNOS is more variable and may be either short (2 to 3 months) or prolonged (more than 2 years).

Dementia

Distinguishing depressive disorders from early dementing disorders (from known or unknown causes) is a complex clinical problem. Apathy, impaired concentration, or memory loss may occur in primary major depressive episodes in the elderly, as well as early in the course of dementing disorders with or without depression. The term pseudodementia refers to the clinical presentation of cognitive impairment due to depression in the elderly. The co-occurrence of depression and dementia is by far the more frequent clinical problem. In some patients with symptoms of both depression and dementia, a personal or family history of depression suggests a depressive condition as the primary diagnosis.

If treatment for the depression succeeds and is associated with disappearance of the "dementing" symptoms, the appropriate diagnosis is major depressive disorder without dementia. If the symptoms of dementia persist, the appropriate diagnosis is dementia and major depressive disorder.

Parkinson's disease is associated with mild dementia in approximately 38 percent of patients, while 46 percent suffer severe dementia in the end stages of the disease. Approximately 50 percent of Parkinson's patients with dementing symptoms have major depressive disorder sometime during the course of the illness. Unlike primary degenerative dementia, Parkinson's dementia is considered a subcortical dementia; it is associated with physiologic changes in the subcortical regions (substantia nigra and globus pallidus). In those with subcortical dementia (e.g., patients with Parkinson's or Huntington's disease), cognitive symptoms appear to improve with improvement of mood, so assessment for and treatment of the depression may be particularly helpful to these patients (Blazer, 1993).

Approximately 30 to 40 percent of Alzheimer's disease patients demonstrate formal depressive mood syndromes and/or psychotic symptoms sometime during their illness. The exact relationship between the two disorders is not clear. The earlier or concurrent presence of depression does not alter either the progression of dementia per se or its neuropsychological features. Some suggest that depression may occur during the early stages of dementia and that treatment of the depression may reduce some of the cognitive difficulties. However, long-term followup shows that many older patients presenting with both depression and cognitive difficulties go on to develop primary degenerative dementia without depressive features (Blazer, 1993).

Diabetes

A variety of metabolic and endocrinologic diseases (e.g., vitamin B12 deficiency; thyroid, parathyroid, and renal diseases) are associated with depressive symptoms/syndromes. The following discussion of diabetes illustrates one such condition.

Numerous recent studies that have estimated the prevalence of depression in treated samples of diabetic adults suggest that major depressive syndrome is approximately three times more common in patients with diabetes than in the general population (Biglan, Toobert, Farmer, et al., unpublished manuscript; Fris and Nanjundappa, 1986; Geringer, Perlmuter, Stern, et al., 1986; Lustman, Griffith, Clouse, et al., 1986; Montague, Eaton, Larson, et al., 1990; Popkin, Callies, Lentz, et al., 1988; Robinson, Fuller, and Edmeades, 1988; Slawson, Flynn, and Kollar, 1963; Wing, Marcus, Blair, et al., 1990). The prevalence of major depression in patients with insulin-dependent diabetes mellitus (IDDM) is similar to that in patients with non-insulin-dependent diabetes mellitus (NIDDM).

General population surveys (i.e., nontreated samples) indicate that the prevalence of depression is elevated in persons with diabetes, compared to those without a chronic medical condition. The sex-and age-adjusted prevalence of lifetime depression was significantly higher in patients with diabetes than in patients without a chronic illness (14.4 and 6.9 percent, respectively) (Wells, Golding, and Burnam, 1989). The excess prevalence of depression in diabetics suggests either an etiologic relationship or a higher detection rate secondary to increased contact with the health care system in patients with co-morbid diabetes and depression. The mean age of onset of depression was 22.1 years in patients with IDDM and 28.6 years in patients with NIDDM. In patients with NIDDM, the onset of depression occurred significantly earlier than did the onset of diabetes (Lustman, Griffith, and Clouse, 1988). A family history of depression was also significantly more common in diabetic patients with depression (35 percent) than in those without depression (3 percent). Depression in association with diabetes is a female-preponderant illness, as it is in general.

Depressions are recognized and treated in fewer than one-third of diabetic patients. Diabetes per se is not associated with sufficient depressive symptoms to impair clinical recognition of depression in diabetes. The symptom of weight loss in diabetes is not specific to depression and should not be used to diagnose the presence of depression in diabetic patients.

Only one systematic followup study of depressed diabetic patients is available (Lustman, Griffith, and Clouse, 1988). Eighteen (64 percent) patients had been depressed within the previous 12 months, and 12 met the criteria for a current major depressive episode at the time of reevaluation. By contrast, only 10 percent of a comparison group of diabetic patients without a mood disorder at index evaluation had developed depression by the time of followup. This significant difference suggests that the risk of developing depression is restricted to a predisposed group and is less related to diabetes per se. These modest data suggest that the natural course of major depression in diabetes is chronic and severe, perhaps even more so than in those with major depressive disorder without other general medical illnesses. No randomized controlled studies of the efficacy of pharmacotherapy and/or psychotherapy have been performed in depressed diabetic patients.

Depression in diabetes is associated with poor glucose regulation, probably because of poor adherence. Since poor glucose regulation is associated with increased complications, attention to treatment of depressive symptoms is particularly relevant in management of patients with diabetes. Even without empirical studies, logic argues for treating the major depression in diabetics as a primary mood disorder, once the diabetes is optimally controlled by routine means.

Coronary Artery Disease

The prevalence of various forms of depression in patients who have had a myocardial infarction is estimated at 40 to 65 percent. High prevalence rates have also been found in patients undergoing coronary artery or heart transplant surgery. The prevalence of minor and major depressive disorders combined has been reported to be as high as 40 percent in patients who have coronary heart disease and 45 percent in those who recently experienced a myocardial infarction (Schleifer, Macari-Hinson, Coyle, et al., 1989). The point prevalence of major depressive disorder is 18 to 25 percent for those with a recent myocardial infarction and 18 to 20 percent in those without a history of myocardial infarction, but with angiographically proven coronary artery disease. Most studies have found that depression in these patients is seldom diagnosed or treated.

The ECA survey ascertained that, over 15 months, patients aged 55 and older with mood disorders had a mortality rate four times higher than expected, and that 63 percent of these deaths were from coronary heart disease or stroke. Other studies have also shown higher myocardial infarction rates in depressed patients. Unfortunately, risk factors for coronary artery disease, such as smoking, were not controlled in these studies.

