Online Medical Reference

Recognition and Treatment of Depression

George E. Tesar

Published: August 2010

Definition and etiology

Depression is a descriptive term often misused as a diagnostic label. Its misapplication can lead to diagnostic errors and mismanagement. Depression is more aptly used to describe a symptom-behavior complex that can be the predominant clinical manifestation of a heterogeneous group of disorders including major depressive disorder (MDD), bipolar disorder (BPD), substance-induced mood disorders, and mood disorder due to a general medical condition.

The symptoms of MDD are nonspecific and are therefore easily confused with a long list of other psychiatric and medical illnesses. Accurate recognition requires that the clinician have a high index of suspicion and know the diagnostic criteria for MDD. In this regard, it is important to distinguish a major depressive episode (MDE) from MDD. An MDE typically represents a single or recurrent episode of MDD, but not necessarily. It could be a consequence of chronic substance abuse, a transient response to life-altering medical illness, or an episode of BPD. In each of these examples, the approach to comprehensive management of an MDE differs from the management of an MDE occurring in the context of MDD. Like other medical illnesses, MDD has significant morbidity and mortality.1 It often complicates other conditions (e.g., diabetes mellitus, stroke, cancer, heart disease) and makes them more difficult to treat.2 It also accelerates mortality from these and other medical illnesses.3

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Prevalence and risk factors

The National Comorbidity Survey Replication (NCS-R) is the most recent, broad-based assessment of MDD in the community.4 The NCS-R gathered data on prevalence rates, severity, disability, and rate and quality of treatment for MDD. The 12-month and lifetime prevalence of clinically significant MDD in the NCS-R were 6.6% and 16.2%, respectively. MDD tends not to occur in isolation; 75% to 80% of persons with either 1-year or lifetime MDD had a comorbid anxiety or substance-related disorder. Although 51.6% of patients received some treatment, only 21.7% of the total population of patients with MDD received adequate treatment during a 1-year period.

The first MDE usually occurs during adolescence or early adulthood. There is a bimodal curve of prevalence, with one peak in the late 20s and early 30s and a second peak around 65 to 70 years of age.

Women are affected by MDD two to three times more often than men. This may be explained by psychobiologic risk factors (e.g., menstrual cycle and pregnancy, gender-related vulnerability to interpersonal conflict or loss) and women's tendency to seek health care more than men do.

MDD occurs at higher rates in patients who seek general medical care. Nearly 70% of all antidepressant prescriptions are written by primary care physicians.5 Depressed patients are high users of medical care, and high users of medical care in general are more likely to have one or more psychiatric disorders. In one study, the 1-month prevalence of MDD in a group of high users was 40.3%.6

The risk of developing MDD is manifold and complex.7 Risk factors include current stress burden; history of early trauma, neglect, abuse, or deprivation; personal and family histories of mood and anxiety disorders; comorbid medical and psychiatric disorders; and personality disorder. Stress is a common, although not invariable, trigger of MDEs, and anyone can develop an MDE. Some, however, especially those with recurrent episodes and family histories of mood, anxiety, or substance abuse disorders, are more likely to develop an MDE even when stress levels are judged to be low. Certain medical disorders (e.g., stroke, neurodegenerative disorders, human immunodeficiency virus [HIV] infection, acquired immunodeficiency syndrome [AIDS], endocrine disorders) are associated with a higher than expected rate of MDD. Diabetes, for example, doubles the odds of comorbid MDD.8 A meta-analysis of studies that examined the prevalence of MDD in adults with diabetes showed that the prevalence of comorbidity was significantly higher in diabetic women (28%) than in diabetic men (18%) and in clinical (32%) rather than community (20%) samples.8

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Pathophysiology and natural history

Emerging data support the hypothesis that stress, genetic predisposition, and early life experiences interact to increase the risk of MDD. Our understanding of the precise pathophysiologic mechanisms of MDD continues to evolve.

Family and twin studies suggest that genetic factors predispose to recurrent MDD.7 There is no one depression gene, nor is depression determined exclusively by genetic factors. Rather, it is more likely that multiple interacting genes code for factors that influence both vulnerability and resilience in the face of stress. One such factor appears to be a polymorphism in the promoter region of the serotonin transporter gene.9,10

The timing of stress is also important. Abnormal stress (e.g., neglect, abandonment, physical or sexual abuse) at critical developmental periods can have long-lasting effects on central nervous system development and function.11

A variety of studies suggest that brain regions involved in depression include the amygdala, hippocampus, hypothalamus, and prefrontal cortex.12 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 regulating serotoninergic activity, an activity that may be impaired in depression.12

