depresion articulo

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DepressionAuthor: Ravinder N Bhalla, MD, Assistant Clinical Professor of Child Psychiatry,

University of Medicine and Dentistry of New Jersey; Medical Director, Mental HealthClinic of Passaic; Consulting Staff, Christian Health Care CenterCoauthor(s):

Pascale Moraille-Bhalla, MD, Medical Director, Outpatient Clinic of Hoboken

University Medical Center; Staff Psychiatrist, Mental Health Clinic ofPassaic Contributor Information and Disclosures

Updated: Aug 17, 2010

Introduction

Major depression, also known as unipolar depression, is one of the more

commonly encountered psychiatric disorders. While many effective

treatments are available, this disorder is often underdiagnosed and

undertreated. Primary care providers should strongly consider thepresence of depression in their patients; studies suggest a high

prevalence of affective disorders among patients seeking medical

attention in the office setting. Following is a case study. A 30-year-old

presented to her primary care doctor with symptoms of frequent

headaches, insomnia, feeling overwhelmed, and have low energy.

Examination was unremarkable and blood workup supported mild iron

deficiency anemia. She returned after one month with improvement in

anemia but worsening of symptoms stated earlier. A Physician

Depression Questionnaire (PDQ-9) revealed that for several weeks she

was feeling sad and had little interest or pleasure in doing thing she used

to enjoy. She also had suicidal thoughts occasionally and could not

concentrate on tasks. She felt like a failure. There were no recognizable

losses. She stated that in the past she had similar feelings, but they were

less intense and lasted for shorter periods. She did not have any period

of euphoria or overproductivity. Her primary care physician prescribed

antidepressants and referred her to a psychiatrist. For related

information, see Medscape's Depression Resource Center.

Pathophysiology

The underlying pathophysiology of major depressive disorder (MDD) has

not been clearly defined. Clinical and preclinical trials suggest a

disturbance in CNS serotonin (ie, 5-HT) activity as an important factor.

Other neurotransmitters implicated include norepinephrine (NE) and

dopamine (DA).1 The role of CNS serotonin activity in the

pathophysiology of major depressive disorder is suggested by the

efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment


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of major depressive disorder. Furthermore, studies have shown that an

acute, transient relapse of depressive symptoms can be produced in

research subjects in remission using tryptophan depletion, which causes

a temporary reduction in CNS serotonin levels. Serotonergic neurons

implicated in affective disorders are found in the dorsal raphe nucleus,

the limbic system, and the left prefrontal cortex.

Clinical experience indicates a complex interaction between

neurotransmitter availability, receptor regulation and sensitivity, and

affective symptoms in major depressive disorder. Drugs that produce only

an acute rise in neurotransmitter availability, such as cocaine, do not

have the efficacy over time that antidepressants do. Furthermore, an

exposure of several weeks' duration to an antidepressant isusually necessary to produce a change in symptoms. This, together with

preclinical research findings, implies a role for neuronal receptor

regulation over time in response to enhanced neurotransmitter

availability.

All available antidepressants appear to work via 1 or more of the following

mechanisms: (1) presynaptic inhibition of uptake of 5-HT or NE; (2)

antagonist activity at presynaptic inhibitory 5-HT or NE receptor sites,

thereby enhancing neurotransmitter release; or (3) inhibition of

monoamine oxidase, thereby reducing neurotransmitter breakdown.2

Frequency

United States

Lifetime incidence of major depressive disorder is 20% in women and12% in men. Prevalence is as high as 10% in patients observed in a

medical setting.

International

Cultural influences on the presentation of depression can be significant.

The practitioner should be aware of differences in the expression of

psychological distress in patients from other countries or cultures.


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Some cultural patterns are mentioned in the Diagnostic and Statistical

Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR);

for example, major depressive disorder may be expressed as fatigue,

imbalance, or neurasthenia in patients of Asian origin.

Mortality/Morbidity

Major depressive disorder is a disorder with significant potential morbidity

and mortality, contributing as it does to suicide, medical illness, disruption

in interpersonal relationships, substance abuse, and lost work time.

Suicide ranks as a leading cause of death in the United States, with a

yearly rate of approximately 200,000 attempts. The number of completed

suicides for 2005 was 32,000.

Suicide continues to rank as the second leading cause of death in

adolescents and represents 10-30% of deaths in those aged 20-35

years. Major depressive disorder plays a role in more than one half of all

suicide attempts, while the death rate from suicide among those with

affective disorders can exceed 15%. Firearms are the most frequent

method used in completed suicides. Risk factors for suicide include (1)

male sex; (2) age older than 55 years; (3) concurrent chronic medical

illness; (4) social isolation (eg, divorced, widowed); (5) depression,especially with severe melancholic or delusional symptoms; (6) substance

abuse or dependence; (7) family history of suicide and/or major

depressive disorder; (8) command hallucinations; (9) access to firearms;

and (10) white race.

Studies also show that major depressive disorder contributes to higher

mortality and morbidity in the context of other medical illnesses, such as

myocardial infarction, and that successful treatment of the depressive

episode improves medical and surgical outcomes.Sex

Major depressive disorder is diagnosed more commonly in women, with a

prevalence twice that observed in men. In prepubertal children, boys and

girls are affected equally.

