eMedicine Specialties > Psychiatry > Adult

Depression

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
Pascale Moraille-Bhalla, MD, Medical Director, Outpatient Clinic of Hoboken University Medical Center; Staff Psychiatrist, Mental Health Clinic of Passaic; Sarah C Aronson, MD, Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland

Updated: May 26, 2009

Introduction

Background

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 Questionaire (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 overproductiviy. 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.

Race

Depression is less common in the black population.

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. For more information about childhood depression, see Mood Disorder: Depression.

Clinical

History

The DSM-IV-TR diagnostic criteria for a major depressive episode are as follows:

• 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.
  • Children with major depressive disorder may also present with initially misleading symptoms such as irritability, decline in school performance, or social withdrawal. Depression can occur in preschool children.³ René Spitz described what he called anaclitic depression in infants being raised in an orphanage.⁴ Childhood depression seems to be a more severe form of the same disorder in adults. Evidence-based treatment guidelines are limited. 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

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).
• 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. Venlafaxine and duloxetine are discussed in more detail in the Medication section.
• St. John's wort (Hypericum perforatum)
  • While St. John's wort is considered a first-line antidepressant in many European countries, it has gained popularity in the United States only recently. Uses include treatment of mild-to-moderate depressive symptoms.
  • Research indicates that it acts as an SSRI and not as a monoamine oxidase inhibitor (MAOI) as previously believed.
  • The dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential.
• 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.⁵
  
  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.
• MAOIs include phenelzine (Nardil) and tranylcypromine (Parnate).
  • MAOIs are widely effective in a broad range of affective and anxiety disorders.
  • Because of the risk of hypertensive crisis, patients on these medications must follow a low-tyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction.
• 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.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, this agency decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except fluoxetine (Prozac), which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the US Food and Drug Administration (FDA) issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. 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.

Dosing

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)

Pediatric

<6 years: Not established
6-12 years: 1-5 mg/kg/d PO in equally divided doses; not to exceed 5 mg/kg/d
>12 years: 25-50 mg/d PO, gradually increase prn to 100 mg/d PO in single or divided doses; not to exceed 150 mg/d

Interactions

Decreases antihypertensive effects of clonidine, but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates; marked increases in blood level of desipramine when used with P-450 2d6 inhibitors such as fluoxetine and paroxetine

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; recent postmyocardial infarction; cardiac conduction abnormalities; receiving MAOI or fluoxetine currently or within past 2 wk

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

All TCAs are toxic in overdose; caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, patients receiving thyroid replacement, and elderly individuals

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.

Dosing

Adult

20 mg PO qam, and increase after several wk by 20 mg/d; not to exceed 80 mg/d

Pediatric

<18 years: Not established; initial doses of 5-10 mg/d PO in children aged 5-18 y have been used; usual maximum dose is 20 mg/d
>18 years: Administer as in adults

Interactions

Increases toxicity of diazepam and trazodone by decreasing clearance; raises blood levels of TCAs, warfarin, neuroleptics, carbamazepine, phenytoin, and benzodiazepines; reduces conversion of codeine to active metabolite, thereby reducing analgesic effects; increases toxicity of highly protein-bound drugs
Serotonin syndrome may occur when used with other serotonergic agents such as buspirone, meperidine, tramadol, dextromethorphan, triptans, mirtazapine, nefazodone, and other SSRIs, but especially with MAOIs

Contraindications

Documented hypersensitivity; currently taking MAOI or within past 2 wk

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic impairment and history of seizures; MAOI should be discontinued at least 14 d before initiating fluoxetine therapy

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).

Dosing

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

Pediatric

Not established

Interactions

Cimetidine, MAOI, sertraline, fluoxetine class 1-C antiarrhythmics, TCAs, and phenothiazines may increase effects of venlafaxine

Contraindications

Documented hypersensitivity; current MAOI or within past 2 wk; uncontrolled hypertension

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Avoid abruptly stopping venlafaxine because withdrawal symptoms (dizziness, malaise) can be prominent; adjust dose in hepatic or renal failure; may experience hypertension; caution in patients with cardiovascular disorders

Desvenlafaxine (Pristiq)

Selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for treatment of major depressive disorder (MDD).