Understanding of the biology of neurotransmission has progressed significantly beyond an appreciation of neurotransmitter synthesis, release, and activation of postsynaptic cell-surface receptors.13 Signal transduction pathways mediated by second and third messengers (e.g., cyclic adenosine monophosphate [cAMP], protein kinases, and neurotrophic 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 (i.e., weeks) than the more-rapid changes in neurotransmission (i.e., hours to days). Moreover, studies of treatment response suggest a close correlation between antidepressant use and increased levels of proteins, such as brain-derived neurotrophic factor (BDNF).13 Central hypercortisolemia can mediate stress-induced effects on the brain that are reversed by antidepressant-induced BDNF production.11,13

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Signs and symptoms

Most clinicians recognize depression when they see it, or perhaps feel it. The welling up of tears in a patient's eyes, sluggishness, demoralization, or a pessimistic attitude attract the experienced clinician's attention to the possibility of an MDE. Any one symptom of an MDE, however, is not specific and may be present in diverse disorders (see “Differential Diagnosis”). Moreover, even the experienced clinician who suspects depression must withhold a reflexive impulse to diagnose and treat it. Not all depressive signs and symptoms are diagnostic of MDD.

Symptoms of anxiety (e.g., worry, nervousness, tension, panic attacks) often accompany depression. These can either be secondary to an MDE or represent a comorbid anxiety disorder (see elsewhere in this section, “ Anxiety Disorders”). The presence of anxiety often confounds the diagnosis of MDD and encourages treatment with benzodiazepines or other minor tranquilizers rather than antidepressant medication. The clinician must be careful to do a thorough evaluation for MDD 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), and substance abuse or dependence.

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For a diagnosis of MDD to be considered, a patient must have five or more of the symptoms or signs listed in Box 1, and at least one of those symptoms must be either depressed mood or loss of interest. These symptoms must be present most of the time nearly every day for a period of 2 or more weeks.14 The well-known mnemonic SIG: E CAPS, developed by Carey Gross (personal communication), can be used to recall these important signs and symptoms (Box 2).

Box 1: Signs and Symptoms of a Major Depressive Episode
Depressed or sad mood*
Markedly diminished interest or pleasure in all or almost all activities, especially those the individual normally enjoys*
Sleep disturbance (insomnia or hypersomnia)
Feeling of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick, but rather a firmly held conviction that might in some instances be considered delusional)
Fatigue or loss of energy
Indecisiveness or diminished ability to think or concentrate
A change in appetite (typically decreased, but can be increased in atypical depression), or a significant weight change (>5% of body weight) when not intentionally trying to lose or gain weight
Psychomotor agitation or retardation nearly every day
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

* One or the other of these must be present for a diagnosis of major depressive episode.
Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000.

Box 2: Mnemonic Used for Diagnosis of Major Depressive Episode: SIG: E CAPS*
SSleep disturbance. Typically, difficulty staying asleep; less often, difficulty falling asleep
IInterest, pleasure, or enthusiasm for usual activities is diminished
GGuilt, self-doubt, or loss of self-esteem that is excessive or unwarranted
EEnergy level is diminished
CConcentration (or attention) span is poor or worse than usual
AAppetite is impaired. Typically it is diminished and associated with weight loss, but in some cases the patient overeats and gains weight
PPsychomotor activity is abnormal. Typically the patient moves and thinks more slowly; some patients, especially the elderly, can be more restless, explosive, or agitated
SSuicidal  thoughts, hopelessness, or thoughts that the patient (and often others) would be better off if the patient were dead

* Signatura (label or let it be printed) for energy capsules.
Adapted from Carey Gross, MD.

A common error is to regard depressive symptoms as an understandable reaction to grave or disabling medical illness. Neither the severity nor meaning of a precipitating or stressful event is directly relevant to the diagnosis of an MDE. Whether or not a sufficient triggering event has occurred, the diagnosis of an MDE depends instead on the presence of a critical number of signs and symptoms (see “Signs and Symptoms”) lasting a sufficient duration. If careful evaluation discloses sufficient number and duration of signs and symptoms, then regardless of the precipitating event the clinician is obliged to make a diagnosis of MDE and recommend appropriate treatment.

MDD is diagnosed (Box 3) exclusively from information obtained at the clinical interview and mental status examination (see elsewhere in this section, “ Behavioral Assessment of the General Medical Patient”). 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 MDD. Laboratory testing is useful only to help rule out medical conditions that can mimic MDD (e.g., hypothyroidism, vitamin B12 deficiency, sleep apnea).