Age

The incidence of clinically significant depressive symptoms increases with

advancing age, especially when associated with medical illness orinstitutionalization.


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However, depression might not meet criteria for major depression

because of somewhat atypical features of depression in elderly persons.

Elderly persons experience more somatic complaints, cognitive

symptoms, and fewer complaints of sad or dysphoric mood. Of particular

importance is the increasing risk of death by suicide, particularly among

elderly men. Rates in women and men are highest in those aged 25-44

years.

Clinical

History

The DSM-IV-TR diagnostic criteria for a major depressive episode

are as follows:

A. At least 5 of the following, during the same 2-week period ,

representing a change from previous functioning; must include either (a)

or (b):

(a) Depressed mood

(b) Diminished interest or pleasure

(c) Significant weight loss or gain

(d) Insomnia or hypersomnia

(e) Psychomotor agitation or retardation

(f) Fatigue or loss of energy

(g) Feelings of worthlessness

(h) Diminished ability to think or concentrate; indecisiveness

(i) Recurrent thoughts of death, suicidal ideation, suicide attempt, or

specific plan for suicide

B. Symptoms do not meet criteria for a mixed episode (ie, meets criteria

for both manic and depressive episode).C. Symptoms cause clinically significant distress or impairment of

functioning.

D. Symptoms are not due to the direct physiologic effects of a substance

or a general medical condition.

E. Symptoms are not better accounted for by bereavement, ie, the

symptoms persist for longer than 2 months or are characterized by

marked functional impairment, morbid preoccupation with worthlessness,

suicidal ideation, psychotic symptoms, or psychomotor retardation.


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Sleep disorders: Obstructive sleep apnea, especially, can cause

significant medical and psychiatric symptoms and often is missed as a

diagnosis. Patients, and, if necessary, their partners, should be

interviewed regarding their sleep quality, daytime sleepiness, and

snoring. Polysomnography can help make the diagnosis and guide

treatment.

Infectious processes: These include syphilis, Lyme disease, and HIV

encephalopathy, which can cause mood and behavior changes.

Pharmacologic agents: Substances that can produce changes in mood

include antihypertensive medications (especially beta-blockers, reserpine,

methyldopa, and calcium channel blockers); steroids; medications that

affect sex hormones (eg, estrogen, progesterone, testosterone,

gonadotropin-releasing hormone [GnRH] antagonists); H2 blockers (eg,ranitidine, cimetidine); sedatives; muscle relaxants; appetite

suppressants; and chemotherapy agents (eg, vincristine, procarbazine, L-

asparaginase, interferon, amphotericin B, vinblastine).

Endocrinologic disorders: Disorders involving the hypothalamic-

pituitary-adrenal axis or thyroid are especially likely to produce changes

in mood. These include Addison disease, Cushing disease,

hyperthyroidism, hypothyroidism, prolactinomas, andhyperparathyroidism.

Substance use, abuse, or dependence: These can cause significant

mood symptoms. This is especially true of alcohol, cocaine,

amphetamines, marijuana, sedatives/hypnotics, and narcotics. Inhalant

abuse also should be considered, particularly among young male

patients. Other substance-related and psychiatric processes either can

present with mood disturbance as the primary symptom or can occur

together with major depressive disorder.

Axis I or II disorder: In cases in which another Axis I or II disorder is

present, a careful psychiatric review of systems should elicit the

alternative or additional diagnosis.

Seasonal affective disorder: Also known as SAD, this form of major

depressive disorder shows a seasonal pattern of exacerbation and

remission. SAD usually is treated with bright light therapy (BLT), with or

without antidepressant medication.


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Dysthymia: This mood disorder presents with low mood as a primary

symptom. Dysthymia can predate a depressive episode. The symptoms

of dysthymia alone do not meet criteria for major depressive disorder and

must be present for at least 2 years.

Anxiety disorders: Patients with anxiety disorders are at higher risk for

developing comorbid depression. In such patients, it is important to

identify the anxiety disorder because they often require specific treatment

approaches. Commonly encountered anxiety disorders include panic

disorder, obsessive-compulsive disorder, generalized anxiety disorder,

posttraumatic stress disorder, and phobia.

Eating disorders: People with eating disorders (EDs) also have a highrate of comorbid major depressive disorder and require specific treatment

approaches. These disorders include bulimia, anorexia nervosa, and ED

not otherwise specified. A large percentage of individuals in this last

group have binge-eating disorder (BED), which, while not currently listed

in the DSM-IV-TRas a specific diagnosis, constitutes most patients with

EDs.

Personality disorders: Certain personality disorders (eg, borderlinepersonality disorder) may present with mood changes as a prominent

symptom. Remember that the presence of a personality disorder can be

difficult to determine in the setting of acute affective symptoms. Many

patients who are depressed who appear labile, demanding, or

pathologically dependent look dramatically different once the depressive

episode has been treated adequately.

Physical

No physical findings are specific to major depressive disorder.

Diagnosis lies in the history and the mental status examination.

Appearance and affect

Most patients with major depressive disorder present to their physician

with a normal appearance.

In patients with more severe symptoms, a decline in grooming and

hygiene can be observed, as well as a change in weight. Patients may


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show psychomotor retardation, which is manifest as a slowing or loss of

spontaneous movement and reactivity. Together with this, major

depressive disorder often produces a flattening or loss of reactivity in the

patient's affect (ie, emotional expression).

