DEFINITION

Major depression (DSM IV, 1994)¹ is a treatable medical disorder. Like other medical illnesses it has significant morbidity and mortality.² It often complicates other conditions and makes them more difficult to treat (eg, diabetes mellitus, stroke, cancer, heart disease).³ It also accelerates mortality from these and other medical illnesses.⁴

Major depression is one of a number of different mood disorders including dysthymia, bipolar disorder, and cyclothymia.¹ Subtypes of major depression include seasonal, postpartum, and atypical.¹ Major depression is distinguished from mood disorder secondary to a medical condition and substance-induced mood disorder.¹ The importance of these distinctions is that they call for different treatment and management strategies and have different prognostic implications.

The clinician must maintain a high index of suspicion for major depression. Stigma, personal philosophy, lack of awareness, and time factors can interfere with recognition of depression when it is present. Survey (or screening) instruments have been used to circumvent some of these barriers (see DIAGNOSIS).

Major depression is diagnosed exclusively from information obtained at clinical interview and mental status examination. Collateral information from family and associates is helpful particularly when the patient minimizes or ignores psychological features of depression. There are no laboratory findings pathognomonic of depression. Laboratory testing is useful only to help rule out medical conditions that can mimic depression (eg, hypothyroidism, vitamin B₁₂ deficiency, sleep apnea, etc.) (Table 1).

The best treatment of depression is usually multi-modal involving both drug and non-drug therapies (see TREATMENT). The goal of treatment is full-remission of the index episode with continued remission for a minimum of 4 to 6 months after initial remission has been achieved.

The National Comorbidity Survey (NCS) is the most recent, broadly-based assessment of psychiatric disorders in the community.⁵ The prevalence of psychiatric disorders was found to be greater than previously determined in the earlier Epidemiologic Catchment Area (ECA) Study.⁶ In the NCS, the life-time and annual prevalence of any mood disorder were 19.3% and 11.3%, respectively. The life-time and annual prevalence of a major depressive episode were 17.1% and 10.3%, respectively. The female-to-male ratio was approximately 2:1.⁵

Other studies show that depression occurs at higher rates in patients who seek general medical care.⁷ Nearly 70% of all antidepressant prescriptions are written by primary care physicians.⁸ Depressed patients are high-utilizers of medical care and high-utilizers of medical care in general are more likely to have one or more psychiatric disorders. In one study the 1-month prevalence of depressive disorders in a group of high-utilizers was 40.3%.⁹

Certain medical disorders (eg, stroke, neurodegenerative disorders, HIV/AIDS, endocrine disorders) are associated with a higher than expected rate of depression. Diabetes, for example, doubles the odds of comorbid depression.¹⁰ A recent meta-analysis of studies that examined the prevalence of comorbid depression in adults with diabetes showed that the prevalence of comorbid depression was significantly higher in diabetic women (28%) than in diabetic men (18%) and in clinical (32%) rather than community (20%) samples.¹⁰

Emerging data support the hypothesis that stress, genetic predisposition, and early life experiences interact to cause depression. The National Alliance for the Mentally Ill has promoted the notion that depression, bipolar disorder, schizophrenia and other disabling psychiatric illnesses are "brain disorders." Although this conclusion is undoubtedly accurate, the precise pathophysiologic mechanisms of depression have not yet been fully elucidated.

Studies of families and twins suggest that genetic factors predispose to recurrent major depressive illness.¹¹ In addition to having a greater risk of major depression, the first-degree relatives of depressed individuals are also more likely to suffer from anxiety disorders, other mood disorders, and chemical dependency.

Abnormal stress at critical developmental periods may have long-lasting effects on central nervous system development. Emerging evidence of central hypercortisolemia in subjects with a history of childhood abuse, deprivation or abandonment supports this notion and is consistent with the finding that patients with major depression are more likely than matched controls to have a personal history of abuse, neglect or deprivation (eg., early parental loss).¹²

A variety of studies suggest that brain regions involved in depression include the hippocampus, hypothalamus, and prefrontal cortex.^13,14 Some of this evidence comes from postmortem receptor studies in depressed suicide victims; animal models of reward, stress, and learned helplessness; and functional neuroimaging studies of depressed patients studied before and after various forms of antidepressant treatment. Normalization of frontal hypometabolism is the most often replicated finding. The presence of dense projections from the subgenual cingulate to the serotonin-rich brainstem dorsal raphe nucleus suggests that this cortical area plays some role in the regulation of serotonergic activity, an activity that may be impaired in depression.¹⁴

Understanding of the biology of neurotransmission has progressed significantly beyond an appreciation of neurotransmitter synthesis, release and activation of post-synaptic cell-surface receptors.¹⁵ Signal transduction pathways mediated by second- and third-messengers (eg, cyclic adenosine monophosphate (AMP), protein kinases and neurotropic factors) affect gene expression and protein production with consequent re-regulation of neurotransmission and clinical improvement. The rate of gene expression corresponds more closely to the rate of antidepressant-associated clinical improvement (ie, weeks) than the more rapid changes in neurotransmission (ie, hours to days). Moreover, studies of treatment response suggest a close correlation between antidepressant usage and increased levels of proteins, such as brain-derived neurotrophic factor (BDNF).