Box 3: Diagnostic Criteria for Major Depressive Disorder
Five or more of the 9 symptoms listed in Box 1, at least one of which is either:
Depressed or sad mood
Markedly diminished interest or pleasure in all or almost all activities, especially those the individual normally enjoys
Symptoms are present most of the day, nearly every day for at least 2 weeks
Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
Symptoms are not better accounted for by bereavement*
Symptoms do not meet criteria for a mixed episode

* On average, bereavement lasts 2 months or less. Grief-triggered symptoms lasting longer than 2 months suggest evolution of a major depressive episode.
A mixed episode is defined by the presence of both depressed and manic symptoms. In addition to having depressive symptoms, the person with a mixed episode is typically irritable, explosive, labile (switches unpredictably from one emotion to another), and pressured (difficult to interrupt). A mixed episode is more consistent with a diagnosis of bipolar disorder rather than major depression and requires different treatment (see the chapter on bipolar disorder).
Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC, American Psychiatric Association, 2000.

Symptom clustering is not the only criterion on which the diagnosis is based. The symptoms must also be present for a sufficient period (most of the time nearly every day for at least 2 weeks) and in one way or another must be distressing or disabling.

The term major in MDD is potentially misleading because it suggests that severity or seriousness is a diagnostic criterion. In fact, MDEs are rated mild, moderate, or severe depending on how distressing or disabling they are. An MDE can be a first and only lifetime occurrence of depression, or it can be a recurrent episode of MDD. Current protocol is to diagnose MDE as either “MDD, single episode” (DSM IV-TR, 296.20) if there is no past history of MDE, mania, or hypomania, or “MDD, recurrent” (DSM IV-TR, 296.30) if there has been at least one past MDE, and to specify whether the episode is mild, moderate, severe, or associated with psychotic features (the fifth digit of the diagnostic code is rated as 1, 2, 3, or 4, respectively).

Subtypes of MDD include seasonal, postpartum, atypical, and psychotic depressions. Seasonal depression, or seasonal affective disorder (SAD), is diagnosed when depressive episodes occur exclusively during one season or another. Most SAD occurs during autumn and winter (October to March), although a small subset occurs during the summer months. Postpartum depression should be considered when depressive symptoms continue beyond 2 weeks after parturition and satisfy diagnostic criteria for MDD. The designation atypical refers to MDEs that are triggered by environmental stresses (especially rejection) and characterized by social withdrawal, hypersomania, and hyperphagia. Finally, psychotic depression is a serious, life-threatening form of MDD associated with a higher rate of suicide and a subsequent dementia rate that is higher than in nonpsychotic MDD. Further discussions of these MDD subtypes appear later.

Detection of an MDE in the context of debilitating medical illness is often difficult. This is because the vegetative symptoms of depression (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 (e.g., crying, expressions of hopelessness or giving up, loss of motivation, excessively low self-esteem). The likelihood of MDD increases significantly when these psychological symptoms accompany the other, nonspecific vegetative symptoms.

Other data that can help confirm or support a clinician's suspicion of MDD include past MDEs (not necessarily detected or formally treated), a family history of mood or anxiety disorders, alcoholism or suicide, and survey tools (Table 1) that screen for depression (see “Screening and Prevention,” later).

Table 1: Patient-Rated Screening and Case-Finding Instruments for Major Depressive Disorder
Instrument Website Reference
Beck Depression Inventory II* Harcourt Assessment.
Beck AT, Ward CH, Mendelson M, et al: An inventory for measuring depression. Arch Gen Psychiatry 1961;4:53-63.
Zung Self-Rating Depression Scale (pdf) Zung WWK. A rating instrument for anxiety disorders. Psychosomatics 1971;12:371-379
PRIME-MD (self-report format)* Archives - PHQ.doc Spitzer RL, Williams JBW, Kroenke K, et al: Patient Health Questionnaire Study Group. Validity and utility of a self-report version of PRIME-MD: The PH Primary Care Study. JAMA1999;282:1737-1744.
Patient Health Questionnaire-9 Kroenke K, Spitzer RL, illiams JB. The PH-9: Validity of a brief depression severity measure. J Gen Int Med. 2002;16:606-613.
Shedler's Quick PsychoDiagnostics Panel 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.

*Copyrighted material for purchase.
These instruments provide measures of major depressive disorder as well as other behavioral disorders that are common in primary care (e.g., panic disorder, generalized anxiety disorder, eating disorders, alcohol abuse, and somatization).
PRIME-MD, Primary Care Evaluation of Mental Disorders.

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Differential diagnosis

Psychiatric diagnoses that warrant consideration when a patient presents with depressive signs and symptoms are listed in Box 4. Grief is a normal, expected response to loss or the threat of loss and is not a diagnosis. Prolonged (unresolved) grieving, however, can become an MDE. Adjustment disorder with depressed mood is a transient, dysfunctional, but generally self-resolving response to stress that lacks sufficient diagnostic criteria for a diagnosis of MDE. The recommended treatment for adjustment disorder with depressed mood is psychotherapy and not antidepressant medication.