Carney, Rich, Freedland, and colleagues (1988) found that major depressive disorder leads to equal and additive disability in patients with coronary artery disease, perhaps resulting from the effects of depression on amplification of symptoms. Several studies have also linked depression with poor adherence to cardiac treatment regimens (Blumenthal, Williams, Wallace, et al., 1982; Guiry, Conroy, Hickey, et al., 1987). Kellet (1990) speculated that depression may be responsible for the poor compliance and, consequently, for the worse outcomes among noncompliant patients.

Some evidence indicates that major depressive disorder generally runs a chronic course during the first 12 months after an acute infarction. Patients who have never experienced a psychiatric disorder before their myocardial infarction have a shorter duration of symptoms. Major, but not minor, depressions follow a chronic course, suggesting that "minor" forms of depression (officially DNOS) may be better understood as transitory adjustment reactions to the medical illness (Schleifer, Macari-Hinson, Coyle, et al., 1989).

Patients with moderate to severe depression during the weeks following the myocardial infarction are more likely than are nondepressed controls to experience social problems over the first year of recovery. They are also slower to return to work and report more stress than do their nondepressed counterparts. Whether their ultimate life expectancy is shorter is not yet clear.

Cancer

The diagnosis of cancer can be a catastrophic event to which many individuals initially react with shock and denial. This early reaction is often followed by emotional turmoil accompanied by anxiety, depressed mood, poor concentration, and cessation of daily activities. This response is normal. Dysphoria and sadness are parts of this normal reaction. These symptoms usually abate within a week or two with support from caregivers, family, and friends (Massie and Holland, 1990). Patients return to normal adaptation over the ensuing weeks to months.

Physicians must be able to differentiate between this normal reaction and a psychiatric disorder. Considerable evidence indicates that, for patients with cancer, a depressive disorder leads to greater distress; decreased physical, social, and occupational functioning; and decreased ability to adhere to medical recommendations. Therefore, diagnosis and effective management of the depressive disorder in patients with cancer are potentially very important.

Several risk factors predispose cancer patients to develop depressive disorders:

• Social isolation.

• Recent losses.

• A tendency to pessimism.

• Socioeconomic pressures.

• A history of mood disorder.

• Alcohol or substance abuse.

• Previous suicide attempt(s).

• Poorly controlled pain.

The depressed patient with cancer must be assessed for suicidal risk. Suicidal risk factors include:

• A prior psychiatric diagnosis (especially depression).

• Increasing age.

• Family history of suicide.

• Poor social support.

• Delirium.

• Advanced disease.

• Disfiguring disease or surgery.

• Substance abuse.

• Poorly controlled pain.

Many drugs used to treat cancer are associated with depressed mood as a side effect (Lesko, Massie, and Holland, 1987). The practitioner is also advised to consider other concurrent medical conditions, medications, and uncontrolled pain, all of which can contribute to depressed mood, especially in the elderly.

The prevalence of clinical depression in cancer patients ranges from 5 to 50 percent. The most systematic study of psychiatric disorders in ambulatory patients with cancer (200 patients) found that 53 percent were coping well and did not have a formal DSM-III diagnosis (American Psychiatric Association, 1980). Of the remaining 47 percent, 68 percent had an adjustment disorder; 13 percent had major depressive, dysthymic, or bipolar disorder; and 19 percent had organic mental, personality, or anxiety disorders. Adjustment disorders with depressed mood and major mood disorders were the most common psychiatric disorders identified in cancer patients.

The highest rates of clinical depression are in those with advanced cancer and with a greater level of disability and discomfort. One study found that 77 percent of bedridden patients met criteria for major depressive syndrome, compared to only 23 percent of functionally independent patients (Bukberg, Penman, and Holland, 1984).

Most studies suggest that 20 to 25 percent of cancer patients suffer major depression at some point during their illness. These percentages are remarkably similar to the rates of depression associated with other medical illnesses and a similar level of physical functioning. The finding that patients with cancer do not evidence a greater rate of major depression than do those with other medical disorders invalidates the common, but incorrect, assumption that persons with cancer should be depressed an assumption that contributes to underdiagnosis and undertreatment of these depressions.

Chronic Fatigue Syndrome

Only a small minority of patients with complaints of chronic fatigue meet the Centers for Disease Control (CDC) criteria for chronic fatigue syndrome. When the patient meets criteria for major depression, dysthymia, or other formal mood syndromes, the mood syndrome is diagnosed. The complaint of chronic fatigue per se is insufficient for the diagnosis of chronic fatigue syndrome. The symptom of chronic fatigue (not the syndrome) is the seventh most common complaint among adult patients in primary care settings and may be a significant problem in as many as 20 to 25 percent of these patients. Studies of patients with chronic fatigue symptoms reveal lifetime rates of psychiatric disorders in the 50 to 77 percent range, based on structured psychiatric interviews. In all studies, major depressive disorder was the most commonly reported illness (lifetime rates ranging from 46 to 75 percent). These studies also found that various anxiety disorders and somatization disorder occurred in 15 to 40 percent of patients with chronic fatigue symptoms (Hickie, Lloyd, Wakefield, et al., 1990; Kroenke, Wood, Mangelsdorff, et al., 1988; Kruesi, Dale, and Straus, 1989; Manu, Lane, and Matthews, 1988; Manu, Matthews, and Lane, 1988).

Most studies that examined the temporal sequence of chronic fatigue symptoms found a 50 to 90 percent onset rate of psychiatric illness (most commonly, major depressive disorder) prior to the onset of chronic fatigue symptoms (Kruesi, Dale, and Straus, 1989; Manu, Matthews, and Lane, 1988).

While the central feature of chronic fatigue syndrome is persistent, excessive fatiguability, it must be accompanied by various other somatic and psychological symptoms, including aching muscles and joints, headache, sore throat, painful lymph nodes, muscle weakness, sleep disturbance, mental fatigue, difficulty in concentrating, emotional lability, and sadness. In chronic fatigue syndrome, the somatic and fatigue complaints are out of proportion to physical and laboratory findings. According to the CDC criteria, the presence of a diagnosable formal psychiatric disorder, such as major depressive or dysthymic disorder, excludes the diagnosis of chronic fatigue syndrome. That is, patients who present with the formal symptomatic CDC criteria for chronic fatigue syndrome and who also meet the criteria for a formal mood disorder are treated for the mood disorder. Whether this mood disorder is etiologically connected to the chronic fatigue syndrome or whether it is an independent illness is unclear.