Central hypercortisolemia may mediate stress-induced effects on the brain that are reversed by antidepressant-induced BDNF production.¹² It has been known for some time that sustained hypothalamic-pituitary-adrenal axis hyperactivity is evident in some, though not all, cases of depression. Elevated central corticotropin-releasing hormone (CRH) contributes not only to central monoamine derangement but also structural and metabolic changes that have been associated with depression.

Major depression is a syndrome characterized by a clustering of typical symptoms.¹

For a diagnosis of major depression to be considered, an individual must report 5 or more of the following symptoms and at least one of those symptoms must be
either (1) or (2)*:

(1) * depressed or sad mood;

(2) * markedly diminished interest or pleasure in all or almost all activities especially those the individual normally enjoys;

(3) sleep disturbance (insomnia or hypersomnia);

(4) feelings of worthlessness or excessive or inappropriate guilt (that is not merely self-reproach or guilt about being sick, but rather a firmly-held conviction that may in some instances be considered delusional);

(5) fatigue or loss of energy;

(6) indecisiveness, or diminished ability to think or concentrate;

(7) a change in appetite (typically decreased, but can be increased in so-called "atypical depression"), or a significant weight change (>5% of body weight) when not intentionally trying to lose or gain weight;

(8) psychomotor agitation or retardation nearly every day; or

(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, a specific plan for committing suicide, or a suicide attempt.¹

A well-known mnemonic developed by Carey Gross, M.D. (personal communication) can be used to recall these important symptoms: SIG: E(nergy) CAPS(ules), ie, a "prescription for energy capsules". (The relevant word in each of the 9 symptom descriptions above and the corresponding first letter of each these words are emboldened).

Symptoms of anxiety (eg, worry, nervousness, tension, panic attacks) frequently accompany depression. The presence of anxiety often confounds the diagnosis of major depression and encourages treatment with benzodiazepines or other minor tranquilizers rather than antidepressant medication. The clinician must be careful to do a thorough evaluation for major depression when symptoms of anxiety are present.

Other symptoms that are commonly associated with depression and whose presence should trigger concern about underlying, unreported or "masked" depression include:

• pain (the more types of pain the patient reports, the greater the likelihood of underlying depression)
  
• sexual complaints - problems with sexual functioning or desire

A common error is to regard depressive symptoms as an understandable reaction to grave or disabling medical illness. Grieving is a normal and expected reaction to sudden, unexpected, life-threatening, or terminal illness. The severity and intensity of a precipitating or stressful event, however, are not directly relevant to the diagnosis of major depression. Whether or not a sufficient triggering event has occurred, the diagnosis of major depression depends instead on the presence of a critical number of signs and symptoms (see SIGNS & SYMPTOMS). If careful evaluation discloses sufficient signs and symptoms, then regardless of the precipitating event the clinician is obliged to make a diagnosis of major depression and recommend appropriate treatment.

In addition to the symptom-dependent criterion:

(A) (ie, 5 or more of the 9 symptoms at least one of which is either (1) or (2) described above) several other criteria must be met to qualify for a diagnosis of major depression. The symptoms must

(B) be present most of the day, nearly every day for at least 2 weeks,

(C) cause clinically significant distress or impairment in social, occupational, or other important areas of functioning,

(D) not be better accounted for by bereavement, and

(E) not meet criteria for a mixed episode.¹

A mixed episode is defined by the presence of both depressed and manic symptoms. In addition to having depressive symptoms the individual with a mixed episode is typically irritable, explosive, labile (ie, switches unpredictably from one emotion to another), and pressured (ie, difficult to interrupt). A mixed episode is more consistent with a diagnosis of bipolar disorder rather than major depression and requires different treatment (see TREATMENT).