Dosing

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

Pediatric

Not established

Interactions

Hypertensive crisis may occur when coadministered with MAOIs (see Contraindications); coadministration with other drugs known to affect serotonergic neurotransmitter systems (eg, SSRIs, triptans) increases risk of serotonin syndrome (ie, agitation, hallucinations, coma, tachycardia, labile blood pressure, hyperthermia, hyperreflexia, incoordination, nausea, vomiting, diarrhea); may increase bleeding risk when coadministered with NSAIDs, aspirin, or warfarin; caution when coadministered with other drugs that affect CNS (eg, alcohol); coadministration with CYP3A4 inhibitors (eg, ketoconazole) may result in higher desvenlafaxine serum levels; may inhibit CYP2D6 and decrease clearance of CYP2D6 substrates (eg, desipramine)

Contraindications

Documented hypersensitivity; coadministration with or within 14 d of stopping an MAOI; allow 7 d after stopping desvenlafaxine before starting an MAOI

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for clinical worsening and suicide risk; may increase risk of suicidal ideation and behavior in children, adolescents, and young adults when taken for MDD or other psychiatric disorders; may cause or exacerbate serotonin syndrome, hypertension, narrow-angle glaucoma, cardiovascular disease, hypercholesterolemia, hypertriglyceridemia, hyponatremia, interstitial lung disease and eosinophilic pneumonia, and seizures; when discontinuing, gradually taper downward to avoid discontinuation symptoms; may exacerbate or activate mania associated with bipolar disorder; caution with renal impairment (decrease dose)

Duloxetine (Cymbalta)

Potent inhibitor of neuronal serotonin and norepinephrine reuptake. Antidepressive action is theorized to be due to serotonergic and noradrenergic potentiation in CNS.

Dosing

Adult

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

Pediatric

Not established

Interactions

Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase blood levels and toxicity; moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines [eg, thioridazine], type 1C antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAOIs may cause serious, sometimes fatal, reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes, including extreme agitation, delirium, and coma (see Contraindications)

Contraindications

Documented hypersensitivity; uncontrolled narrow-angle glaucoma; do not administer within 14 d after stopping MAOIs; do not initiate MAOIs within 5 d of stopping duloxetine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating

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

Dosing

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)

Pediatric

<6 years: Not established
6-12 years: 15-60 mg/kg/d PO divided tid/qid; not to exceed usual adult dose
>12 years: Administer as in adults

Interactions

Drug levels may be reduced by urinary alkalinizing agents (eg, acetazolamide); lithium increases toxicity of thiazide diuretics, haloperidol, phenothiazines, neuromuscular blockers, carbamazepine, fluoxetine, ACE inhibitors, NSAIDs, metronidazole, and calcium channel blockers

Contraindications

Documented hypersensitivity; severe cardiovascular disease; renal failure; pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Prior to beginning lithium therapy, obtain baseline BUN, creatinine, TSH, CBC, and electrolytes; pregnancy should be excluded; obtain baseline ECG for individuals >40 y or with heart disease
Advise patients of possible adverse effects (eg, GI distress, polydipsia/polyuria, acne, weight gain, mild cognitive changes, fine hand tremor); reduce GI symptoms and tremor by using divided doses; manage acne with interventions (eg, benzoyl peroxide)
Hypothyroidism can occur, and TSH should be monitored q6mo; diabetes insipidus has occurred and responds to discontinuation of the drug, little evidence that lithium causes renal damage over time; benign leukocytosis often appears, and requires no intervention unless there is evidence of another underlying problem
ECG showing T-wave flattening or inversion requires no intervention unless there is suspicion of a separate cardiac condition
Counsel patients to maintain adequate water intake because dehydration or restricted sodium intake can enhance lithium reabsorption by the kidney and lead to toxicity; reduce doses if creatinine clearance is decreased and in elderly persons
Prolongs effects of neuromuscular blockers; lithium toxicity is related closely to serum levels and can occur at therapeutic doses; serum lithium determinations are required to monitor therapy

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.

Dosing

Adult

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

Pediatric

Not established

Interactions

Toxicity is increased with MAOIs, phenothiazines, and CNS depressants; increases toxicity of digoxin and haloperidol

Contraindications

Documented hypersensitivity; current MAOIs or within past 2 wk

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or hepatic impairment

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.

Dosing

Adult

15 mg (range 15-45 mg) PO hs; dose increases should not be made more frequently than q1-2wk

Pediatric

Not established

Interactions

May increase effect of CNS depressants; concurrent administration with MAOI may trigger hypertensive crisis

Contraindications

Documented hypersensitivity; MAOI within 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause drowsiness; discontinue use if patient develops sore throat, fever, or other signs of infection; suicide ideation is inherent in depression and may persist until significant remission occurs; severe neutropenia reported in clinical trials

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.

