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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.
Frequency
United States
International
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.
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:
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).
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.
Physical
No physical findings are specific to major depressive disorder.
Diagnosis lies in the history and the mental status examination.
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.
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.
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.
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.
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)
Adult
Adult
Venlafaxine (Effexor)
Adult
Desvenlafaxine (Pristiq)
Adult
Duloxetine (Cymbalta)
Adult
Buspirone (BuSpar)
Adult
Adult
Tranylcypromine (Parnate)
Adult
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
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.
The following Web sites are great resources for patient and family
education:
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
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.