Survey instruments have been advocated to assist in the diagnosis of depression. They have been used either to screen for depression and other common psychiatric disorders or to verify and reinforce a clinical impression. Examples of well-known survey instruments include:

• Beck Depression Inventory
• Zung Depression Scale
  
• PRIME-MD (self-report format) ¹⁶

These and other instruments can be completed by hand, telephone ¹⁷, or computer ¹⁸ without requiring the clinician's valuable time. An important incidental finding in studies of these technologies is that patients are more likely to reveal personal information to a computer than they are in a face-to-face clinical encounter.^17,18

Once sensitive information surfaces it must be dealt with. The clinician's response to information about hopelessness or suicidal ideation for example has important clinical and potential legal ramifications. One recourse is to avoid asking questions that elicit such information; another is to ignore clues to presence of depression. Another more effective measure is to delegate responsibility for follow-up to another clinician in the practice. On-site collaboration with one or more mental health specialists (nurse clinician, psychiatrist, psychologist, social worker) has been found to offer the most effective means of dealing with the problem of depression in primary care.¹⁹

Since depressive symptoms are non-specific both patient and clinician generally feel obliged first to rule out other medical conditions. Indeed, both medical conditions and other psychiatric diagnoses must be considered when depressive symptoms are present (Table 1).

The clinician is encouraged to rule-in major depression when the clustering of typical symptoms (see SIGNS & SYMPTOMS) and other diagnostic criteria (see DIAGNOSIS) are present. Early and effective treatment with antidepressant medication should not interfere with a thorough work-up. Moreover, a successful response to antidepressant medication could forestall unnecessary, repeat office visits and laboratory testing.

Discerning depression in the context of debilitating medical illness is frequently difficult. This is because the vegetative symptoms of depression (ie, anorexia, insomnia, fatigue, and impaired attention) can occur as manifestations of severe medical or surgical illness itself. When the cause of these symptoms is ambiguous the clinician is forced to rely on the presence or absence of typical psychological symptoms or behavior (eg, crying, expressions of hopelessness or giving-up, loss of motivation, excessively low self-esteem). The likelihood of major depression increases significantly when these psychological symptoms accompany the other less specific somatic symptoms.

Given that mild depression is often self-limited, the best approach in any given patient may be to withhold treatment and monitor. This should not be viewed as a missive to ignore or overlook mild depression. Depression that is mild, if persistent can also have adverse long-term consequences.²⁰ Instead, the clinician should put depression - whatever its intensity - on the problem list and recommend treatment if symptoms persist and cause significant distress or dysfunction.

Treatment success depends on at least four factors addressed in the AHCPR guideline: (1) a strong therapeutic alliance with the patient; (2) selection and identification of one or more appropriate treatments; (3) optimal treatment dosage (or intensity in the case of non-drug treatments); and (4) optimal treatment duration.²¹ Timely application of each of these principles depends on the phase of treatment. The AHCPR guideline lists three phases of treatment for major depression: acute, continuation, and maintenance. The indications, goals, duration and strategies of treatment with antidepressant medication during each phase are presented in Table 2 and can also be reviewed by consulting the AHCPR guideline.

In addition to medication a variety of treatments have been found to be helpful for depression and include psychotherapy, exercise, light therapy, and electroconvulsive therapy (ECT).

Antidepressant Medications
Antidepressant medication should be considered for most cases of moderate-to-severe depression. A large variety of antidepressants is available (Table 3). There is no single-best agent and selection depends on the patient's antidepressant treatment history, potential drug-drug interactions, and desired side-effect profile. There is no test available that predicts individual response to antidepressant medication in general or to any single agent. Empiric trial-and-error is necessary with a 60% to 70% chance of success with any one agent. If a trial of the first agent is unsuccessful, the diagnosis should be reviewed for accuracy and then, if depression is still present, another antidepressant should be tried. There is some debate over what constitutes treatment success. Many patients who initially respond favorably still have residual symptoms. Increasing the antidepressant dosage, augmentation strategies or switching to another medication are treatment options for such patients. Referral to a psychiatrist should be considered for persistent depression that has not responded to one or at most two trials of antidepressant medication.

Antidepressant Side Effects and Selection
Familiarity with antidepressant class and side effect profile helps inform treatment selection (Table 3). In an antidepressant-naïve patient virtually any antidepressant qualifies as a first-line agent. Serotonin selective reuptake inhibitors (SSRI) including fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa) and paroxetine (Paxil) enjoy the widest prescription in the United States and are generally the first to be prescribed. When compared to SSRIs in drug trials venlafaxine (Effexor), bupropiron (Wellbutrin), nefazodone (Serzone), and mirtazapine (Remeron) have similar efficacy and like the SSRIs have generally favorable side-effect profiles. Unlike the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), all of these newer antidepressants produce lower risk of significant cardiovascular side effects and are comparatively safe in overdose. SSRIs and venlafaxine can cause sexual dysfunction (delayed or inhibited sexual climax) in at least 25% whereas bupropion, mirtazapine, and nefazodone do not. The risk of hypertension increases with daily doses of venlafaxine greater than 225 mg. Mirtazapine can cause unacceptable weight gain due in part to increased appetite and it also increases the risk of orthostatic hypotension. Nefazodone is generally well-tolerated except for sedation and GI side effects; twice-daily dosing is recommended and a long titration phase is typically necessary due to a potentially high therapeutic ceiling (600 mg daily).