Dosing

Adult

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

Pediatric

Not established

Interactions

Primarily metabolized by CYP-450 3A4 and 2C19 though no evidence of competitive inhibition; coadministration with alcohol or other centrally acting drugs increases CNS depression; do not use concurrently or within 14 d of administering MAOIs; cimetidine increases AUC and maximum serum concentration; coadministration with sumatriptan and SSRIs has caused weakness and hyperreflexia

Contraindications

Documented hypersensitivity; do not use concurrently or within 14 d of administering MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with history of seizures, mania, suicide; common adverse effects include insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating, fatigue, and somnolence

Tranylcypromine (Parnate)

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

Dosing

Adult

10 mg PO bid; titrate as tolerated with 10-mg increments; usual dose is 30-60 mg/d PO in divided doses

Pediatric

Not established

Interactions

Increases effect or toxicity (serotonin syndrome, hypertensive crisis, CNS depression, cardiac arrhythmias, anticholinergic effects) of appetite suppressants, antidepressants, sympathomimetics (including decongestants), SSRIs, dopaminergic agents, caffeine, chocolate, tryptophan, tyrosine, tyramine, carbamazepine, and St. John's wort

Contraindications

Documented hypersensitivity; uncontrolled hypertension; cardiac disease; cerebrovascular disease; pheochromocytoma; concurrent use with meperidine has been associated with coma, death, excitation, respiratory distress, sweating, and cardiovascular collapse

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include orthostatic hypotension, sexual dysfunction, weight gain, and headache; patients should follow a low-tyramine diet and be aware of restrictions regarding potential OTC and prescription drug interactions

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.

Dosing

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

Pediatric

Not established

Interactions

Do not coadminister with other drugs that cause or increase risk of serotonin syndrome (eg, SSRIs [fluoxetine, sertraline, paroxetine], SNRIs [venlafaxine, duloxetine], TCAs [imipramine, amitriptyline], MAOIs [isocarboxazid, phenelzine, tranylcypromine], mirtazapine, bupropion, meperidine, tramadol, methadone, propoxyphene, pentazocine, dextromethorphan, cyclobenzaprine, oral selegiline, St John's wort)
Do not ingest tyramine-containing foods and beverages (eg, aged cheese, wine, beer, dried or fermented meats [sausage], fava beans, soybean products, yeast extract, sauerkraut) with patches that release > 6 mg/24 h or for 2 wk following discontinuation of patch;
Sympathomimetic amines (eg, cold products or appetite depressants containing pseudoephedrine, phenylephrine, phenylpropanolamine, ephedrine) increase risk of hypertensive crisis
General or local anesthesia containing sympathomimetics or cocaine increases risk of hypertensive crisis (avoid elective surgery during treatment and for at least 10 d after discontinuing patch
If surgery is required immediately, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may used cautiously)
Carbamazepine and oxcarbazepine may increase plasma levels
Alcohol may increase mental and motor skills impairment

Contraindications

Documented hypersensitivity; SSRIs; dual SNRIs; TCAs; bupropion; mirtazapine; meperidine and other analgesics; carbamazepine; oxcarbazepine; sympathomimetic amines

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause mild redness on skin at application site; may cause lightheadedness or postural hypotension secondary to decreased blood pressure; applying direct heat to patch may increase amount of drug absorbed from patch so avoid direct heat exposure (eg, heating pads, electric blankets, sauna, hot tubs, prolonged sunlight); as with all antidepressants, labeling includes a warning for risk of increased suicidality in children and adolescents; all patients with depression should be monitored closely for suicidality; rule out risk of bipolar disorder before initiating antidepressant therapy (treatment with antidepressants alone may precipitate a mixed/manic episode); may impair judgment, thinking, or motor skills

CNS stimulants

Used in patients with resistant depression.

Dextroamphetamine (Dexedrine)

Augmenting agent in resistant depression, most studied in treating patients who are medically ill and depressed. Available as a sustained-release preparation.