Psychomotor agitation or restlessness also can be observed in some

patients with major depressive disorder.

Mood and thought process

Patients report a dysphoric mood state, which may be expressed as

sadness, heaviness, numbness, or sometimes irritability and mood

swings. They often report a loss of interest or pleasure in their usual

activities, difficulty concentrating, or loss of energy and motivation. Their

thinking often is negative, frequently with feelings of worthlessness,hopelessness, or helplessness. While it is not uncommon for patients with

major depressive disorder to show ruminative thinking, it is important to

evaluate each patient for evidence of psychotic symptoms because this

affects initial management.

Psychosis, when it occurs in the context of unipolar depression, usually

is congruent in its content with the patient's mood state; for example, the

patient may experience delusions of worthlessness or some progressivephysical decline. Symptoms of psychosis should prompt a careful history

evaluation to rule out a history of bipolar disorder, schizophrenia or

schizoaffective disorder, substance abuse, or organic brain syndrome.

Cognition and sensorium: Patients with major depressive disorder often

complain of poor memory or concentration. Most commonly, no significant

deficits are found on cognitive examination. If present, such findings may

represent pseudodementia; however, they may indicate an underlying

dementia or other organic brain syndrome and should be investigated.

The level of consciousness (ie, sensorium) should be normal. A

fluctuating or depressed sensorium suggests delirium, and the patient

should be evaluated for organic contributors.

Speech: Speech may be normal, slow, monotonic, or lacking in

spontaneity and content. Pressured speech should suggest mania, while

disorganized speech should prompt an evaluation for psychosis. Racing

thoughts could also be an indication of mania or hypomania.


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Thought content, suicidality, and homicidality

The thought content of patients who are depressed usually is consistent

with their dysphoric mood. Patients often report feeling overwhelmed or

inadequate, helpless, worthless, or hopeless.

Thought content always should be assessed for hopelessness, suicidal

ideation, or homicidal/violent ideation or intent.

A history of suicide attempts or violence is a significant risk factor for

future attempts, and this should be noted in the history.

Hallucinations and delusions, including command hallucinations, could be

part of presentation. These are usually mood congruent but could be

mood incongruent. These psychotic elements, especially command

hallucinations, are associated with increased suicidal and homicidal

actions.Depression screening tests such as PDQ-9 and Mood Disorder

Questionnaire (MDQ) could be used easily in a primary care setting

to screen for depression and bipolar disorder. The Hamilton and the

Beck Depression inventory could also be similarly useful but are more

detailed and time consuming.

CausesThe specific cause of major depressive disorder is not known. As with

most psychiatric disorders, major depressive disorder appears to be

multifactorial in its origin.

Biological contributors

Genetic susceptibility plays a role in the development of major depressive

disorder. Individuals with a family history of affective disorders (7%),

panic disorder, and alcohol dependence (8%) carry a higher risk for majordepressive disorder.

Certain neurologic illnesses increase the risk of major depressive

disorder. Examples include Parkinson disease, stroke, multiple sclerosis,

and seizure disorders.

Exposure to certain pharmacologic agents also increases the risk;

medications such as reserpine or beta-blockers, as well as abused

substances such as cocaine, amphetamine, narcotics, and alcohol are

associated with higher rates of major depressive disorder.


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Chronic pain, medical illness, and psychosocial stress also can play a

role in both the initiation and maintenance of major depressive disorder.

The psychological component of these risk factors is discussed below.

However, neurochemical hypotheses point to the deleterious effects of

cortisol and other stress-related substances on the neuronal substrate of

mood in the CNS.

Psychosocial contributors: While major depressive disorder can arisewithout any precipitating stressors, stress and interpersonal lossescertainly increase risk. Psychodynamic formulations find that significantlosses in early life predispose to major depressive disorder over thelifespan of the individual, as does trauma, either transient or chronic.

Differential Diagnoses

Adjustment Disorders Obsessive-Compulsive Disorder

Alcoholism Opioid Abuse

Anemia Panic Disorder

Anorexia Nervosa Personality Disorders

Anxiety Disorders Phobic Disorders

Apnea, Sleep Porphyria, Acute Intermittent

Bipolar Affective Disorder Posttraumatic Stress Disorder

Bulimia Premenstrual Dysphoric Disorder

Cannabis Compound

Abuse

Primary Hypersomnia

Chronic Fatigue Syndrome Primary Insomnia

Cushing Syndrome Prolactinoma

Dissociative Disorders Schizoaffective Disorder

Dysthymic Disorder Schizophrenia

Graves Disease Schizophreniform Disorder

Hashimoto Thyroiditis Sedative, Hypnotic, Anxiolytic Use

Disorders

Hypercalcemia Sleep Disorder, Geriatric

Hyperparathyroidism Somatoform Disorders

Hyperthyroidism Stimulants

Hypochondriasis Suicide

Hypoglycemia Syphilis

Hypopituitarism(Panhypopituitarism)

Systemic Lupus Erythematosus


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Hypothyroidism Thyroiditis, Subacute