Therapeutic Trial of Antidepressant Medication
Fundamental to all successful antidepressant therapy is an adequate treatment trial, ie, both adequate dosage and duration of treatment. There is substantial evidence that a majority of patients with major depression do not receive adequate treatment trials. The clinician must arrange for follow-up to ensure that the maximal recommended dosage of medication has been taken daily for at least 4 to 6 weeks. If some response is evident within the first 4 weeks, treatment should be continued at least 6 weeks. No response to a therapeutic dose of medication by week 4 is an almost certain indication that another agent should be tried (see AHCPR guideline).

Psychotherapies
Psychotherapy alone may be effective for mild-to-moderate depression or as an adjunct to antidepressant medication for moderate-to-severe depression. Most PCPs are unlikely to provide psychotherapy, but knowledge about this treatment modality should facilitate selection and referral of appropriate patients.² Commonly-used models of psychotherapy include cognitive-behavioral therapy (CBT), interpersonal therapy (IPT), and insight-oriented approaches such as psychodynamic and client-centered therapies. Formats in which psychotherapies are delivered include individual, group, marital (or couples), family, and intensive outpatient programs.

Exercise
Exercise should be recommended to all depressed patients. Its effects enhance mood and if nothing else exercise provides a structured activity that if performed regularly can increase the depressed patient's sense of competence.

Light Therapy for Seasonal Mood Disorder
Light therapy has been used effectively to treat seasonal depression. Seasonal Affective Disorder (SAD, or seasonal mood disorder) is a major depression that occurs each year at the same time, usually starting in fall or winter and ending in spring or early summer. It is more than just "the winter blues" or "cabin fever." A rare form of SAD, known as summer depression, begins in late spring or early summer ending in fall. Morning light therapy for at least 30 minutes every day is the most effective. Improvement can occur within 2 to 4 days and reach full benefits within 2 to 4 weeks. An appliance that delivers at least 10,000 LUX is recommended. Companies that manufacture lamps with the appropriate specifications include SunBox and Northern Light Technologies.

Electroconvulsive Therapy (ECT)
ECT is perhaps the most effective antidepressant treatment available. It is generally used only as a last resort because of the need for anesthesia. A significant number of cases that are resistant to antidepressant medication, however, will benefit from ECT. Maintenance ECT is indicated for those whose recurrent depressions do not respond to maintenance antidepressant medication.

Mood Stabilizers
Mood stabilizers are indicated for the treatment of bipolar disorder. These are agents that prevent mood from becoming too high (hypomanic or manic) or too low (depressed). The longest used and best known mood stabilizer is lithium. In the last twenty years since discovery of the mood stabilizing properties of carbamazepine a variety of anticonvulsants have been identified and promoted as mood stabilizers. Valproic acid, in particular its congener, divalproex sodium (Depakote) compared favorably with lithium in a large multi-center randomized, controlled trial of these agents for acute mania. Still other anticonvulsants such as lamotrigine (Lamictal), gabapentin (Neurontin), and topiramate (Topomax) have shown promise as mood stabilizers. Olanzapine (Zyprexa), a new atypical antipsychotic, has received Food and Drug Administration (FDA)-approval for use in the short-term management of acute mania. Other antipsychotic medications (eg, haloperidol, risperidone, olanzapine, quetiapine, and ziprasidone) have also been effective for acute mania or as an adjunct to mood stabilizer medication. None, however, including olanzapine, is classified as a mood stabilizer since they are not particularly effective for the treatment or prevention of depression.

When an episode of depression occurs in the context of bipolar disorder it is prudent to first start a mood stabilizer and then add an antidepressant only if necessary. Use of an antidepressant alone runs the risk of precipitating an acute manic episode. The clinician should always inquire about a history of mania or hypomania during evaluation of depression. Although antidepressant medication is often necessary during the treatment of bipolar disorder, the evidence strongly suggests that its concomitant use with a mood stabilizer increases the risk of mood instability and rapid cycling.