Fibromyalgia

Fibromyalgia (fibrositis) is a syndrome of diffuse, aching, musculoskeletal pain associated with chronic insomnia, daytime tiredness, morning stiffness, dysesthesia in the hands, and symptoms of irritable bowel type. The American College of Rheumatology has published the currently accepted criteria for the diagnosis of fibromyalgia (Wolfe, Smythe, Yunus, et al., 1990).

Two studies have compared fibromyalgia and rheumatoid arthritis patients in structured psychiatric interviews. In one, patients with fibromyalgia had significantly higher rates of lifetime major depressive disorder than did rheumatoid arthritis patients (71 versus 14 percent), and they had significantly more first-degree relatives with mood and anxiety disorders (Hudson, Hudson, Pliner, et al., 1985). The second study also found higher rates of mood disorders in patients with fibromyalgia than in those with rheumatoid arthritis (20 versus 8.7 percent). Statistical significance was not attained, probably because of the small sample size (Alfici, Sigal, and Landau, 1989).

Antihypertensives

Various blood pressure medications have been linked to depressive symptomatology, although much of the evidence for the association has been weak or equivocal.

Goodwin and Bunney (1971) found a 5 to 20 percent risk of depression in patients treated with reserpine. Depression was related to the dosage; more severe depressions were reported in patients receiving more than 0.5 mg per day. A history of depression was associated with a higher incidence of depressive symptoms and a higher incidence of severe depression. These data suggest that, if reserpine is used, the dosage should not exceed 0.5 mg per day, and the drug should be avoided in patients with a history of mood disorders.

Beta-adrenergic blocking agents have been associated with depressive symptomatology, with lethargy being the main symptom reported. In one study, depression was found to be no greater, and perhaps less, in the beta-blocker group than in controls (Bartels, Glasser, Wang, et al., 1988). Another study evaluated various beta-blockers at varying dosages (Carney, Rich, teVelde, et al., 1987). The treated group experienced a 21 percent incidence of depression, but the control group of hypertensive patients on other medications had a 33 percent incidence of depression. Bant (1978) compared hypertensive patients on various medications and a control group of medically ill (nonhypertensive) patients. He found a "high" prevalence of depression in both groups, but no preponderance in the hypertensive patients. Hypertensive patients with a personal or family history of psychiatric illness had a higher level of depression. The Veterans Administration Cooperative Study used patient symptom questionnaires and reported only a 1 percent incidence of depression with propranolol, which is consistent with that found in the general population (VA Cooperative Study Group on Hypertensive Agents, 1982). On the other hand, patients with a personal or family history of depression may be prone to develop depression when treated with propranolol. Data are not available to recommend avoiding propranolol in such patients, but the clinician should be alert to the possibility of depressive reactions in patients beginning this treatment. There is no clear-cut contraindication for its use in any particular patient group.

Studies reviewed fail to show a causal relationship between alpha-methyldopa given in typical dosages and depression. While alpha-methyldopa can be used in patients with a history of depression, they appear to be at greater risk for depression while they are taking it.

A review of 44 studies evaluating the use of clonidine for hypertension found a 1.5 percent incidence of depression (Paykel, Fleminger, and Watson, 1982). This finding indicates that clonidine is rarely associated with depression.

The psychiatric side effects of calcium-channel blockers have been reported to include depression. While most of the data are from case reports, some comprehensive, double-blind, crossover studies have evaluated the potential use of verapamil in the treatment of bipolar disorder. Since there are no controlled reports of depressive disorders associated with calcium-channel blockers, they can be used in depressed patients. At present, there is no evidence that angiotensin I converting enzyme (ACE) inhibitors are associated with depression.

Hormones

Glucocorticoids are well known to cause depression or psychosis. Lewis and Smith (1983) found that 5 percent of steroid-treated patients experienced severe psychiatric reactions (mostly mood disorders), which usually occurred early in the course. Risk factors were female gender, a diagnosis of systemic lupus erythematosus, and high doses of prednisone.

The practitioner is advised to monitor patients on steroids carefully for development of mood syndromes (both manic and depressive types). If they occur, treatment with steroid taper and use of neuroleptics or ECT is indicated. Tricyclic antidepressants may be less useful and may be ineffective or actually aggravate symptoms (Hall, Popkin, and Kirkpatrick, 1978). In patients for whom steroids are medically necessary, lithium prophylaxis can be tried (Falk, Mahnke, and Poskanzer, 1979).

Anabolic steroids used for athletic enhancement deserve comment. Pope and Katz (1988) found that 22 percent of young bodybuilders who returned their questionnaires suffered from a full mood syndrome, 12 percent had psychotic symptoms, and 12 percent suffered depression when cycled off the drug. The greatest use of these drugs seems to be among young men and women focused on enhancing their physiques. Practitioners should be aware of these drugs and ask about them in all who present with a mood syndrome.

Case reports of depression associated with the use of oral contraceptives are available, but many of the better documented studies found little relationship. Slap (1981) found that 9 of 12 studies reported some depressive symptoms in 15 to 56 percent of oral contraceptive users. However, many of these studies were not well controlled or did not use standard criteria to define depression. One study found a 6.6 percent incidence of depression in those who used oral contraceptives versus a 2 percent incidence in those who had never used them (Herzberg and Coppen, 1970); a 10 percent incidence rate was found in a followup study (Herzberg, Johnson, and Brown, 1970). These agents are not contraindicated in depressed or formerly depressed patients; however, careful observation is recommended when initiating treatment.

Histamine-2 Receptor Blockers

Multiple case reports have linked histamine-2 receptor blockers (cimetidine and ranitidine) to depressive, manic, and psychotic behaviors. When closely evaluated, however, these cases occur in patients who are otherwise severely ill with multiple system failure or renal or hepatic insufficiency. The panel recommends individualized dosage reduction if the drug is to be used in patients known to have renal or hepatic impairment.

Anticonvulsants

Numerous investigators have evaluated the depressant effects of phenobarbital and carbamazepine. Many, however, do not define depression in standard ways. "Depression" is usually attributed to the generalized psychomotor slowing and sedation noted in association with these drugs. In a carefully documented study of patients on phenobarbital and carbamazepine using depression criteria, 40 percent of 64 patients on anticonvulsant drugs had clinical major depression (34 percent with a family history of mood disorder) (Robertson, Trimble, and Townsend, 1987). Patients on phenobarbital were more depressed than those on carbamazepine. There are no comparative controlled studies.