Insomnia Vascular Dementia

Lyme Disease Wernicke-Korsakoff Syndrome

Menopause

Other Problems to Be Considered

Dementia due to HIV disease Thyrotoxicosis

Workup

Laboratory Studies

No diagnostic laboratory tests are available for diagnosis of major

depressive disorder. Based on the clinical history and physical findings,

focused laboratory studies are useful in excluding potential medical

illnesses that may present as major depressive disorder. These might

include the following:

CBC count

Thyroid-stimulating hormone (TSH)

Antinuclear antibody (ANA)

Erythrocyte sedimentation rate (ESR)

Vitamin B-12Rapid plasma reagin (RPR)

HIV test

Electrolytes and calcium levels and renal function test

Liver function tests

Blood alcohol, blood, and urine toxicology screen

ABG

Dexamethasone suppression test (Cushing disease)

Cosyntropin stimulation test (Addison disease)

Imaging Studies

CT scan or MRI of the brain

Other Tests : EEG

Procedures

Lumbar puncture for VDRL, Lyme antibody, cell count, chemistry, andprotein electrophoresis.


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Treatment

Medical Care

A wide range of effective treatments is available for major depressive

disorder. Brief psychotherapy (eg, cognitive behavioral therapy,

interpersonal therapy) has been shown in clinical trials to be an effective

treatment option, either alone or in combination with medication.

Medication alone also can relieve symptoms. However, the combined

approach generally provides the patient with the quickest and most

sustained response.

Initial pharmacotherapy: All antidepressants on the market are

potentially effective. Usually, 2-6 weeks at a therapeutic dose level areneeded to observe a clinical response. The choice of medication should

be guided by anticipated safety and tolerability, which aid in compliance;

physician familiarity, which aids in patient education and anticipation of

adverse effects; and history of prior treatments. Treatment failures often

are caused not by clinical resistance, but by medication noncompliance,

inadequate duration of therapy, or inadequate dosing.

SSRIs include fluoxetine (Prozac), paroxetine (Paxil), sertraline

(Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram(Lexapro). This group has the advantage of ease of dosing and low

toxicity in overdose. Common adverse effects include GI upset, sexual

dysfunction, and changes in energy level (ie, fatigue, restlessness).

Escitalopram has been shown to have superior efficacy to other

antidepressants in the treatment of more severe depression.5

Escitalopram has also been shown to be at least as effective as SNRIs

and better tolerated, even in severe depression.6

Selective serotonin/norepinephrine reuptake inhibitors (SNRIs)

include venlafaxine (Effexor) and duloxetine (Cymbalta).

Safety, tolerability, and side effect profiles are similar to that of the SSRIs,

with the exception that the SNRIs have been associated (rarely) with a

sustained rise in blood pressure. SNRIs can be used as first-line agents,

particularly in patients with significant fatigue or pain syndromes

associated with the episode of depression. The SNRIs also have an

important role as second-line agents in patients who have not responded

to SSRIs.


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Atypical antidepressants include bupropion (Wellbutrin), nefazodone

(Serzone), mirtazapine (Remeron), and trazodone (Desyrel). This group

also shows low toxicity in overdose and may have an advantage over the

SSRIs by causing less sexual dysfunction and GI distress.

Bupropion is associated with a risk of seizure at higher doses, especially

in patients with a history of seizure or EDs.

Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2-, and

histamine (H1) receptors and, thus, can be very sedating. Adverse effects

such as drowsiness and weight gain may tend to improve over time and

with higher doses.

Trazodone is very sedating and usually is used as a sleep aid rather than

as an antidepressant.A 2007 research review by the Agency for Healthcare Research and

Quality (AHRQ) compared 12 second-generation antidepressants:

bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,

mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and

venlafaxine.

The AHRQ review found that overall, 38% of patients did not respond

during 6-12 weeks of treatment with these agents, and 54% did not

achieve remission.7

The AHRQ noted that there is no reliable way to predict whether an

individual patient will respond. The average effectiveness of the

antidepressants appeared similar, but the studies reviewed were not

designed to test variation among patients responses to individual drugs.

However, the AHRQ did find moderately strong evidence of differences

among individual second-generation antidepressants with respect to

onset of action and some measures (eg, sexual functioning) that could

affect health-related quality of life.

Tricyclic antidepressants (TCAs) include amitriptyline (Elavil),

nortriptyline (Pamelor), desipramine (Norpramin), clomipramine

(Anafranil), doxepin (Sinequan), protriptyline (Vivactil), trimipramine

(Surmontil), and imipramine (Tofranil).

This group has a long record of efficacy in the treatment of depression

and has the advantage of lower cost. They are used less commonly now

because of the need to titrate the dose to a therapeutic level and because

oftheir considerable toxicity in overdose.


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Adverse effects largely are due to their anticholinergic and antihistaminic

properties and include sedation, confusion, dry mouth, orthostasis,

constipation, urinary retention, sexual dysfunction, and weight gain.

Caution should be used in patients with cardiac conduction abnormalities.

