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Depression Overview

April 2008, Vol 1, No 3 - Clinical
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Depression is a common condition that often remains undiagnosed and untreated; however, symptoms are more likely to be recognized today than in past decades. Survey data suggest that female, nonwhite patients are more likely to report depressive symptoms, especially those who are less educated, poor, and covered by Medicaid. Depression may be a finding suggestive of dysthymic disorder, minor or major depressive disorder, seasonal affective disorder, episodic depression, or a sign of an associated mood disorder, such as bipolar disorder. Many effective treatments are available that are well tolerated. This article outlines the diagnostic approach used in primary care, as well as the different treatment options available for this condition. Depression can have serious consequences and must be treated appropriately.

Among adults responding to the 2006 National Health Interview Survey, 11% reported having feelings of sadness during all, most, or some of the time in the 30 days before the interview; 6% reported feeling hopeless; 5% felt worthless; and 14% felt that everything was an effort.1 Women were more likely to report such symptoms than men (13% vs 9%, respectively). Non-Hispanic black adults and Hispanic adults were more likely to report feelings of sadness or hopelessness than non-Hispanic white adults. Level of education was inversely associated with feelings of sadness, hopelessness, worthlessness, or with the feeling that everything was an effort. Adults with less than a high school diploma reported the highest levels of such feelings, and those classified as poor were twice as likely to report these feelings as those not classified as poor. Persons under age 65 who were covered by Medicaid were more likely (27%) to report depressive symptoms than those who were uninsured (14%) or those with private health insurance (7%). Among those aged 65 and older, Medicare and Medicaid "dual-eligible" patients were more likely to report feelings of sadness (28%) than those covered by Medicare alone (13%) or those with private health insurance (11%).1

Depression is a common condition that frequently remains undiagnosed and untreated. Nevertheless, depression is more likely to be diagnosed today than in past decades, because the social stigma associated with this condition has lessened; available treatments are effective and well tolerated; and primary care physicians, to whom most patients initially present and from whom most patients receive initial therapy, have become more willing to diagnose and treat this condition.

Depression may be suggestive of dysthymic disorder, major depressive disorder (MDD), seasonal affective disorder, episodic depression, or a sign of an associated mood, bipolar, or psychotic disorder. Depression may also be episodic, in response to bereavement or a major life change. In addition, it may play a significant role in specific clinical settings, such as during pregnancy or the postpartum period,2 adolescence, or at the end of life.3 This type of depression is beyond the scope of this discussion.


Risk Factors
Risk factors that predispose patients to depression include:

  • Female gender
  • History of anxiety
  • History of eating disorders
  • First-degree relative with a history of depression
  • History of or current drug or alcohol abuse
  • History of or current sexual abuse or domestic violence.

In addition, patients with major medical conditions or with chronic medical conditions are at a greater risk of experiencing depressive symptoms. These conditions may include cardiac illnesses (ie, myocardial infarction, coronary artery atherosclerotic disease, and arrhythmias), cerebrovascular disease (after a stroke or a transient ischemic attack), diabetes, chronic lung or renal disease, cancer, and chronic pain disorders.4

Although the rates of major depression are highest among the 25- to 44-year-old age-groups, patients in older age-groups may be at increased risk, because of the loss of or separation from a spouse or peers, cognitive or physical impairments, and a higher prevalence of chronic diseases.5 This population may present specific challenges regarding the diagnosis and treatment because of a high prevalence of comorbid conditions and a higher utilization of other medications.6

Table 1
Table 1

The characteristic symptoms of depression include loss of interest in activities that have historically proved to be pleasurable, sadness, irritability, feelings of worthlessness, hopelessness, guilt or anxiety, concerns over death, or suicidal ideation. Associated symptoms may include changes in appetite, weight loss or weight gain, sleep disturbances, psychomotor activity, decreased energy, indecisiveness, or distracted attention. Patients with depression may also present with somatic complaints and may be frequent users of primary care, urgent care, and emergency or inpatient services. Patients with depression may also be those whom clinical staff identifies as "difficult" to treat. The American Psychiatric Association's (APA) criteria for a major depression episode are listed in Table 1.

Patients who are experiencing psychosocial stressors and who do not meet the criteria of major depression episode may be suffering from an adjustment disorder, or posttraumatic stress disorder. Recurrent episodes of major depression are called major depressive disorder, a condition associated with a high mortality. Patients with severe MDD have a high rate of suicide, and epidemiologic studies indicate that patients with MDD who are older than age 55 have a 4-fold increase in rates of death.7 Depressive episodes associated with manic episodes are classified as bipolar disorder.