Dosing

Adult

5-60 mg/d PO in divided doses

Pediatric

Not established

Interactions

Coadministration with MAOIs may precipitate hypertensive crisis and, with anesthetics, may precipitate arrhythmias; dextroamphetamine may increase toxicity of phenobarbital, propoxyphene, meperidine, TCAs, phenytoin, and NE

Contraindications

Documented hypersensitivity; psychosis; agitation; hyperthyroidism; uncontrolled hypertension; cardiac disease; glaucoma; current MAOI or within past 2 wk; substance abuse

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in angina, glaucoma, cardiovascular disease, and psychopathic personalities

Methylphenidate (Ritalin)

Most studied in treating patients who are medically ill and depressed. Available as a sustained-release preparation.

Dosing

Adult

2.5 mg PO qam; may increase dose q2-3d by 2.5-5 mg to maximum 60 mg/d; if unable to sleep because of taking medication late in day, take last dose before noon or 6 pm

Pediatric

Not established

Interactions

Reduces effects of guanethidine and bretylium; toxicity of phenytoin, TCAs, warfarin, primidone, and phenobarbital may increase when administered concurrently with methylphenidate; MAOIs increase toxicity of methylphenidate

Contraindications

Documented hypersensitivity; psychosis; agitation; hyperthyroidism; uncontrolled hypertension; cardiac disease; glaucoma; current MAOI or within past 2 wk; substance abuse

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in dementia, seizures, and hypertension

Thyroid hormones

May modulate the effect of antidepressants.

Liothyronine (T3, Cytomel)

Synthetic salt of endogenous thyroid hormone, may convert nonresponders (to antidepressants) to responders by increasing receptor sensitivity and enhancing effects of TCAs.

Dosing

Adult

5 mcg PO qd; titrate prn to 25-50 mcg PO qd

Pediatric

Not established

Interactions

Increased effect/toxicity of sympathomimetics and vasopressors; decreases beta-blocker effect; increases/decreases effects of antidiabetic agents and corticosteroids; effect decreased by barbiturates, carbamazepine, phenytoin, and rifampin

Contraindications

Documented hypersensitivity; hyperthyroidism; cardiac disease; osteoporosis; adrenal insufficiency; use as weight loss therapy

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Symptoms of hyperthyroidism; increased risk of cardiac dysfunction; monitor glucose levels of patients with diabetes

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.
• 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.⁶ 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
    • The addition of bright-light therapy to any antidepressant
  • Aripiprazole (Abilify) was recently approved as an adjunct to antidepressants. More recently, 2 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.⁷ 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 separate 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.
• 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.⁸ 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.⁹  
  
  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.¹⁰

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.
  • Thase performed a meta-analysis comparing the efficacy of the dual-acting agent duloxetine with the SSRI antidepressants in terms of remission rates. His meta-analysis and other similar pooled analyses demonstrated that antidepressants with multiple neurotransmitter actions, such as venlafaxine, mirtazapine, and duloxetine, appear to have distinct advantages in terms of faster onset of action, higher rates of remission, and increased efficacy in addressing the somatic/pain symptoms often inherent in the patient with depression.¹¹

References

1. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. Mar 2007;64(3):327-37. [Medline].

2. Ansorge MS, Hen R, Gingrich JA. Neurodevelopmental origins of depressive disorders. Curr Opin Pharmacol. Feb 2007;7(1):8-17. [Medline].

3. Sheikh RM, Weller EB, Weller RA. Prepubertal depression: diagnostic and therapeutic dilemmas. Curr Psychiatry Rep. Apr 2006;8(2):121-6. [Medline].

4. Spitz R. Anaclitic depression: An inquiry into the genesis of psychiatric conditions in early childhood. Psychoanalytic Study of the Child. 1946;Vol 2:313-342.

5. Agency for Healthcare Research and Quality. Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression. AHRQ: Agency for Healthcare Research and Quality. Available at http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=7%20&DocID=61. Accessed May 18, 2009.

6. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. Nov 2006;163(11):1905-17. [Medline].

7. Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. Jun 2007;68(6):843-53. [Medline].

8. Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE Jr, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. Nov 2000;157(11):1873-5. [Medline].

9. Solomon DA, Leon AC, Maser JD, Truman CJ, Coryell W, Endicott J. Distinguishing bipolar major depression from unipolar major depression with the screening assessment of depression-polarity (SAD-P). J Clin Psychiatry. Mar 2006;67(3):434-42. [Medline].

10. Sachs GS. Program and abstracts of the 58th Institute on Psychiatric Services Annual Meeting. The systematic treatment enhancement program for bipolar disorder (STEP-BD): recent findings and their implications. 2006:Symposium 13.