In a meta-analysis, Fournier et al evaluated the benefit of antidepressant

drugs compared with placebo according to initial symptom severity in

patients with depression. Six studies representing 718 patients were

included. The analysis found that the magnitude of medication superiority

over placebo increased with increases in baseline depression severity. In

patients with minimal or nonexistent depression symptoms, benefit of

antidepressant medication compared with placebo was measured as

minimal or nonexistent. Patients exhibiting very severe depressionshowed a substantial benefit with use of antidepressant drugs compared

with placebo.8

Nonpharmacologic treatments

Electroconvulsive therapy (ECT) is a highly effective treatment for

depression and may have a more rapid onset of action than drug

treatments. Advances in brief anesthesia and neuromuscular paralysis

have improved the safety and tolerability of this modality. Risks includethose associated with brief anesthesia, postictal confusion, and, more

rarely, short-term memory difficulties. ECT is used when a rapid

antidepressant response is needed, when drug therapies have failed,

when there is a history of good response to ECT, or when there is patient

preference. ECT is particularly effective in the treatment of delusional

depression.

Light therapy: Broad-spectrum light exposure has long been in use for the

treatment of SAD. Some evidence now exists that it may have some

efficacy in nonseasonal depression or as an augmenting agent with

antidepressant medication.

Transcranial magnetic stimulation: This modality is in investigational

stages for the treatment of major depressive disorder. Initial results

suggest that it may be an effective intervention without the risks and

adverse effects of ECT.

Vagus nerve stimulation also is in investigational stages and has shown

some efficacy in treatment-resistant depression.


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Consultations

Consultation can be important at many stages of the treatment process.

Certainly, consultation should be sought if treating physicians exhaust the

options with which they feel comfortable.

A psychiatrist must be involved in the care of patients in whom

more severe symptoms develop and for whom a more intensive level of

care will be needed (eg, suicidal ideation, psychosis, mania, severe

decline in physical health). Expertise in pharmacotherapy, other somatic

therapies, and psychotherapy should be readily available. Collaboration

of psychiatrists and family practitioners/internists is of particular

importance in patients with acute and chronic medical issues. A

psychologist can be involved if psychological testing or more intensive

specialized psychotherapy (eg, interpersonal therapy, cognitive behavior

therapy) is needed.

With the patient's consent, communication with the patient's therapist can

be invaluable in guiding medical treatment of major depressive disorder.

The therapist can provide information regarding clinical progress,

symptoms, and adverse effects. This can facilitate timely and appropriate

medical interventions.Diet

Dietary restrictions are necessary only when prescribing MAOIs. Foods

high in tyramine, which can produce a hypertensive crisis in the presence

of MAOIs, should be avoided. These foods include soy sauce,

sauerkraut, aged chicken or beef liver, aged cheese, fava beans, air-dried

sausage and similar meats, pickled or cured meat or fish, overripe fruit,

canned figs, raisins, avocados, yogurt, sour cream, meat tenderizer,

yeast extracts, caviar, and shrimp paste. Beer and wine also should be

avoided.

Activity

Physical activity and exercise contribute to recovery from major

depressive disorder. Patients should be counseled regarding stress

reduction.


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Medication

The following are examples from various classes of antidepressants and

augmenting agents that are used with TCAs or SSRIs to augment

therapeutic effect in resistant depression. Available medications fromeach class are listed in Treatment.

SSRIs are greatly preferred over the other classes of antidepressants.

Because the adverse effect profile of SSRIs is less prominent, improved

compliance is promoted. SSRIs do not have the cardiac arrhythmia risk

associated with tricyclic antidepressants. Arrhythmia risk is especially

pertinent in overdose, and suicide risk must always be considered when

treating a child or adolescent with mood disorder.

Physicians are advised to be aware of the following information and use

appropriate caution when considering treatment with SSRIs in the

pediatric population.

The FDA has asked that additional studies be performed because

suicidality occurred in both treated and untreated patients with major

depression and thus could not be definitively linked to drug treatment.

Antidepressants

Have central and peripheral anticholinergic effects, as well as sedative

effects, and block the active reuptake of NE and serotonin. SSRIs are

metabolized via the cytochrome P-450 system and may have drug

interactions on that basis. The degree of enzyme inhibition varies among

SSRIs. Effects on blood levels and bioavailability of coadministered drugs

account for most clinically significant SSRI-drug interactions.

Desipramine (Norpramin)

Commonly used TCA. Fairly specific NE reuptake inhibitor. May have

effects in the desensitization of adenyl cyclase and down-regulation of

beta-adrenergic or serotonin receptors. Tends to have fewer

anticholinergic and antihistaminic adverse effects than other TCAs.

Adult

25 mg PO qhs, increase gradually prn to 150-250 mg/d PO in divideddoses, not to exceed 300 mg/d Used with an SSRI (25-75 mg/d)


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Fluoxetine (Prozac)

Commonly used SSRI, first of the SSRIs to become available in the

United States. Selectively inhibits presynaptic serotonin reuptake with

minimal or no effect in reuptake of NE or DA.

Adult

20 mg PO qam, and increase after several wk by 20 mg/d; not to exceed

80 mg/d

Venlafaxine (Effexor)

Mixed serotonin and NE reuptake inhibitor. In addition, causes beta-

receptor down-regulation. In lower doses (75 mg/d) acts much like anSSRI. SSRI-like adverse effects such as GI upset often improve at higher

doses (150- 300 mg/d).