The panel suggests close monitoring of all patients on phenobarbital for signs of depression, especially those with a known personal or family history of depression. No current data suggest that drug levels predict the risk of depression in these patients, and carbamazepine has actually been an effective prophylactic agent for both depressive and manic episodes in bipolar disorder (Ballenger and Post, 1980).

Levodopa

Another therapeutic agent long associated with mood symptoms is levodopa (L-dopa). Most of the studies reviewed did not use currently accepted criteria for diagnosis of depression and employed variable assessment scales.

In an evaluation of 33 Parkinson's disease patients on various forms of therapy (anticholinergics, amantadine, L-dopa, and L-dopa plus carbidopa), 22 were depressed (12 had a history of mood disorders) and 11 had no mood symptoms (none had a history) (Mindham, Marsden, and Parkes, 1976). There was no general relationship between L-dopa dosage and psychiatric disturbance, though those on L-dopa may have had increased mood symptoms. Given the frequency of depression in untreated Parkinson's disease, the effects of these medications remain unclear. However, there is no clear evidence that L-dopa increases the incidence of depression in these patients when there is no history of depression.

Antibiotics

Mood disorders associated with antibiotics have largely been noted in case reports, without controlled studies. Dapsone has been reported to cause depression and anger. In these cases, symptoms have resolved within days of discontinuing the drug, and the symptoms have recurred on rechallenge. Isoniazid is reported to be related to psychotic syndromes and delirium. Amphotericin B shows a dose-related delirium and electroencephalograph changes when injected intrathecally. By and large, antibiotic use should be based on medical indications rather than on concern about mood disorders.

Antiarrhythmics

Digoxin has been studied only with regard to its toxicity and the related delirium. There are no reports of mood disorders per se related to digoxin. Procainamide has been linked in several case reports to mania.

Clinical Clues

Major depressive disorder is common in primary care outpatients (4 to 8 percent), and nonmajor forms are even more common (6 to 14 percent). Both recognition and diagnosis of depression rest on an awareness of risk factors for depression, as well as elicitation of the key signs, symptoms, and history of illness. The primary risk factors for depression are:

• Prior episodes of depression.

• Family history of depressive disorder.

• Prior suicide attempts.

• Female gender.

• Age of onset under 40.

• Postpartum period.

• Medical co-morbidity.

• Lack of social support.

• Stressful life events.

• Current alcohol or substance abuse.

A variety of clinical clues may further alert the practitioner to the likelihood of a mood disorder.

One major depressive episode is associated with a 50 percent chance of a subsequent episode; two episodes, with a 70 percent chance of a subsequent episode; and three or more episodes, with a 90 percent chance of recurrent depression over a lifetime (NIMH Consensus Development Conference, 1985).

First-degree relatives of bipolar disorder patients are at substantially higher risk for developing either a recurrent major depressive disorder (roughly 12 percent) or bipolar disorder (roughly 12 percent). Strong scientific evidence points to a genetic vulnerability to bipolar disorder. For those with more recurrent forms of major depressive disorder, genetic factors also appear to play a significant role. For those with less recurrent forms of major depressive disorder, the role of genetic factors is unclear. It is known, however, that patients who develop major depressive disorder before age 20 have a greater familial morbidity for depression (Goodwin and Jamison, 1990).

Suicide attempts are frequently associated with mood disorders. In addition, a history of suicidal ideation and/or attempts increases the patient's risk for subsequent suicidal ideation/attempts. Additional risk factors for suicide include:

• Hopelessness.

• Physical illnesses.

• Family history of substance abuse.

• Caucasian race.

• Depression.

• Substance abuse.

• Male gender.

• Advanced age.

• Presence of psychotic symptoms.

• Living alone.

The signs and symptoms of depression can be sought by direct interview, which may be supplemented with self-report ratings and/or by a history obtained from the patient's spouse or a friend. Depressive disorder is diagnosed on the basis of positive evidence -- not by exclusion. For example, patients with or without other general medical conditions either do or do not have a depressive syndrome. Depression should not be explained away or discounted as a commonplace "reaction" to the concurrent general medical condition. Similarly, life events, including losses of important people or key roles, usually precede the onset of major depressive episodes. Thus, the presence of selected untoward life events should not be used to explain away the major mood episode.

Some patients may initially deny the depressed mood, but may identify the somatic symptoms (sleep, appetite, and weight changes). Upon further discussion, the interviewer should return to the issues of mood and interest. Patients may initially complain about sleep, appetite, energy, concentration, and sex drive changes or about chronic or intermittent pain or anxiety. The clinician should be alert to considering the diagnosis of depressive illness in these patients.

If symptoms of depression are present, it is important to determine their time course. How long has the patient been in an episode of major depressive disorder? Were there prior episodes? What degree of interepisode recovery has occurred? How severe are the current symptoms? The more severe forms of depression, characterized by marked suicidal thinking, multiple neurovegetative symptoms, and markedly impaired functioning, argue strongly for the use of medication. A chronic or multiepisode history argues for more prolonged treatment. Symptom severity should be gauged by either clinical interview or rating scales, since severity plays a role in treatment planning (Depression Guideline Panel, forthcoming).

When there is historical, symptomatic, or physiologic evidence to suggest an underlying general medical disorder as the cause of the depression, physical examination and laboratory tests to detect the specific disorder(s) should be used as appropriate in the differential diagnosis. The presence of another medical condition does not exclude the depressive syndrome. In fact, it increases the probability that a depressive syndrome may be present. The depression is either present or absent, based on the patient's signs/symptoms. If the patient has a depression, the first steps in its treatment differ according to whether another general medical condition is present and thought to be causal, whether alcohol or substance abuse is present, and whether another nonmood psychiatric disorder is present and causal.

Screening Instruments

Differential Diagnosis of Depression

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.

   • 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)

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

   • 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.

   • Exclude alternative causes (1 through 4, above) for depressive symptoms or syndromes to diagnose a primary mood disorder.

Table 8. Steps in detecting and treating depressive (more...)

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).[1]

(5) Treat potential causes.

(6) Reevaluate for mood syndromes.

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

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

Depression Guideline Panel Members: Biosketches

• A. John Rush, MD, Chair

• Betty Jo Hay Distinguished Chair in Mental Health Professor and Vice Chairman for Research, Department of Psychiatry

• University of Texas Southwestern Medical Center

• Dallas, Texas

Dr. Rush received his BA from Princeton University and his MD from the College of Physicians and Surgeons of Columbia University.