The clinical practice guideline for the diagnosis and treatment of major depression in primary care first published by the Agency for Health Care Policy and Research (AHCPR) in 1993 ²¹ is available from the National Library of Medicine. Clinical practice guidelines for both major depression and for bipolar disorder are also available at the American Psychiatric Association (APA) website.

The complete AHCPR clinical practice guideline for evaluation and treatment of depression in primary care, published in 1993, is out of date and archived. An abridged, up-to-date version, however, is available at text.nlm.nih.gov (go to Evidence Reports, scroll to and select AHCPR Supported Guidelines; then go to Quick Reference Guides for Clinicians, scroll to and select 5. Depression in Primary Care (Quick Reference Guide).

The Depression in Primary Care - Quick Reference Guide is recommended for use by primary care practitioners. It is brief, digestible, and timely. The authors note: "This Quick Reference Guide for Clinicians contains excerpts from the Clinical Practice Guideline, Vols 1 and 2.²¹ It was not designed to stand on its own. Practitioners should review the Clinical Practice Guideline carefully to become familiar with the diagnosis, differential diagnoses, and treatment options for patients with major depressive disorder and then use the Quick Reference Guide to help them remember the major decision points in diagnosing and treating major depressive disorder." Busy clinicians are not likely to read the entire two-volume Clinical Practice Guideline and will do well to review the Quick Reference. It requires some updating with respect to the antidepressant medications listed in Table 2 but is otherwise current. Specifically, the three newest antidepressants are omitted, namely, citalopram (Celexa), mirtazapine (Remeron) and nefazodone (Serzone). Fluvoxamine (Luvox), another serotonin-selective reuptake inhibitor (SSRI), has been used throughout the world for treatment of depression. In the United States, however, it is FDA-approved only for obsessive-compulsive disorder. For complete information on currently available antidepressants in the U.S. (Table 3).

1. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington DC, 1994
   
   
2. Tuma, TA. Outcome of hospital-treated depression at 4.5 years: an elderly and a younger adult cohort compared. Brit J Psychiatry. 2000;176:224-228.
   
   
3. Franco K, Tamburino M, Campbell N, Zrull J, Evans C, Bronson D. The added costs of depression to medical care. Pharmacoeconomics. 1995;7:284-291.
   
   
4. Penninx BJ, Beekman ATF, Honig A, et al. Depression and cardiac mortality. Arch Gen Psychiatry. 2001;58:221-227.
   
   
5. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry. 1994;51:8-19.
   
   
6. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US Mental and Addictive Disorders service system: Epidemiologic Catchment Area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50:85-94.
   
   
7. Regier DA, Goldberg ID, Taube CA. The de facto US mental health services system. Arch Gen Psychiatry. 1978;35:685-693.
   
   
8. Barrett JE, Barrett JA, Oxman TE, Gerber PD. The prevalence of psychiatric disorders in a primary care practice. Arch Gen Psychiatry.1988;45:1100-1106.
   
   
9. Katon W, Von Korff M, Lin E, et al. Distressed high utilizers of medical care: DSM III-R diagnoses and treatment needs. Gen Hospital Psychiatry. 1990;12:355-362.
   
   
10. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24:1069-1078.
    
    
11. Kendler KS. Genetic epidemiology in psychiatry: taking both genes and environment seriously. Arch Gen Psychiatry. 1995;52:895-899.
    
    
12. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001;158:575-581.
    
    
13. Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830-843.
    
    
14. Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675-682.
    
    
15. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999;46:1181-1191.
    
    
16. Spitzer RL, Kroenke K, Williams JBW. Validation and utility of self-report version of PRIME-MD. JAMA. 1999:282:1737-1744.
    
    
17. Kobak KA, Taylor LVH, Dottl SL et al. A computer-administered telephone interview to identify mental disorders. JAMA. 1997;278:905-910.
    
    
18. Shedler J, Beck A, Bensen S. Practical mental health assessment in primary care: validity and utility of the Quick PsychoDiagnostics (QPD) panel. J Fam Practice. 2000;49:614-621.
    
    
19. Katon W, von Korff M, Lin E, et al. Collaborative management to achieve treatment guidelines: impact on depression in primary care. JAMA. 1995;273:1026-1031.
    
    
20. Schulz R, Beach SR, Ives DG, Martire L, Ariyo AA, Kop W. Association between depression and mortality in older adults: the Cardiovascular Health Study. Arch Int Med. 2000;160:1761-1768.
    
    
21. Agency for Health Care Policy and Research (AHCPR): Clinical Practice Guideline: Depression in Primary Care, Volumes I & II. US Government Printing Office, Washington DC, 1993.

This information is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition.

In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this web site.