Adult

Immediate release: 75 mg/d PO divided bid/tid with food, and increase in

75 mg/d increments q4d to 225-375 mg/d Extended release: 75 mg PO

qd with food, and increase in 75 mg/d increments q4d to 225 mg/d; for

some new patients may be desirable to start at 37.5 mg/d for 4-7 d beforeincreasing to 75 mg qd

Desvenlafaxine (Pristiq)

Selective serotonin and norepinephrine reuptake inhibitor (SNRI)

indicated for treatment of major depressive disorder (MDD).

Adult

50 mg PO qd (swallow whole, do not divide, crush, chew, ordissolve) Moderate renal impairment: 50 mg PO qd Severe renal

impairment: 50 mg PO qod

Duloxetine (Cymbalta)

Potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Antidepressive action is theorized to be due to serotonergic and

noradrenergic potentiation in CNS.


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Adult

20 mg PO bid; may increase to 60 mg/d administered qd or divided as 30

mg bid

Lithium carbonate (Eskalith, Lithane, Lithobid)

Can be used as an effective augmenting agent in combination with an

antidepressant in cases of treatment-resistant depression. Influences

reuptake of serotonin and/or NE at cell membrane. Serum levels should

be monitored weekly to biweekly until levels are stabilized, at which point,

levels can be checked every 3-4 months. Serum levels can be tested

after 5 days at a given dose, usually just prior to the am dose. As with

most medications, the lowest effective dose should be used to avoid

adverse effects and toxicity.

Adult

600-1800 mg/d PO in divided doses; maximum usual maintenance dose

is 2.4 g/d or 450-900 mg bid of sustained release form Target blood

levels may be lower than those needed in bipolar disorder, but should be

above 0.4 mEq/L (reference range: 0.4-0.8 mEq/L)

Buspirone (BuSpar)

Marketed as an antianxiety medication; however, may have

antidepressant effect at doses above 45 mg/d. Effects may increase

when used in combination with SSRIs and TCAs. Buspirone is a partial 5-

HT agonist with serotonergic and some dopaminergic effects in CNS. Has

anxiolytic effect but may take up to 2-3 wk for full efficacy.

Adult

15 mg/d PO divided tid and increase by 5 mg/d q2-4d; not to exceed 60

mg/d

Mirtazapine (Remeron, Remeron SolTab)

Exhibits both noradrenergic and serotonergic activity. In cases of

depression associated with severe insomnia and anxiety, has been

shown superior to other SSRI drugs. Adult 15 mg (range 15-45 mg) PO

hs; dose increases should not be made more frequently than q1-2wk


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Escitalopram (Lexapro)

SSRI and the S-enantiomer of citalopram. Used to treat depression and

appropriate as first-line agent. Mechanism of action is thought to be

potentiation of serotonergic activity in CNS resulting from inhibition ofCNS neuronal reuptake of serotonin. Onset of depression relief may be

obtained after 1-2 wk, which is sooner than other antidepressants.

Adult

10 mg PO qd initially; if needed, may increase to 20 mg/d after 1 wk

Tranylcypromine (Parnate)

Treats major depression. Binds irreversibly to MAO, thereby reducingmonoamine breakdown and enhancing synaptic availability.

Adult

10 mg PO bid; titrate as tolerated with 10-mg increments; usual dose is

30-60 mg/d PO in divided doses

Selegiline transdermal patch (Emsam)

Irreversible MAOI. Has greater affinity for MAO-B compared with MAO-A;however, at antidepressant doses, inhibits both isoenzymes. MAO-A and

MAO-B catabolize neurotransmitter amines in CNS (eg, norepinephrine,

dopamine, serotonin). Indicated for treating MDD. At lowest strength (ie, 6

mg delivered over 24 h), may be used without the dietary restrictions

required for oral MAOIs used to treat depression.

Adult

Starting dose: 6 mg/24 h patch; apply topically once q24h; removeprevious day's patch when applying new patch Dosage range: 6-12

mg/24 h patch; if dose increase is warranted, increase by 3 mg/24 h at

>2-wk intervals; not to exceed 12 mg/24 h Apply to dry, intact, nonoily,

nonhairy skin on upper torso (ie, below neck, above waist), upper thigh,

or outer surface of upper arm; avoid reapplication to same site on

consecutive days


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Follow-up

Further Inpatient CareInpatient care is indicated in major depressive disorder when there is a

risk of harm to the patient, to others, or when the patient's symptoms are

sufficiently severe to warrant initiation of treatment in a more controlled

setting. These commonly include situations of depression with psychotic

features, progressive inanition, suicidality, or inability to care for oneself at

home. When ECT is indicated as therapy, many practitioners initiate

treatment on an inpatient basis, although outpatient initiation of therapy is

increasingly common.

The current climate of insurance controls on treatment typically does not

allow prolonged inpatient stays in the treatment of major depressive

disorder. Hospitalization is used more commonly to control acute severe

symptoms, with early discharge to home or to lower levels of care such as

partial hospitalization.

Further Outpatient Care

The successful treatment of major depressive disorder requires good

follow-up care after the acute episode is resolved. This ongoing care

usually takes place in an outpatient setting.

Major depressive disorder tends to be a recurrent condition. While some

patients experience a single episode, observing recurrences over time is

more common (50-80%). A percentage of individuals have relapses of

sufficient frequency to warrant long-term use of antidepressants as a

preventive therapy. Other patients can discontinue treatment after

resolution of an episode and can restart treatment when symptoms

reappear. Most studies suggest that, once an episode is resolved

successfully, treatment should be continued for 6 months to 1 year to

reduce the risk of relapse of symptoms. The decision to continue

treatment beyond that time depends on patient preference and past

history of recurrences.