He is currently the Director of the Mental Health Clinical Research Center, an NIMH-funded center studying the biology, psychology, pharmacology, and psychotherapy of mood disorders. Dr. Rush has published extensively on both the psychology and biology of depression. He has received several NIMH grants to study depression and has helped develop and study the efficacy of cognitive therapy in treatment of depressed outpatients. His research has sought to identify biologic and psychological predictors of specific treatment responses, as well as relapse and recurrence. He serves as the Chair of the DSM-IV Work Group on Mood Disorders for the American Psychiatric Association.

Dr. Rush is a Fellow of the American College of Psychiatry, the American Psychiatric Association, and the American College of Neuropsychopharmacology. He is Past President of the Society for Psychotherapy Research.

• William E. Golden, MD

• Director, General Internal Medicine

• Associate Professor, Department of Medicine

• University of Arkansas for Medical Sciences

• Little Rock, Arkansas

Dr. Golden received his AB from Brown University (1975) and his MD from Baylor College of Medicine (1978). He completed his internal medicine residency and chief residency at Rush-Presbyterian St. Luke's Medical Center in Chicago (1983). Dr. Golden is Director of the Quality Assurance Research and Education Center, Director of the Division of General Internal Medicine, and Associate Professor of Medicine at the University of Arkansas for Medical Sciences. He is currently Chairman of the Quality Assurance Committee of University Hospital. He has had several funded projects in quality assurance and has expertise in perioperative care and medical informatics. He has authored more than 40 journal articles and book chapters on perioperative care, medical education, and quality improvement.

Dr. Golden is a trustee of the American Society of Internal Medicine and a member of the board of directors of the American Medical Review Research Center. He serves on the American Medical Association Council on Medical Education and has recently been appointed to the Liaison Committee on Medical Education. He is a member of many internal medicine societies and has served numerous roles in educational activities and policy-making matters for these organizations.

• Gladys Walton Hall, PhD, MSW

• Associate Professor, School of Social Work

• Howard University

• Washington, District of Columbia

Dr. Hall received her BS from Morgan State University (1966), MSW from the University of Connecticut (1971), and PhD from the University of Maryland (1982). She recently completed a post-doctoral fellowship at the National Institute of Mental Health (1990).

Dr. Hall teaches clinical social work methods courses and is a licensed clinical social worker with experience in the private and public sectors. Her private practice is in a comprehensive medical setting and includes the treatment of depressed women. She has authored several publications in the area of depression (childhood depression) and served on various professional boards, both national and local (including the D.C. Mental Health Association). Her research focus is on the psychosocial factors related to the co-morbidity of depression and conduct disorder among children.

• Col. Moses Herrera, MD

• Chief, Primary Care Clinic

• Robins Air Force Base Hospital

• Robins Air Force Base, Georgia

Dr. Herrera is a Fellow of the American Academy of Family Practice. He has many years of experience in the practice of family medicine, including obstetrics, geriatrics, pediatrics, and adolescent medicine, as well as in short-term psychotherapy and in the diagnosis and treatment of depression. He has served on the Mental Health Committee of the American Academy of Family Practice. With his experience, Dr. Herrera can speak with particular regard to the utility of guidelines as they may be applied to family practice in military medicine.

• Artie Houston

• Consumer Representative

• Fort Worth, Texas

Mrs. Houston represents patients (consumers). She has lived successfully with manic-depressive illness, which was diagnosed in 1968. She played a prominent role in the establishment of the National Depressive and Manic-Depressive Association (NDMDA) and served as its executive vice president and president in 1988-89. Mrs. Houston founded the first NDMDA chapter in Tarrant County, Texas, and served as its president for 2 years. She has a background in business and public relations. She served for 15 years as the business director of a large blood center in Fort Worth, Texas. Mrs. Houston has an extensive history of volunteer work in the areas of depression, manic-depressive illness, and hemophilia.

• Roger G. Kathol, MD

• Professor of Psychiatry and Internal Medicine

• University of Iowa Hospitals and Clinics

• Iowa City, Iowa

Dr. Kathol received his BA from the University of Kansas (1970) and his MD from the University of Kansas School of Medicine (1974). He completed his residency in internal medicine at the University of Iowa (1978) and his residency in psychiatry at the University of Iowa (1980). He completed a 1-year fellowship in endocrinology at the University of Otago in Wellington, New Zealand (1981).

Dr. Kathol is the director of the combined Internal Medicine/Psychiatry Unit and the General Hospital Psychiatry Services at the University of Iowa Hospitals and Clinics. He currently teaches both psychiatrists and internists about the diagnosis and treatment of medical and psychiatric disorders in patients with complex and combined medical/psychiatric difficulties. He has received NIMH and private foundation grants for clinical research on depressive disorders in the medically ill, on endocrine changes in patients with primary depression, and on pharmacokinetic drug interactions. His research has contributed to the understanding of depression in the medically ill, as well as the potential relationship of hypothalamic-pituitary-adrenal axis dysfunction in patients with primary affective disorder.

Dr. Kathol has lectured widely, is on the editorial board of several journals, holds membership on the boards of national organizations, and is published widely in the area of psychiatric pathology as seen in medically ill patients. He is board-certified in both internal medicine and psychiatry, and is a Fellow of the American College of Physicians, the American Psychiatric Association, and the American Academy of Psychosomatic Medicine. He is the current president of the Academy of Clinical Psychiatry and is a founding officer of the Association of Medicine and Psychiatry.

• Wayne Katon, MD

• Professor of Psychiatry

• Chief of Consultation-Liaison Psychiatry

• University of Washington Medical School

• Seattle, Washington

Dr. Katon received his BA from the University of Vermont (1971) and his MD from the University of Oregon (1976). He completed his residency in psychiatry at the University of Washington (1979).

Dr. Katon is Chief of the Division of Consultation-Liaison at the University of Washington and head of the Psychiatry Liaison Service to Family Medicine at University and Providence Medical Centers. Dr. Katon received the American Academy of Family Practice Award for Excellence in Teaching. He has taught medical students, psychiatric residents, and family medicine practitioners in the area of psychiatric disorders in family practice and primary care. He has received independent NIMH funding for the study of depression and chronic tinnitus, a randomized trial of psychiatric consultation for patients who are high medical service utilizers, and a randomized trial of psychiatric consultation in treatment of major depression in primary care.

Dr. Katon has published widely in the area of psychopathology (depression, panic disorders, and somatization) in the primary care setting. He has authored more than 100 journal articles and chapters and a book commissioned by NIMH entitled Panic Disorder in the Medical Setting. His research has sought to identify the psychological and social factors associated with medically unexplained somatic symptoms (chest pain, back pain, irritable bowel syndrome, tinnitus, pelvic pain, and dizziness). He is a recognized national and international authority on psychiatric disorders in family practice and general internal medicine.

