Depression

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

University of Medicine and Dentistry of New Jersey; Medical Director, Mental Health
Clinic of Passaic; Consulting Staff, Christian Health Care Center Coauthor(s):
Pascale Moraille-Bhalla, MD, Medical Director, Outpatient Clinic of Hoboken
University Medical Center; Staff Psychiatrist, Mental Health Clinic of
Passaic 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 the
presence 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
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 is
usually 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 and

12% 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.
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 or
institutionalization.
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.
Atypical presentations
Patients with major depressive disorder may not initially present with a
complaint of low mood, anhedonia, or other typical symptoms.
In the primary care setting, where many of these patients first seek
treatment, the presenting complaints often can be somatic, such as
fatigue, headache, abdominal distress, or change in weight. Patients may
complain more of irritability than of sadness or low mood.
Elderly persons may present with confusion or a general decline in
functioning.
Of teenagers diagnosed with major depressive disorder, bipolar disorder
is diagnosed in 50% of them as they grow into adulthood. Further
research is needed in this area.

The differential diagnosis in patients presenting with alterations in mood

is extensive and should include consideration of the following:

Mood disorders secondary to CNS conditions: These include a broad

range of physiologic and structural CNS processes that can produce
changes in mood and behavior. Note that major depressive disorder can
produce measurable cognitive deficits or a worsening of preexisting
dementia. This decline in cognitive functioning, which, on formal testing,
appears to arise from impaired concentration or motivation, is referred to
as pseudodementia or, more currently, as dementia of depression and
should remit with successful treatment of the depressive episode. Major
depressive disorder does not cause focal neurologic signs. Such findings
should prompt an evaluation for other organic syndromes.

Alzheimer disease: This disease and other degenerative and vascular

dementias can be associated with affective symptoms. Mood disorders
are very prominent in Parkinson disease, Huntington disease, multiple
sclerosis, stroke, and seizure disorders.

Neoplastic lesions of the CNS: These lesions also can cause changes
in mood and behavior before the onset of focal neurologic signs.
Inflammatory conditions: Conditions such as systemic lupus
erythematosus (SLE) can produce a wide range of neuropsychiatric signs
and symptoms, likely because of alterations in the blood-brain barrier and
an autoimmune cerebritis.
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, and
hyperparathyroidism.
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.
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 high
rate 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-TR as a specific diagnosis, constitutes most patients with
EDs.

Personality disorders: Certain personality disorders (eg, borderline

personality 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
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 progressive
physical 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.
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.

Causes
The 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 major
depressive 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.
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 arise

without any precipitating stressors, stress and interpersonal losses
certainly increase risk. Psychodynamic formulations find that significant
losses in early life predispose to major depressive disorder over the
lifespan 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 Primary Hypersomnia
Abuse
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 Systemic Lupus Erythematosus
(Panhypopituitarism)
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-12
Rapid 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, and
protein electrophoresis.
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 are
needed 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.
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
of their considerable toxicity in overdose.
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 depression
showed 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 include
those 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.
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.
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 from
each 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 divided

doses, not to exceed 300 mg/d Used with an SSRI (25-75 mg/d)
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 an
SSRI. 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 before
increasing 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, or

dissolve) 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.
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
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 of
CNS 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 reducing

monoamine 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; remove

previous 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
Follow-up
Further Inpatient Care
Inpatient 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 off

the medication.
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.
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 Pitfalls
The 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.12 The 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.
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 medication
Considering 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.13 To 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 <.05).
 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 disorder
involves 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 bipolar
major depression.17
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 often
may 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.
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 for postpartum major depressive disorder are 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. Studies
suggest 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. Other
common 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.