Box 4: Differential Diagnosis of Major Depressive Disorder: Psychiatric Disorders
  • Bipolar disorder
  • Cyclothymia
  • Dysthymia
  • Agoraphobia
  • Generalized anxiety disorder
  • Posttraumatic stress disorder
  • Social anxiety disorder
  • Alcohol- or drug-induced mood disorder
  • Amphetamine or cocaine withdrawal
  • Hypochondriasis
  • Somatization disorder
  • Avoidant
  • Borderline
  • Histrionic
  • Narcissistic
Organic Mental
  • Delirium (hypoactive)
  • Dementias (subcortical)
  • Mild cognitive impairment
  • Adjustment disorder with depressed mood
  • Attention deficit disorder

MDD is one of a number of mood disorders including dysthymia, BPD, and cyclothymia.14 Dysthymia and cyclothymia are considered subsyndromal variants of MDD and BPD, respectively. Dysthymia is diagnosed when chronic low-grade depressive symptoms (insufficient number and intensity to qualify as MDE) are present 50% of the time or more for 2 or more years. Dysthymia often accompanies chronic, disabling medical illness and is less responsive to antidepressant treatments than MDD. This may be explained in part by the continuing stress of enduring medical symptoms and disability, or it may be due to the ineffective coping of a patient with a personality disorder.

Bipolar disorder (BPD) is an essential consideration in the differential diagnosis of MDD. An MDE—not mania or hypomania—is the most common clinical presentation in patients with BPD. Correct identification of bipolar depression (MDE in the context of BPD) depends on eliciting a history of manic or hypomanic episodes. This can be difficult and time-consuming for even the most astute clinician. However, making the correct diagnosis has important implications for treatment selection and prognosis (see elsewhere in this section, “ Bipolar Disorder”).

Diagnoses that resemble but by definition are not mood disorders include adjustment disorder with depressed mood, depression secondary to a general medical condition, and substance-related mood disorder.14 The causes of these are different from those of MDD, and they therefore warrant a different approach to management. In most instances the diagnosis of adjustment disorder with depressed mood is relevant to persons who do not have a personal or family history of mood disorder. Depression secondary to a general medical condition and substance-related mood disorder imply that the MDE has been triggered by and will resolve with treatment of the underlying medical condition or chemical dependency.

Because depressive symptoms are nonspecific, both patient and primary care specialist generally feel obliged first to rule out other medical conditions (Box 5). When a full constellation of signs and symptoms that meet diagnostic criteria for an MDE is present, however, MDD should be handled as a diagnosis of inclusion rather than exclusion. Early and effective treatment with antidepressant medication need not interfere with a thorough medical workup. Moreover, a successful response to antidepressant medication could forestall unnecessary laboratory testing and repeat office visits.

Box 5: Differential Diagnosis of Major Depressive Disorder: General Medical Conditions
  • Fibromyalgia
  • Polymyalgia rheumatica
  • Adrenal insufficiency
  • Cushing's syndrome
  • Diabetes
  • Hyperparathyroidism
  • Testosterone deficiency
  • Thyroid dysfunction
  • Infectious mononucleosis
  • Influenza
  • Tertiary syphilis
  • Tuberculosis
  • Viral hepatitis
  • Disseminated carcinomatosis
  • Pancreatic cancer
  • Dementias
  • Frontal lobe syndrome
  • Huntington's disease
  • Mild cognitive impairment
  • Parkinson's disease
  • Periventricular small vessel disease
  • Postconcussive syndrome
  • Sleep apneas
  • Anticholinesterases (donepezil)
  • Beta blockers (especially propranolol)
  • Corticosteroids
  • Contraceptives
  • Cyclosporine
  • H2 Blockers (cimetidine, famotidine, ranitidine)
  • Interferon
  • Methyldopa
  • Metoclopramide
  • Reserpine
  • Vincristine
  • Vinblastine
Vitamin Deficiency
  • B12
  • C
  • Folate
  • Niacin
  • Thiamine

AIDS/HIV, acquired immunodeficiency syndrome or human immunodeficiency virus infection

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General Approach

The standard of care for a moderate to severe MDE (not an MDE occurring in the context of BPD or ongoing substance abuse) combines antidepressant medication with patient education, psychotherapy, or other nondrug treatments. Because a mild MDE is often self-limited, the best approach in any given patient may be to withhold treatment and monitor. This should not be viewed as permission to ignore or overlook mild depression. 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.

Suicide Risk Assessment

The workup of a patient with depressive symptoms must include an assessment of suicide risk (see elsewhere in this section, “ Psychiatric Emergencies”). Most patients with mood disorders do not make suicide attempts or commit suicide. However, at least 50% of suicides are committed by patients with a mood disorder. If the patient does not spontaneously mention or allude to suicidal thoughts or thoughts of death, the clinician must ask. Contrary to the beliefs of some, asking does not sow the seed of suicidal thinking. Although patients are typically reluctant to talk about such issues, they generally experience relief when given the opportunity to do so.