History and Physical Examination
When taking the medical history, it is important to identify the severity and duration of the symptoms and any previous episodes, because depression tends to be recurrent. One should determine whether there is a family history of depression or other psychiatric illness—both major depression and bipolar disorder are heritable conditions. Recognition of manic or psychotic symptoms may identify patients who may require earlier referral to a psychiatrist. A history of suicidal thoughts, plans, or actions must be ascertained and again may identify patients who need more urgent referral.

Although the physical examination is fairly insensitive for identifying depression, a thorough physical examination is important to identify contributing or causal illnesses, such as chronic liver or renal disease, endocrine disease (hypothyroidism or adrenal insufficiency), congestive heart failure, dementia, or other conditions.

In primary care settings, the point prevalence of major depression ranges from 5% to 9% among adults, and up to 50% of depressed patients are not recognized. 8 The related conditions of dysthymia (a chronic low-grade depression) and minor depression are as common as major depression in primary care settings. Depressive disorders are estimated to affect from 0.8% to 2.0% of children and 4.5% of adolescents.9

Some of the barriers that may contribute to these percentages include:

  • Inadequate knowledge of diagnostic criteria
  • Competing priorities and comorbid conditions
  • Time limitations
  • Stigma associated with "labeling" a patient as depressed
  • Poor reimbursement mechanisms.

Because of these barriers, a number of case-finding instruments have been developed and validated, including the Beck Depression Inventory, the Center for Epidemiological Studies-Depression Scale, the Zung Self-Assessment Depression Scale, the General Health Questionnaire, and the Hopkins Symptom Checklist, among others.9

Recently, 2 related tools are increasingly being used to screen and diagnose depression. The Patient Health Questionnaire (PHQ)-2 is an abbreviated version, consisting of the anhedonia and mood items of the PHQ-9. The PHQ-2 can be used as a very brief and quick depression-screening tool in primary care. In primary care patients, a PHQ-2 score of 3 or more has 83% sensitivity and 92% specificity for identifying patients with major depression.10


If the PHQ-2 is positive, screening may be confirmed by completing all the questions on the PHQ-9 (Figure). The PHQ-9 can be used as a screening tool, with summed score ranging from 0 (no depressive symptoms) to 27 (all symptoms occurring daily). A PHQ-9 score of 10 or more has been found to have 88% sensitivity and 88% specificity for a diagnosis of major depression.10 The PHQ-9 can also be used as a diagnostic assessment; with major depression diagnosed if 5 or more of the 9 symptoms have been present at least more than half the days of the past 2 weeks and 1 of these symptoms is either depressed mood or anhedonia.

Drug Therapy

Untreated depression is associated with increased deaths, adverse outcomes, deficits in function, increased use of health services, poor on-the-job performance, and increased absenteeism. Treatments most frequently used by primary care physicians are (1) medications and (2) psychotherapy in cooperation with a psychologist, psychiatrist, or therapist. More than half of depressed patients respond to initial treatment with medications.

Table 2
Table 2
Table 2 (cont)
Table 2

Medication options are numerous (Table 2), and treatment recommendations should be tailored to the individual patient on the basis of the symptom profile, side effects of the drugs, comorbid conditions, and previous responses to treatment if available. Most drugs focus on serotonin and norepinephrine levels in the brain, supported by the major theory of depression known as the monoamine-deficiency hypothesis. The biochemical basis for this hypothesis and numerous other theories have been recently reviewed elsewhere.11

Several classes of drugs have been found effective in treating depression, through increasing the concentrations of the neurotransmitters serotonin and norepinephrine in the postsynaptic cleft of neurons in the central nervous system. These agents include selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), and dual-action agents that inhibit the reuptake of serotonin and norepinephrine. Monoamine oxidase inhibitors (MAOIs) increase concentrations of neurotransmitters by inhibiting their degradation. Other agents increase the availability of neurotransmitters by blocking alpha-adrenergic autoreceptors, as well as serotonin (5-HT)2a reuptake and 5-HT3 receptors, and histamine H1 receptors.

Mood stabilizers, such as lithium, and anticonvulsants, such as lamotrigine, valproic acid, divalproex, or carbamazepine, may play an adjunctive role to antidepressants in the treatment of bipolar disorder. Antipsychotics and atypical antipsychotics may play a role in treating depression with psychotic features, as well as resistant major depression and bipolar depression.12 However, patients with these conditions may be more appropriately managed in conjunction with a psychiatrist.