If antidepressants need to be discontinued, the clinician should taper offthe medication.


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In a recent study, latency to relapse was 0.4 vs 1 in a group of patients

who relapsed after their antidepressant (any class) was tapered (due to

any reason) over 1-7 days compared with the group who had a slower

discontinuation over 7-14 days. This study has clinical implications that

tapering over 7-14 days is helpful for discontinuation symptoms

associated with certain antidepressants and it also delays relapse in

relapsed patients for all antidepressants.11

Psychotherapy is an invaluable treatment modality in the management of

major depressive disorder, addressing as it does both potential

precipitating and maintaining factors of the depressive episode. In

moderate-to-severe depression, psychotherapy is most effective once the

somatic and melancholic symptoms have improved with medication.While psychotherapy can help with the interpersonal and cognitive

dysfunction that can arise from, and predispose to, depressive illness,

long-term psychotherapy does not appear to have a major role in treating

major depressive disorder.

Complications

Potential complications of major depressive disorder may develop across

the biopsychosocial spectrum.

Medical: Completed suicides number more than 30,000 per year in the

United States. Other adverse outcomes may arise from attempts at self-

injury, untreated medical conditions, or physical decline due to inanition.

Medical and surgical prognosis and recovery also are affected adversely

by concurrent major depressive disorder.

Psychosocial: Major depressive disorder, particularly when chronic or

untreated, can contribute to unemployment or failure in school, social

isolation, substance abuse, and marital/family dysfunction.

Prognosis

With appropriate treatment, 70-80% of individuals with major depressive

disorder can achieve a significant reduction in symptoms, although as

many as 50% of patients may not respond to the initial treatment trial.


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Untreated at 1 year, 40% of individuals with major depressive disorder will

continue to meet criteria for the diagnosis, while an additional 20% will

have a partial remission. Partial remission and/or a history of chronic

major depressive disorder are risk factors for recurrent episodes and

treatment resistance.

Patient Education

Education plays an important role in the successful treatment of major

depressive disorder. Patients should be aware of the rationale behind the

choice of treatment, potential adverse effects, and expected results. The

involvement of the patient in the treatment plan can enhance medication

compliance and referral to counseling. Over the long term, patients also

may become aware of signs of relapse and may seek treatment early.

For excellent patient education resources, visit eMedicine's Depression

Center. Also, see eMedicine's patient education article Depression.

The following Web sites are great resources for patient and family

education:

National Institute of Mental Health, Depression

MedlinePlus, Depression

FamilyDoctor.org, Depression

Depression and Bipolar Support Alliance

Families for Depression Awareness

Miscellaneous

Medicolegal PitfallsThe most common medical pitfall in the treatment of major depressive

disorder is the management of treatment-resistance depression (TRD).

According to Rush et al, 67% of patients fail to remit with first-line

therapy.12The Sequenced Treatment Alternatives to Relieve Depression

(STAR*D) trial applied various treatment strategies with an final remission

rate of 67%. At this point, reassessing, diagnosing, and treating the

patient becomes important, as well as having a broad range of strategies

available to offer the patient.


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Assessment should include (1) adequacy of medication dose, duration of

treatment, and compliance; (2) accuracy of diagnosis and possible

medical conditions; and (3) possible comorbid psychiatric conditions such

as substance abuse, anxiety disorders, or personality disorders.

Assuming that (1) the assessment of the diagnosis is correct, (2) there

are no significant complicating diagnoses, and (3) the current treatment

has been at a therapeutic dose for a sufficient amount of time, possible

interventions for persistent symptoms can include the following:

Increasing the medication dose to the maximum tolerated

Changing to a different antidepressant

Adding psychotherapy or more intensive care if not already

completed

Augmenting the current medicationConsidering the use of ECT

Augmentation combinations can include the following:

Lithium plus any antidepressant

Buspirone plus a TCA or SSRI

Triiodothyronine added to any antidepressant

A TCA added to an SSRI

Methylphenidate or dextroamphetamine added to any

antidepressant other than an MAOI

Aripiprazole (Abilify) was recently approved as an adjunct to

antidepressants. More recently, 3 positive, double-blind, placebo-

controlled trials investigating the use of adjunctive aripiprazole in major

depressive disorder were published.

In the first such study, Berman and colleagues focused on the use of

aripiprazole augmentation for patients resistant to up to 1-3 retrospective

(historical) antidepressant trials.13To confirm treatment resistance, those

patients underwent an 8-week, open-label trial with either an SSRI

(fluoxetine, sertraline, paroxetine, or escitalopram) or an SNRI

(venlafaxine).

The patients who made insufficient symptom improvement had either

aripiprazole or placebo added to their SSRI or SNRI regimen, under

double-blind conditions and for a total of 6 weeks. A statistically

significant difference in remission rates was also observed, with 26%

remission for aripiprazole versus 15% remission for placebo (P


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This study also reported relatively low rates of discontinuation due to

intolerance in the 2 treatment groups (2% for aripiprazole and 1.7% for

placebo (P>.05).