• Catherine L. Matchett, MD

• Matchett Medical Center, President

• Grapevine, Texas

Dr. Matchett is a Fellow of the American Academy of Family Practice in private practice, who serves approximately 3,500 families in the North Texas area. She completed a rotating internship and 2 years in a psychiatry residency, passing the written boards in psychiatry before completing a amily practice residency.

Dr. Matchett is Vice President of the Dallas Chapter of the American Academy of Family Practice. She has a strong interest in preventive medicine and patient education. She has developed and lectured on the utilization of patient education materials and educational methods to facilitate detection and recognition of a wide variety of common health problems, including several disorders that are commonly missed or misdiagnosed by primary care physicians, including depression, anxiety disorders, premenstrual syndrome, and headache disorders. These materials are used to engage patient participation in the process of identification and translation of symptoms into a proper diagnosis so that recognized treatment strategies may be employed. There is an assumption that patient compliance with treatment increases when the patient is educated and actively involved in the treatment process.

• Frederick Petty, PhD, MD

• Associate Professor, Department of Psychiatry

• Veterans Administration Medical Center

• University of Texas Southwestern Medical Center

• Dallas, Texas

Dr. Petty received his PhD from the Georgia Institute of Technology (1971) and his MD from the University of Tennessee (1976). He completed his residency in psychiatry at the University of Iowa (1980).

Dr. Petty is the recipient of a Research Career Development Award from the Department of Veterans Affairs. He was the Director of the Consultation/Liaison Service at both the Iowa City and Dallas Department of Veterans Affairs Medical Centers. He conducts both basic and clinical research on the biology of stress and depression, as well as on biologic markers for alcoholism. Dr. Petty has received independent, peer-reviewed funding to conduct his research from the Veterans Administration Merit Review Board, NIMH, and NIAAA. He has lectured widely to family practice and general internal medicine physicians regarding the differential diagnosis and management of mood disorders. Dr. Petty is Director of the Depression Clinic at the Department of Veterans Affairs Medical Center in Dallas.

• Herbert C. Schulberg, PhD

• Professor of Psychiatry, Psychology and Medicine

• University of Pittsburgh School of Medicine

• Pittsburgh, Pennsylvania

Dr. Schulberg received his BA from Yeshiva College (1955), his PhD from Columbia University, and his MS Hygiene from the Harvard School of Public Health (1963). He completed 2 years of pre-doctoral internships in clinical psychology at several Veterans Administration facilities.

Dr. Schulberg is Director of the Primary Care Consultation Program at the Western Psychiatric Institute and Clinic. He is a Fellow of the American Psychological Association, and was previously president of the American College of Mental Health Administration and a Visiting Scientist at the NIMH. He has published more than 125 peer-reviewed articles, chapters, and books that focus on the delivery and evaluation of psychiatric services, as well as the recognition, differential diagnosis, and treatment of depression and other psychiatric disorders in the primary care setting. Dr. Schulberg is a recognized national authority in this area. He has received several NIMH grants that support his research efforts. Presently, Dr. Schulberg is directing an NIMH-funded 4-year study of the clinical efficacy and cost efficiency of various treatments for major depression in primary care practice.

• G. Richard Smith, Jr., MD

• Professor and Director

• Centers for Mental Healthcare Research

• VA HSR & D -- Field Program for Mental Health

• University of Arkansas for Medical Sciences

• Little Rock, Arkansas

Dr. Smith received his MD from the University of Arkansas (1977), where he completed his residency in psychiatry. He was a Fellow in Psychiatry and Medicine at the University of Rochester (1980-81). He has served as residency director in the Department of Psychiatry at the University of Arkansas. He has published in the areas of alexithymia, somatization disorder, consultation-liaison, and immunology. He has received NIMH and Robert Wood Johnson Foundation research support for studies of somatization disorder and psychosocial disabilities associated with myocardial infarction. He has been developing disease-specific outcome modules for psychiatric conditions.

Dr. Smith currently serves as Chair of the NIMH Initial Review Group on Mental Health Services Research. He is Director of the Centers for Mental Healthcare Research, which include the NIMH Center for Rural Mental Healthcare Research and the Veterans Affairs Field Program for Mental Health.

• Gail Wiscarz Stuart, PhD, RN, CS

• Associate Professor and Chief, Division of Psychiatric Nursing

• Department of Psychiatry and Behavioral Sciences

• Professor, College of Nursing

• Medical University of South Carolina

• Charleston, South Carolina

Dr. Stuart received her MS in psychiatric nursing from the University of Maryland (1973) and her PhD in behavioral sciences from Johns Hopkins University (1985). She is a certified specialist in adult psychiatric and mental health nursing from the American Nurses Association and maintains a private practice of psychotherapy.

Dr. Stuart's clinical and research interests involve the study of depression, anxiety disorders, and mental health care delivery systems. As Chief of the Division of Psychiatric Nursing, in the Department of Psychiatry, Dr. Stuart is responsible for overseeing the clinical inpatient units at the Institute of Psychiatry. She is also the coordinator of the graduate program in psychiatric nursing at the Medical University of South Carolina in Charleston.

Dr. Stuart has received multiple honors and awards for her work from a large number of organizations and is a Fellow of the American Academy of Nursing. She serves on the NIMH Task Force on Psychiatric Nursing and the NIMH Research Resource Panel for the Severely Mentally Ill, among other national appointments. Dr. Stuart has been the principal investigator or coinvestigator on several independent research grants, including studies of the pharmacotherapy and childhood environments of patients with panic disorder, bulimia, and depression. She has written several nationally recognized textbooks on psychiatric nursing and has a substantial list of peer-reviewed journal publications in both the areas of psychiatric disorders and the role of nursing in health care delivery.