There are 3 phases in the treatment of depression—the acute phase, the continuation phase, and the maintenance phase. During the acute phase, treatment should be initiated and follow-up scheduled at 1- to 2-week intervals to ensure a response. If a certain medication has worked previously for a patient or a family member, this may be an appropriate first choice.

Antidepressants are started at low doses and titrated upward at appropriate time intervals based on response and side effects. If a patient's response to a drug is inadequate at appropriate treatment doses, a change to a medication in the same or another class may be appropriate (patients who do not respond to one SSRI may respond to another agent within the class).

Once an adequate response has been achieved in the acute phase, the continuation phase begins and can last as long as 9 months from remission. During this phase, treatment goals are to eliminate residual symptoms, to restore previous level of functioning, and to prevent recurrence or relapse. If there is no recurrence of symptoms during the first 6 months of treatment, a consideration to wean the medication and assess for the possibility of "early discontinuation" may be reasonable. If symptoms return, the medication should be re-titrated upwards to an effective dose and maintained for an additional 3 to 6 months. Early discontinuation does have a higher rate of relapse.12 Discontinuation in itself may produce symptoms ("discontinuation syndrome"), including balance problems, gastrointestinal upset, myalgias, weakness, sensory and sleep disturbances, anxiety, agitation, and emotional volatility.

A maintenance phase treatment for 12 to 36 months may be indicated for patients with recurrent episodes of depression, residual symptoms, chronic major depression, or patients with severe episodes (ie, high risk of suicide, severe psychosis).

Initial pharmacologic therapy may include SSRIs, NRIs, or mixed/dual-action medications. MAOIs should be restricted to patients who do not respond to other treatments because of potential side effects, interactions, and the need for dietary restrictions.13 Recent concerns regarding reports of life-threatening hepatic failure in patients treated with nefazodone have prompted the US Food and Drug Administration (FDA) to alter the drug's labeling and to include a "black box" warning regarding liver failure. A combination product of the SSRI fluoxetine plus the antipsychotic olanzapine (called Symbyax) has been approved by the FDA for the treatment of bipolar depression, but it may also be effective in some patients whose major depression is complicated by psychotic features, and in treatment-resistant depression.14

Nonpharmacologic Therapies


Psychotherapy may be an effective treatment for depression alone, or in combination with medications for mild to moderate disease, but psychotherapy alone is not recommended for severe disease. Cognitive behavioral therapy, interpersonal therapy, marital therapy, and certain problem-solving techniques may be effective as treatment or adjuvant treatment in patients with substantial psychosocial stressors, interpersonal difficulties, or comorbid developmental or personality disorders.

Electroconvulsive Therapy
Electroconvulsive therapy (ECT) should be considered with appropriate expert consultation for patients with MDD who have a high degree of symptom severity and functional impairment, or for patients in whom psychotic symptoms or catatonia are present. ECT may be the treatment of choice when there is an urgent need for a response, such as in patients who are suicidal or are refusing food and nutritionally compromised.15 The maximum response to ECT is typically achieved within 3 weeks and also may be useful in patients who are medication-resistant or pregnant.

Monitoring, Patient Education
Posttreatment monitoring should include ongoing assessment of the risk of suicide, as well as the incidence of manic or psychotic symptoms, which may develop over the course of appropriate therapy. Monitoring should include measurement of treatment effectiveness, assessing the need to adjust doses, or identify alternative or adjunctive therapies, and should actively assess the patient for side effects. The use of a defined tool may help patients to see a quantifiable improvement in symptoms associated with treatment, and may make patients more likely to adhere to therapeutic regimens.

Patient education should include information regarding the responsiveness of symptoms to treatment, risks of treatment, issues related to suicide, and the recurrent nature of the disorder. Information regarding birth control and breast-feeding may be important for female patients of childbearing age.

Depression and Suicide Risk

The worst possible outcome in a case of diagnosed or undiagnosed depression is suicide. In 2001, suicide was the 11th leading cause of death (n = 30,000; age-adjusted rate, 10.7 per 100,000 persons)16; the age-adjusted rate for the period 2002-2005 was 10.86 per 100,000.17 Although the US Preventive Services Task Force has concluded that in the general population there is insufficient evidence to recommend for or against screening for suicide risk,16,18 the task force has recognized that the strongest risk factors for attempted suicide include mood disorders or other mental disorders, comorbid substance abuse disorders, a history of deliberate self-harm, and a history of suicide attempts.18 Therefore, it is reasonable to conclude that in any patient diagnosed with depression, suicide risk screening should take place at the time of diagnosis, and at every follow-up intervention.