The results of a second study of identical design recently presented at a

major scientific meeting also demonstrated greater remission rates for

patients treated with adjunctive aripiprazole compared with patients given

placebo. The results of these 2 trials lead to the approval, by the US Food

and Drug Administration (FDA), of a new treatment indication for

aripiprazole as adjunctive treatment to antidepressants for

antidepressant-resistant major depressive disorder. This was the first-

ever approval for an adjunctive treatment in major depressive disorder,

and the first-ever approval for the use of any medication for treatment-

resistance depression by the FDA.14

The third trial also demonstrated that aripiprazole augmentation is

efficacious and well-tolerated in patients with major depressive disorder

who have not adequately responded to antidepressant monotherapy. The

primary outcome was improvement in depressive symptoms as assessed

by a decrease in the Montgomery-Asberg Depression Rating Scale

(MADRS).15

Another common pitfall in the treatment of major depressive disorderinvolves the risk of suicidal or homicidal behavior. Routinely interviewing

patients at each visit for suicidal or homicidal ideation and documenting

the assessment are important. Legitimate concern regarding the patient's

safety, or his or her possible danger to others, takes precedence over

confidentiality. In such circumstances, the physician has a duty to act

either to prevent self-injury suicide or to warn an identified potential target

of violence.

Another common pitfall is misdiagnosing bipolar depression as major

depressive disorder, which leads to insufficient or inadequate treatment if

not switching to an outright manic episode. Some patients with treatment-

resistance depression may fall under this phenomena. The Mood

Disorders Questionnaire is helpful in this differentiation between unipolar

and bipolar depression.16 Screening Assessment of Depression-Polarity

(SAD-P) found presence of delusions during a current episode of major

depression, a number of prior episodes of depression, and a family

history of major depression or mania to be highly correlated with bipolarmajor depression.17


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The STEP-BD study demonstrated that when treating bipolar depression,

using a mood stabilizing medication alone resulted in a similar outcome

compared with using a mood stabilizer plus an antidepressant

medication. Therefore, adding the antidepressant medications showed no

additional benefit. In addition, the results suggested that adding

paroxetine or bupropion to the mood stabilizer showed no increased risk

of hypomanic or manic symptoms. Lamotrogine was found to be helpful in

bipolar depression but only quetiapine is FDA-approved for treatment of

acute bipolar depression.18

Special Concerns

Pregnancy can present a potentially difficult clinical situation when

complicated by depression. Major depressive disorder is quite common in

women during the childbearing years. Major depressive disorder can

have a significant negative impact on a woman's experience of pregnancy

and parenting, as well as on her functioning as a new parent. As with all

medical conditions that arise during pregnancy, the risks and benefits of

pharmacotherapy should be evaluated.

While it is preferable to avoid the use of medication during pregnancy, the

benefits of prompt medical treatment of major depressive disorder oftenmay outweigh the risks of exposure of the fetus to an antidepressant.

While untested in controlled trials, there is no clear evidence that

available antidepressants are teratogenic. In severe depression during

pregnancy, especially in cases of psychosis, agitation, or severe

retardation, ECT can be the safest and quickest treatment option.

Depression in the postpartum period is a common and, potentially, very

serious problem. Prompt diagnosis and intervention are essential to

mitigate the negative impact on the mother and her infant.

More than 80% of women can develop mood disturbances in the

postpartum period. Most of these women experience a transient

syndrome called baby blues, which is characterized by tearfulness and

mood changes that resolve spontaneously in a few days to 2 weeks.

However, more than 10% of women meet criteria for major depressive

disorder during the first year following delivery. Many of these patients

are not identified as depressed and do not receive treatment.


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Postpartum psychosis, while far less common, does occur, and is more

likely to arise in patients with a history of psychosis or bipolar disorder.

Principles of treatment forpostpartum major depressive disorderare the

same as for depression during any other time of life. The patient should

be assessed for danger to herself or to her children, as well as for other

symptoms such as psychosis or substance abuse. Most antidepressants

probably can be used safely during breastfeeding; however, this has not

been studied thoroughly, and the same risk-benefit considerations should

be applied as when treating depression during pregnancy.

Seasonal affective disorder

This is a form of major depressive disorder that arises during the winter

months and resolves during the spring and summer months. Studiessuggest that SAD also is mediated by alterations in CNS 5-HT. SAD

appears to be triggered by alterations in circadian rhythm and sunlight

exposure. Patients with SAD are more likely to report atypical symptoms

such as hypersomnia and increased appetite. BLT for SAD is used at an

intensity of 10,000 lux for 30-90 minutes daily, usually within an hour of

arising in the morning.

As with any effective antidepressant, therapeutic light boxes have the

potential to precipitate a manic episode in susceptible individuals. Othercommon adverse effects include eye irritation, restlessness, and transient

headaches. These lamps are not a significant source of UV light.

Conventional antidepressants, with or without BLT, also can be used to

treat SAD.

Remission versus response

In recent years, an increased emphasis has been on achieving remission

in the treatment of depression. Remission is defined as having minimal or

no symptoms (17-item Hamilton Depression Rating Scale [HAMD 17]

score 7). Patients who do not achieve remission are more likely to have

a relapse.

Response is defined as a 50% reduction in symptoms.


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