Reviewing Consultants for Diagnosis Issues [1]

• The Psychobiology of Fibromyalgia (Fibrositis) Syndrome

• I. John Russell, MD, PhD

• Department of Medicine University of Texas Health Science Center at San Antonio

• San Antonio, Texas

• Screening Laboratory Evaluation in Psychiatric Patients: A Critical Review

• Theodore J. Anfinson, MD

• Department of Internal Medicine University of Iowa College of Medicine

• Iowa City, Iowa

• Roger G. Kathol, MD

• University of Iowa Hospitals and Clinics

• Iowa City, Iowa

• Screening Ambulatory Depressives for Causative Medical Illnesses: The Example of Thyroid Functioning

• Mark S. Bauer, MD

• Department of Psychiatry University of Pennsylvania

• Philadelphia, Pennsylvania

• Chronic Fatigue Syndrome

• Susan S. Beland, MD

• Division of General Internal Medicine University of Arkansas for Medical Sciences

• Little Rock, Arkansas

• Depression vs. Dementia

• Dan G. Blazer II, MD, PhD

• Department of Psychiatry Duke University Medical Center

• Durham, North Carolina

• Recognition and Detection of Bipolar Disorder

• Charles L. Bowden, MD

• Linder Funderburg, MD

• University of Texas Health Science Center at San Antonio

• San Antonio, Texas

• Depression and Coronary Artery Disease

• Robert M. Carney, PhD

• Washington University School of Medicine

• St. Louis, Missouri

• Depression Rating Scales

• W. Edward Craighead, PhD

• Duke University and Duke University Medical Center

• Durham, North Carolina

• Treatment of Depression in Patients with Co-morbid Eating Disorders

• Michael J. Devlin, MD

• B. Timothy Walsh, MD

• Columbia University College of Physicians and Surgeons

• New York, New York

• Completed Suicide: A Review

• Arlene P. Hegg, MD

• Boulder, Colorado

• Critical Review of Data Supporting Affective Disorder Caused by Nonpsychotropic Medication

• Teresa D. Long, MD

• Roger G. Kathol, MD

• University of Iowa Hospitals and Clinics

• Iowa City, Iowa

• Depression in Adults with Diabetes

• Patrick J. Lustman, PhD

• Department of Psychiatry Washington University School of Medicine

• St. Louis, Missouri

• Depression in the Cancer Patient

• Jimmie C. Holland, MD

• Chief, Psychiatric Services

• Memorial Sloan-Kettering

• New York, New York

• The Depressed Alcoholic: Clinical Features and Medical Management

• Frederick Petty, PhD, MD

• Associate Professor, Department of Psychiatry

• Veterans Administration Medical Center

• University of Texas Southwestern Medical Center

• Dallas, Texas

• The Detection of Personality Variables Relevant to the Treatment of Depression in Primary Care: A Review of the Literature

• Bruce Pfohl, MD, MS

• University of Iowa College of Medicine

• Iowa City, Iowa

• Douglas R. Langbehn, MD, MS

• University of Iowa Department of Psychiatry

• Iowa City, Iowa

• Treatment of Depression in the Elderly

• Charles F. Reynolds III, MD

• University of Pittsburgh School of Medicine

• Western Psychiatric Institute and Clinic

• Pittsburgh, Pennsylvania

• Treatment of Depressive Disorders Following Stroke

• Robert G. Robinson, MD

• University of Iowa College of Medicine

• Iowa City, Iowa

• Epidemiology of Depression in Primary Care

• Herbert C. Schulberg, PhD

• University of Pittsburgh School of Medicine

• Pittsburgh, Pennsylvania

• Wayne Katon, MD

• Professor of Psychiatry Chief of Consultation-Liaison Psychiatry

• University of Washington Medical School

• Seattle, Washington

• Self-Report and Projective Measures in the Detection, Differential Diagnosis, and Management of Depressive Disorders in Outpatient Primary Care Settings

• Brian F. Shaw, PhD

• University of Toronto Toronto Hospital and the Hospital for Sick Children

• Toronto, Canada

• The Epidemiology and Treatment of Coexisting Depression, Somatoform Disorders, Somatization, and Pain

• G. Richard Smith Jr., MD

• Professor and Vice Chair of Psychiatry

• University of Arkansas for Medical Sciences Centers for Mental Health Care Research

• Little Rock, Arkansas

• Depressive Syndromes and Their Treatment in Children and Adolescents

• Elizabeth Weller, MD

• Ronald A. Weller, MD

• Ohio State University

• Columbus, Ohio

• Diagnostic Co-morbidity in Anxiety and Mood Disorders: Community and Primary Care Populations

• Richard E. Zinbarg, PhD

• University of Oregon

• Eugene, Oregon

• David H. Barlow, PhD

• Department of Psychiatry

• State University of New York at Albany

• Albany, New York

Scientific Reviewers [2]

• Hagop S. Akiskal, MD

• Senior Science Advisor,

• Office of the Director

• National Institute of Mental Health

• Rockville, Maryland

• Deborah Allen, MD

• Professor and Chairman,

• Department of Family Medicine

• Indiana University School of Medicine

• Indianapolis, Indiana

• Kenneth Z. Altshuler, MD *

• Professor and Chairman,

• Department of Psychiatry

• University of Texas

• Southwestern Medical Center

• Dallas, Texas

• Aaron T. Beck, MD*

• Professor, Department of Psychiatry

• University of Pennsylvania

• Philadelphia, Pennsylvania

• W. Eugene Broadhead, MD, PhD, FAAFP

• Associate Professor, Department of Community and Family Medicine

• Duke University Medical Center

• Durham, North Carolina

• C. Robert Cloninger, MD*

• Washington University Medical School

• St. Louis, Missouri

• Allen J. Frances, MD*

• Professor and Chairman,

• Department of Psychiatry

• Duke University Medical Center

• Durham, North Carolina

• Ellen Frank, PhD*

• University of Pittsburgh School of Medicine

• Western Psychiatric Institute and Clinic

• Pittsburgh, Pennsylvania

• Jack Froom, MD

• Professor,

• State University of New York at Stony Brook

• Stony Brook, New York

• Junius J. Gonzales, MD

• Chief, Primary Care Research Program

• Services Research Branch

• National Institute of Mental Health

• Rockville, Maryland

• Frederick K. Goodwin, MD

• Director,

• National Institute of Mental Health

• Bethesda, Maryland

• Philip S. Holtzman, PhD*

• Harvard University

• Cambridge, Massachusetts

• Neil Jacobson, PhD

• Professor, Department of Psychology

• Center for Clinical Research University of Washington

• Seattle, Washington

• Lewis L. Judd, MD

• Mary Gilman Marston Professor and Chair,

• Department of Psychiatry

• UCSD School of Medicine

• La Jolla, California

• T. Byram Karasu, MD

• Professor of Psychiatry

• Albert Einstein College of Medicine Bronx Municipal Hospital Center Jacobi Hospital

• Bronx, New York

• Donald F. Klein, MD

• Columbia University, College of Physicians & Surgeons

• New York, New York

• Gerald Klerman, MD (deceased)