The patient who has risk factors for suicide (e.g., personal or family history of attempts or completions, alcoholism, drug abuse, severe anxiety, violence, or impulsivity) and asserts intent or plan should be referred for urgent or emergent evaluation. Clinician skill, judgment, and experience as well as resource availability influence disposition and whether a routine (within 2 weeks), urgent (within 24-48 hours), or emergent (within 12 hours on site or at another site—emergency department or psychiatrist's office—to which the patient's transport is assured) referral is made.

Patient Education

Patients are often relieved when a diagnosis has been identified that accounts for their symptoms. The stigma of a diagnosis of MDD can be dispelled with information about its medical underpinnings and the availability of effective treatments. Educating the patient helps foster a strong therapeutic alliance and adherence to treatment.

In addition to medication, a variety of treatments are indicated for MDD and include psychotherapy, exercise, light therapy, and a growing number of neuromodulation techniques, the most established of which is electroconvulsive therapy (ECT) (discussed later).

Antidepressant Medications

General Approach

The pharmacologic treatment of MDD is generally divided into three phases: acute, continuation, and maintenance. The indications, goals, duration, and strategies of treatment during these phases are presented in Table 2 and can also be reviewed by consulting the Agency for Healthcare Research and Quality (formerly the Association for Health Care Policy and Research).15

Table 2: Phases of Treatment with Antidepressant Medication
Phase of Treatment Typical Duration Indication(s) Goals Strategy
Acute 4-12 wk Single or recurrent episode of major depression Remission of index episode Select antidepressant

Start at subtherapeutic dose to minimize risk of side effects

Increase at roughly weekly intervals to therapeutic dose

Refer to psychiatrist instead or after two unsuccessful medication trials
Continuation 4-6 mo Goal of acute phase treatment achieved Continued remission
Prevent relapse (return of the index episode)
Continue same dose required to achieve remission during acute phase

Monitor for relapse

If relapse occurs, increase dose, initiate augmentation strategy, or switch to new agent
Maintenance >9-12 mo

Optimal duration is uncertain
Three prior episodes of depression or

Two prior episodes plus

First-degree relative with major mood disorder;

Recurrence within 1 yr of prior effective treatment;

Onset of first episode before age 20 yr;

Both episodes were severe, sudden, or life-threatening in the past 3 yr
Prevent recurrence of depression Continue same dose used successfully during continuation phase

Monitor for recurrence

Increase dose, initiate augmentation strategy, or switch to a new agent if there is a recurrent episode

Adapted from Agency for Health Care Policy and Research: Clinical Practice Guideline: Depression in Primary Care, vols. I and II. Washington, DC, U.S. Government Printing Office, 1993.

Antidepressant medication should be considered for moderate to severe MDD.16 A large variety of antidepressants is available (see Table 2). There is no single best agent, and selection depends on the patient's antidepressant treatment history, potential drug interactions, and desired side-effect profile (Tables 2,and 3,) and Table 4 (opens in new window).

Table 3: Antidepressant Drugs Approved by the FDA*
Generic Trade Drug Class Date of Approval (m/d/y) Starting Dose (mg/d) Therapeutic Range (mg/d) Half-Life§ (h) Schedule
Amitriptyline Elavil TCA 4/7/1961 25 150-300 12-24 qhs
Amoxapine Asendin NSRI 9/22/1980 100 200-300 8-30 bid
Bupropion Wellbutrin NDRI 12/30/1985 75 300-450 20 tid
Wellbutrin SR NDRI 10/4/1996 100 300-450 20 bid
Wellbutrin XL NDRI 8/29/2003 150 300-450 20 qd
Citalopram Celexa SSRI 7/17/1998 10 20-40 35 qd
Desipramine Norpramin TCA 11/20/1964 25 150-300 21-23 qd
Doxepin Sinequan TCA 9/23/1969 25 150-300 17-51 qhs
Duloxetine Cymbalta NSRI 8/3/2004 20 30-60 12 bid
Escitalopram Lexapro SSRI 8/14/2002 10 10-20 27-32 qd
Fluoxetine Prozac, Serafem SSRI 12/29/1987 10 20 4-16 d qd
Imipramine Tofranil TCA 4/16/1959 25 150-300 11-25 qhs
Tofranil PM TCA 3/11/1973 75 qhs
l-Deprenyl Emsam (Selegiline) MAOI 2/27/2006 6 12 10 qd**
Maprotiline Ludiomil NRI/TetraCA 12/1/1980 25 150 43-90 qhs
Mirtazapine Remeron Other 6/14/1996 15 15-45 20-40 qhs
Nefazodone‡‡ Other 9/16/2003 200 600 2-4 bid-tid
Nortriptyline Pamelor TCA 8/1/1977 10 75-150 16-44 qd
Paroxetine Paxil SSRI 12/29/1992 10 20-40 24 qd
Paxil-CR SSRI 2/16/1999 12.5 25-62.5 21 qd
Phenelzine Nardil MAOI 6/9/1961 15 45-90 12 bid-tid
Protriptyline Vivactyl TCA 9/27/1967 5 15-30 60-90 tid
Sertraline Zoloft SSRI 12/30/1991 50 50-200 26 qd
Tranylcypromine Parnate MAOI 2/21/1961 10 20-60 4-8 bid-tid
Trazodone†† Desyrel Other 12/24/1981 100 300-600 3-9 bid-tid
Trimipramine Surmontil TCA 6/12/1979 25 11-23 qhs
Venlafaxine Effexor NSRI 12/28/1993 25 225-375 5-11 tid
Effexor XR NSRI 10/20/1997 37.5 225-375 5-11 qd