There is little evidence to determine best practices for how this can best be achieved. Not only is there a baseline risk that patients with depression may attempt suicide, but during the course of treatment the concern is that this risk may be increased transiently. As stated in the APA's Practice Guideline for Depression, "The risk of suicide in some patients recovering from major depressive disorder increases transiently as they develop the energy and capacity to act on self-destructive plans made earlier in the course of their illness."15 The FDA's review of relevant research on this topic in response to concerns about the safety of antidepressant use in children and adolescents has led to additional warnings and a "black box" warning for all antidepressant medications regarding their use in children and adolescents.19 The label change notes, "Pooled analyses of short-term (4-16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive compulsive disorder, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials."19

It is unclear whether this risk is the same for all drugs, or whether it extends to adults to this degree. Over the long-term, treating depression is necessary to reduce risk of injury, yet in the short-term the treatment may increase the risk, meaning that caregivers must be especially vigilant.


  1. Pleis JR, Lethbridge-Cejku M. Summary health statistics for U.S. adults: National Health Interview Survey, 2006. Vital Health Stat, Series 10 (235);Dec 2007:7-9.
  2. Miller L. Postpartum depression. JAMA. 2002 Feb 13;287(6):762-765.
  3. Qaseem A, Snow V, Shekelle P, Casey DE Jr, Cross JJ Jr, Owens DK. Evidence-based intervention to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146.
  4. Roose SP, Glassman AH, Seidman SN. Relationship between depression and other medical illnesses. JAMA. 2001 Oct 10;286(14):1687-1690.
  5. Crystal S, Sambamoorthi U, Walkup JT, Akincigil A. Diagnosis and treatment of depression in the elderly medicare population: predictors, disparities and trends. J Am Geriatr Soc. 2003 Dec;51(12):1718-1728.
  6. Unützer J. Clinical practice: late life depression. N Engl J Med. 2007 Nov 29;357(22):2269-2276.
  7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition/Text Revised. DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.
  8. Mulrow CD, Williams JW, Gerety MB, et al. Case-finding instruments for depression in primary care settings. Ann Intern Med. 1995 June 15;122(12):913-921.
  9. U.S. Preventive Services Task Force. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136(10):760-764.
  10. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003 Nov;41(11):1284-1292.
  11. Belmaker RH, Agam G. Mechanisms of disease: major depressive disorder. N Engl J Med. 2008 Jan 3;358(1):55-68.
  12. Mann JJ. The medical management of depression. N Engl J Med. 2005 Oct 27;353;17:1819-1834.
  13. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry. 2000 Apr;157(4 suppl):1-45.
  14. Fochtmann LJ, Gelenberg AJ. Practice Guideline for the Treatment of Patients with Major Depressive Disorders. 2nd ed. Arlington, VA: American Psychiatric Association; 2005. Accessed March 21, 2008.
  15. Karasu TB, Gelenberg A, Merriam A, Wang P. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2nd ed. April 2000. American Psychiatric Association. Accessed March 21, 2008.
  16. Gaynes BN, West SL, Ford CA, et al. Screening for suicide risk in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004 May 18;140(10):822-835.
  17. National Center for Injury Prevention and Control. WISQARS (Webbased Injury Statistics Query and Reporting System). Accessed March 24, 2008.
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  19. US Food and Drug Administration. Labeling change request letter for antidepressant medications. Rockville, MD; October 28, 2004. Accessed March 24, 2008.
Stakeholder Perspective

Depression is common and is associated with high costs to society. Improvements in case identification and treatment can be achieved through practice improvements and through the applications of more advanced care systems, through chronic disease state management techniques, improved patient education, telephone follow-up, and intensive case management. 1 These models may be developed through employer-provider models, payor-employer models, and so on.2

Once identified, patients must have access and the ability to afford appropriate treatment modalities. There must be no barriers to treatment, appropriate modalities must be able to be initiated quickly at diagnosis, and they must be continued uninterrupted through the course of treatment. Clinical professionals with expertise in medical management and psychotherapy must be available to initiate therapy.

Specialists with expertise must be made available to handle referrals for more specialized care, including those who do not respond to initial therapy, candidates for ECT, and more complex cases of depression with manic or with psychotic symptoms, or those at high risk for suicide.

  1. Dobscha SK, Corson K, Hickam DH, et al. Depression decision support in primary care: a cluster randomized trial. Ann Intern Med. 2006 Oct 3;145(7):477-487.
  2. Dietrich AJ, Oxman TE, Williams JW, et al. Re-engineering systems for the treatment of depression in primary care: cluster randomised controlled trial. Br Med J. 2004;329:602. doi:10.1136/bmj.38219.481250.55.
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