• Professor, Department of Psychiatry Director of Research

• New York Hospital/ Cornell Medical Center Payne Whitney Clinic

• New York, New York

• Rodger Kobes, MD,PhD*

• Timberlawn Psychiatric Hospital

• University of Texas Southwestern Medical Center

• Dallas, Texas

• Helena Chmura Kraemer, PhD

• Stanford University

• Stanford, California

• David J. Kupfer, MD

• Western Psychiatric Institute and Clinic

• University of Pittsburgh

• Pittsburgh, Pennsylvania

• Jerome Levine, MD*

• Department of Psychiatry (MPRC)

• University of Maryland School of Medicine

• Baltimore, Maryland

• William T. McKinney, MD*

• University of Wisconsin School of Medicine

• Madison, Wisconsin

• Kathleen Merikangas, PhD*

• Yale University School of Medicine

• New Haven, Connecticut

• Deborah M. Nadzam, PhD, RN*

• Associate Director of Outcomes Research and Development

• Joint Commission on Accreditation of Healthcare Organizations

• Oak Brook Terrace, Illinois

• Robert M. Post, MD*

• National Institute of Mental Health

• Bethesda, Maryland

• Lon S. Schneider, MD*

• University of Southern California School of Medicine

• Los Angeles, California

• Myrna M. Weissman, PhD*

• Columbia University

• New York, New York

• Thomas N. Wise, MD

• Professor of Psychiatry

• Georgetown University

• Washington, District of Columbia

Organizations and Individuals Providing Peer and Pilot Review [3]

• American Nurses Association

• Washington, District of Columbia

• Contact: Karen O'Connor, MA, RN

• Sandra E. Benter, DNSC, RN, CS

• Psychotherapy and Consultation Practice

• Owings Mills, Maryland

• John M. Davis, MD

• Illinois State Psychiatric Institute

• Chicago, Illinois

• David L. Dunner, MD

• Professor, Department of Psychiatry

• University of Washington

• Seattle, Washington

• William H.M. Finney, MD, MPH

• Shepherd's Clinic

• Baltimore, Maryland

• Terry E. Fitzgerald

• National Council,

• Community Mental Health Centers

• Rockville, Maryland

• Frederick K. Goodwin, MD

• Director,

• National Institute of Mental Health

• Bethesda, Maryland

• Edgar Heim, MD

• Professor and Co-chair

• Psychiatrische Univ. Poliklinik

• Bern, Switzerland

• Shirley Hibbeln

• Education Consultant

• National Depressive and Manic-Depressive Association

• Chicago, Illinois

• Robert M.A. Hirschfeld, MD

• Professor and Chairman, Department of Psychiatry

• University of Texas Medical Branch

• Galveston, Texas

• IMCARE Practice Guidelines Network

• IMCARE (Internal Medicine Center to Advance Research and Education)

• American Society of Internal Medicine

• Washington, District of Columbia

• Contact: Bernard M. Rosof, MD, President

• Betty F. King Executive Director

• Harold A. Kaminetzky, MD, FACOG

• Director, Practice Activities

• American College of Obstetricians and Gynecologists

• Washington, District of Columbia

• Gerald Klerman, MD (deceased)

• President

• Association for Clinical Psychosocial Research

• Don R. Lipsitt, MD

• President,

• American Association of General Hospital Psychiatrists

• Cambridge, Massachusetts

• Russ Newman, PhD, JD

• Deputy Executive Director for Professional Practice

• American Psychological Association

• Washington, District of Columbia

• Pharmaceutical Manufacturers Association Health Outcomes Work Group

• Washington, District of Columbia

• Contact: Hugh H. Tilson, MD, DrPH

• Harold Alan Pincus, MD

• American Psychiatric Association

• Washington, District of Columbia

• John B. Reichman, MD

• American Academy of Clinical Psychiatry

• Pocatello, Idaho

• Lorraine Richter, BS

• Education Chairman

• National Depressive and Manic-Depressive Association

• Chicago, Illinois

• Joseph A. Rogers

• Mental Health Association of Southeastern Pennsylvania

• Philadelphia, Pennsylvania

• Peter M. Silberfarb, MD

• Dartmouth Medical School

• Dartmouth Hitchcock Medical Center

• Lebanon, New Hampshire

• Jeff Susman, MD

• Department of Family Medicine

• University of Nebraska Medical Center

• Omaha, Nebraska

• Robert L. Thomas

• National Association of Private Psychiatric Hospitals

• Washington, District of Columbia

• Joyce E. Thompson, CNM, DrPH, FAAN

• University of Pennsylvania School of Nursing

• Philadelphia, Pennsylvania

Organizations and Individuals Providing Additional Scientific, Technical, and Administrative Support

• University of Texas Southwestern Medical Center

• Dallas, Texas

• M. Trivedi, MD,

• Scientific Assistant to the Chair

• M. White, MM, Project Manager

• L. Arnold

• W. Hendrickse, MD, MRCP

• G. Kramer

• D. Savage

• Agency for Health Care Policy and Research,

• Rockville, Maryland

• J.J. Clinton, MD, Administrator

• K. McCormick, PhD, RN,

• Director, Office of the Forum

• E. Corrigan

• C. Crofton, PhD

• G. Hernandez, RN

• S. King, MD

• V. Montgomery

• K. Pearson, RPh, MPH

• R. Siegel

• L. Williams

• Editorial Associates,

• Washington, District of Columbia

• G. Martin

• Fast Word, Dallas, Texas

• Health Systems Research,

• Washington, District of Columbia

• MedStat Systems, Inc.,

• Ann Arbor, Michigan

• Mikalix & Company,

• Waltham, Massachusetts

• M. Madison, MPA, and staff

• Moshman and Associates,

• Bethesda, Maryland

• National Institute of Mental Health,

• Bethesda, Maryland

• F. Goodwin, MD, Director

• J. Burke, MD, MPH

• J. Gonzales, MD

• A. Leshner, PhD

• G. Norquist, MD, MSPH

• National Library of Medicine,

• Bethesda, Maryland

• I. Auston, MLS, and staff

• University of California at Los Angeles, California

• D. Schriger, MD, MPH

• University of California at Berkeley, California

• T.W. Hu, PhD

• University of Pittsburgh Medical Center,

• Pittsburgh, Pennsylvania

• M. McDonald, MFA

• Washington Consulting Group, Inc.,

• Washington, District of Columbia

• C.L. Smith