* Obtained from FDA website on January 1, 2007.
Elderly, debilitated, or anxious patients might need to start treatment at lower doses than these.
Increase dose until either therapeutic or adverse effects occur.
§ The wide ranges reported are a function of active metabolites or individual metabolic rates.
Still in production but have limited usefulness because of the adverse effect profiles. Therefore, use is relegated to severe, treatment-resistant depression. Amoxapine and maprotaline can cause severe extrapyramidal side effects and have low toxic-to-therapeutic ratios, leading to elevated risks of seizures and cardiac arrhythmias at high-normal doses. The U.S. manufacturer discontinued production of Serzone when a small number of reports of fatal hepatitis appeared in the literature. Several generic manufacturers, however, continue to produce it.
The levo-isomer and therefore a close chemical relative of citalopram, escitalopram has distinctive activity that distinguishes it clinically from citalopram.
**Administered transdermally from a patch that must be changed daily.
††In low doses (50-150 mg) it is effective for promoting and maintaining sleep.
‡‡No longer manufactured.
FDA, United States Food and Drug Administration; MAOI, monoamine oxidase inhibitor; NDRI, norepinephrine-dopamine reuptake inhibitor; NRI/TetraCA, norepinephrine reuptake inhibitor/tetracyclic antidepressant; NSRI, norepinephrine-serotonin reuptake inhibitor; SSRI, serotonin selective reuptake inhibitor; TCA, tricyclic antidepressant.

There is no test available that predicts individual response to antidepressant medication in general or to any single agent in particular. Empirical trial and error are necessary, with a favorable response in roughly one half and remission in nearly one third of patients with a single therapeutic medication trial.17 If the first agent is ineffective, the diagnosis should be reviewed for accuracy and then, if depression is still present, another antidepressant should be tried. At least one within-class alternative should be tried before switching to an agent from a different class (see Table 2).17

Many patients who initially respond favorably still have residual symptoms. Increasing the antidepressant dosage, using 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.

Selecting Antidepressants

Familiarity with antidepressant classes and side-effect profiles helps inform treatment selection (see Tables 2 and 3). In an antidepressant-naïve patient, virtually any antidepressant qualifies as a first-line agent. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro), enjoy the widest prescription in the United States and are generally the first to be prescribed. Compared with SSRIs, bupropion (Wellbutrin), mirtazapine (Remeron), and the norepinephrine-serotonin reuptake inhibitors (NSRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta) have similar efficacy and favorable side-effect profiles. Many clinicians consider venlafaxine and duloxetine superior to SSRIs, but the database is insufficient to verify this impression.

Unlike the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), all of these newer antidepressants have a lower risk of cardiovascular side effects and are comparatively safe in overdose. SSRIs and NSRIs can cause sexual dysfunction (delayed or inhibited sexual climax) in 25% to 40%, whereas bupropion, mirtazapine, and nefazodone are much less likely to do so. The risk of hypertension increases with daily doses of venlafaxine greater than 225 mg. Mirtazapine, like TCAs (e.g., amitriptyline, imipramine, doxepin), can cause unacceptable weight gain, and it also increases the risk of orthostatic hypotension. The U.S. manufacturer of Serzone (nefazodone) discontinued the product in 2004 because of reports of fatal liver toxicity. Generic nefazodone, however, continues to be manufactured. Like maprotaline and amoxapine (see Table 2), it should be reserved for treatment-resistant MDD when other agents have failed.

After remission has been achieved in the acute phase, the antidepressant dosage used to achieve remission should be continued for another 4 to 6 months.15 Thereafter, the decision to prescribe maintenance therapy depends on the number and severity of past MDEs.

Any decision to discontinue medication should be followed by gradually tapering medication. This involves reducing the total daily dosage by approximately 30% weekly, or more slowly if the patient develops withdrawal symptoms (e.g., tremulousness, excitability, vertigo, nausea, or other nonspecific discomfort). Attempts to discontinue antidepressant medication may be thwarted either by the patient's intolerance of withdrawal or by recurrence of depressive symptoms. Distinguishing drug withdrawal from symptom recurrence can be difficult but is best accomplished by prolonging the taper.

Therapeutic Trial

Fundamental to all successful antidepressant therapy is a therapeutic trial of adequate dosage and adequate duration of treatment.15 There is substantial evidence that a majority of patients with MDD do not receive adequate treatment trials.4 The clinician must arrange for follow-up to ensure that the maximum 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 for at least 6 weeks. No response to a therapeutic dose of medication by week 4, however, is an almost certain indication that another agent should be tried.15


Psychotherapy alone may be effective for mild to moderate MDD or as an adjunct to antidepressant medication for moderate to severe MDD.15 Most primary care physicians are unlikely to provide psychotherapy, but knowledge about this treatment modality should facilitate selection and referral of appropriate patients. 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. The goal of psychotherapy is to relieve depressive symptoms by exploring for and resolving issues such as grief, cognitive distortions, role changes, interpersonal disputes, and impaired coping.


Exercise should be recommended to all depressed patients. Numerous studies substantiate its positive effect on mood. If nothing else, exercise provides a structured activity that, when performed regularly, can enhance the depressed patient's sense of competence and self-esteem.

Light Therapy for Seasonal Affective Disorder

Light therapy has been used effectively to treat seasonal depression. SAD (or seasonal mood disorder) is a subtype of MDD that occurs annually, usually starting in fall or winter and ending in spring or early summer. It is more than just “winter blues” or “cabin fever.” Morning light therapy for at least 30 minutes every day is the most effective treatment. 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.

An unusual form of SAD that occurs during the summer months appears to be triggered by unusual heat sensitivity. Not surprisingly, the treatment involves minimizing heat exposure.

Electroconvulsive Therapy and Other Neuromodulation Technologies

Electroconvulsive therapy (ECT) is perhaps the most effective antidepressant treatment available.15 It is typically used only as a last resort because of the need for hospital-level care and general anesthesia. A significant number of patients who are resistant to antidepressant medication, however, benefit from ECT. Maintenance ECT is indicated for those whose recurrent depressions do not respond to maintenance antidepressant medication.

Vagus nerve stimulation (VNS) received Food and Drug Administration approval in 2005 for treatment of refractory depression. Its special value may be in reducing the need for ECT and medication therapies in the maintenance phase of treatment.

Other novel neuromodulation techniques that are still under investigation include repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS). The efficacy of rTMS remains controversial, and the need for daily treatments administered by a technician presents logistic challenges. The use of DBS for treatment-refractory depression has produced some exciting results, but the scope of its application has yet to be determined.

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Prevention and screening

The primary prevention of MDD depends on socioeconomic and biologic strategies that alter risk factors, such as economic deprivation, child abuse and neglect, and genetic predisposition. Probably the most that can be done at present, however, is in the realm of secondary and tertiary prevention. This involves overcoming barriers to timely recognition and treatment of MDD. Education, universal access to treatment, and provision of uniformly effective treatments are important and as-yet-unachieved goals.

Survey instruments can be used to assist in diagnosing MDD (see Table 1). They have been used either to screen for depression and other common psychiatric disorders or to verify and reinforce the diagnosis of clinical impression. Survey instruments can be completed by hand, telephone, or computer without requiring the clinician's valuable time. An important incidental finding in studies using computer-driven technologies is that patients are more likely to reveal personal information to a computer than they are in a face-to-face clinical encounter.

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. Rather than ignoring or avoiding such information, a more effective measure is to delegate responsibility for follow-up to another clinician in the practice (e.g., physician's assistant, clinical nurse specialist). 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.18

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Special populations

Geriatric Age Group

In general, geriatric depression responds well to traditional therapies, but it takes longer to respond to antidepressant medications, and elderly patients can exhibit greater sensitivity to potentially activating agents (e.g., fluoxetine, sertraline, and bupropion). Use of TCAs and other agents that cause postural hypotension should be reserved for second- or third-line use. Use of venlafaxine in the elderly is associated with a higher-than-average risk of urinary hesitancy or retention. Patients with periventricular small-vessel disease and those with multiple lacunar infarcts can present with signs and symptoms that resemble depression (e.g., apathy, psychomotor retardation, lack of initiative), and for these reasons might respond to antidepressant medication suboptimally or not at all.

Children and Adolescents

All patients treated with antidepressants should be carefully monitored at all times for intensification of suicidal thinking, but especially following initiation of treatment. There appears to be a greater risk of antidepressant-induced suicidal ideation shortly after starting antidepressant medication in children and adolescents. It is believed that undiagnosed BPD may be an important variable that accounts for this finding.

Pregnant Women

All antidepressant medications are classified as Class C by the Food and Drug Administration. Although all antidepressant medications pose an unsubstantiated risk to the developing fetus, withholding of antidepressant medication in cases of moderate to severe depression can also pose substantial risk to both the mother and fetus. Therefore, any woman who becomes pregnant and is either taking antidepressant medication or might require it should be referred for consultation to a psychiatrist, preferably one with specialty knowledge in this area.

Substance Abusers

Detection of substance abuse, like MDD, often requires a high index of suspicion. When both occur simultaneously, the standard of care is to require cessation of substance abuse followed by reassessment to determine continuing indication for antidepressant treatment. Many MDEs that occur in the context of substance abuse resolve with cessation of the abused substance, particularly alcohol. Cessation of cocaine dependence, however, is typically followed by severe depression that requires aggressive antidepressant treatment. Treatment with antidepressant medication is necessary when MDD is comorbid with substance abuse, but timing is important to avoid implying to the patient that antidepressant treatment is compatible with continued substance use.

Suicidal Patients and Others at Risk

Not all patients who voice suicidal thinking are at imminent risk of self harm. Because of the difficulty of accessing specialty services it behooves the generalist to develop some sophistication in risk assessment (see elsewhere in this section, “ Psychiatric Emergencies”).

Psychotic Patients

Patients with MDD and psychosis require aggressive antidepressant and antipsychotic treatment. If oral medication is ineffective, then ECT is indicated. In general, the first priority in the treatment of psychotic depression is control of psychotic thinking and behavior. Administration of an atypical antipsychotic usually serves this purpose. Olanzapine (Zyprexa) 2.5 to 5 mg or quetiapine (Seroquel) 25 to 100 mg daily are recommended starting doses. Referral to a psychiatrist is recommended if improvement is not rapid.

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  • Major depressive disorder, a common medical disorder with clinically significant morbidity and mortality, is often undiagnosed and undertreated.
  • Detection of a major depressive episode in the primary care setting often requires a high index of suspicion.
  • Case-finding (or screening) instruments can be used for early detection, verification of clinical impression, or data collection and documentation.
  • Optimal treatment of a major depressive episode depends on whether it represents an episode of recurrent major depressive disorder or bipolar disorder or if it is a consequence of medical illness or substance abuse.
  • A therapeutic trial of antidepressant medication constitutes a sufficient dosage taken for a sufficient period of time.
  • Nonpharmacologic antidepressant therapies include brief psychotherapy, exercise, and light therapy; these are effective either alone or in combination with antidepressant medication.

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Suggested Readings

  • Agency for Health Care Policy and Research (AHCPR): Clinical Practice Guideline: Depression in Primary Care, Volumes I & II. Washington, DC: U.S. Government Printing Office, 1993.
  • American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association, 2000
  • 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.
  • 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.
  • DeBattista C, Schatzberg AF. Psychotropic dosing and monitoring guidelines. Primary Psychiatry. 2006, 13: 61-81.
  • Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry. 1999, 46: 1181-1191.
  • Heim C, Newport DJ, Bonsall R, et al: Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001, 158: 575-581.
  • Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in women. Am J Psychiatry. 2002, 159: 1133-1145.
  • Kessler RC, Berglund P, Demler O, et al: The epidemiology of major depressive disorder. Results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003, 289: 3095-3105.

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  2. American Psychiatric Association. Practice Guideline for Psychiatric Evaluation of Adults. 2nd ed 2006, Washington, DC: American Psychiatric Association,
  3. Stuart MR, Libermann JA. The Fifteen Minute Hour: Applied Psychotherapy for the Primary Care Physician. 2nd ed 1993, Westport, Conn: Praeger,
  4. World Health Organization. Integrating mental health services into primary health care. 2007, Geneva: World Health Organization,
  5. 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.
  6. Trzapacz PT, Baker RW. The Psychiatric Mental Status Examination. 1993, New York: Oxford University Press,
  7. Strub RL, Black FW. The Mental Status Examination in Neurology. 2nd ed 1987, Philadelphia: FA Davis,
  8. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975, 12: (3): 189-198.
  9. Borson S, Scanlon J, Brush M, et al: The Mini-Cog: a cognitive “vital signs” measure for dementia screening in multilingual elderly. Int J Geriatr Psychiatry. 2000, 15: 1021-1027.
  10. Rush JA, Pincus HA, First MB, et al: Handbook of Psychiatric Measures. 2000, American Psychiatric Association: Washington DC,
  11. Kroenke K, Spitzer RL. The PHQ-9: A new depression and diagnostic severity measure. Psychiatr Ann. 2002, 32: 509-521.
  12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed 2000, Washington, DC: American Psychiatric Association,
  13. Jackson JL, Kroenke K. Difficult patient encounters in the ambulatory clinic: Clinical predictors and outcomes. Arch Int Med. 1999, 159: 1069-1075.

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