11. Thase ME. Evaluating antidepressant therapies: remission as the optimal outcome. J Clin Psychiatry. 2003;64 Suppl 13:18-25. [Medline].

12. Aronson SC, Ayres VE. Depression: A treatment algorithm for the family physician. Hospital Physician. 2000;[Full Text].

13. Brown C, Schulberg HC. Diagnosis and treatment of depression in primary medical care practice: the application of research findings to clinical practice. J Clin Psychol. Apr 1998;54(3):303-14. [Medline].

14. Charlifue S, Gerhart K. Changing psychosocial morbidity in people aging with spinal cord injury. NeuroRehabilitation. 2004;19(1):15-23. [Medline].

15. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. Jul 15 1999;46(2):212-20. [Medline].

16. Elkin I, Shea MT, Watkins JT, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Arch Gen Psychiatry. Nov 1989;46(11):971-82; discussion 983. [Medline].

17. Katon W, Von Korff M, Lin E, et al. Collaborative management to achieve treatment guidelines. Impact on depression in primary care. JAMA. Apr 5 1995;273(13):1026-31. [Medline].

18. Leon AC, Olfson M, Broadhead WE, et al. Prevalence of mental disorders in primary care. Implications for screening. Arch Fam Med. Oct 1995;4(10):857-61. [Medline].

19. [Best Evidence] Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. Apr 2008;28(2):156-65. [Medline].

20. Murray ML, Wong IC, de Vries CS. Treating major depression in children and adolescents: research is needed into safer and more effective drugs. BMJ. Feb 28 2004;328(7438):524-5. [Medline].

21. Nelson JC. Augmentation strategies for treatment of unipolar major depression. Mod Probl Pharmacopsychiatry. 1997;25:34-55. [Medline].

22. Pascual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. Jul 27 1996;348(9022):233-7. [Medline].

23. Persad E. Electroconvulsive therapy in depression. Can J Psychiatry. Mar 1990;35(2):175-82. [Medline].

24. Thomas SA, Friedmann E, Wimbush F, Schron E. Psychological factors and survival in the cardiac arrhythmia suppression trial (CAST): a reexamination. Am J Crit Care. Mar 1997;6(2):116-26. [Medline].

Keywords

clinical depression, major depression, depression treatment, anxiety depression, major depressive disorder, MDD, unipolar depression, unipolar affective disorder, serotonin, norepinephrine, dopamine, selective serotonin reuptake inhibitors, SSRIs, tricyclic antidepressants, TCAs, norepinephrine, NE, dopamine, DA, suicide, suicidality, dysthymia, electroconvulsive therapy, ECT, electroshock therapy, shock therapy, light therapy

seasonal affective disorder, SAD, antidepressants, lithium, psychotherapy, cognitive behavioral therapy, CBT, neurasthenia, insomnia, hypersomnia, psychomotor agitation, psychomotor retardation, feelings of worthlessness, anhedonia, irritability, dementia of depression, pseudodementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, seizure disorders, systemiclupuserythematosus, SLE, autoimmune cerebritis, obstructive sleep apnea, syphilis, Lyme disease, HIV encephalopathy, Addison disease, Cushing disease, hyperthyroidism, hypothyroidism, prolactinomas

hyperparathyroidism, alcohol abuse, cocaine abuse, amphetamines abuse, marijuana abuse, narcotics abuse, inhalant abuse, bright light therapy, anxiety disorders, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, posttraumatic stress disorder, phobia, eating disorders, bulimia, anorexia nervosa, psychosis, organic brain syndrome, hopelessness, psychosocial stress, chronic pain

Contributor Information and Disclosures

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
Ravinder N Bhalla, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry
Disclosure: Bristol Meyer Squib Honoraria Speaking and teaching; Astrazeneca Honoraria Speaking and teaching

Coauthor(s)

Pascale Moraille-Bhalla, MD, Medical Director, Outpatient Clinic of Hoboken University Medical Center; Staff Psychiatrist, Mental Health Clinic of Passaic
Pascale Moraille-Bhalla, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: Nothing to disclose.

Sarah C Aronson, MD, Associate Professor, Departments of Psychiatry and Medicine, Case Western Reserve School of Medicine/University Hospitals of Cleveland
Sarah C Aronson, MD is a member of the following medical societies: American Academy of Family Physicians, American Medical Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

Medical Editor

Barry I Liskow, MD, Professor of Psychiatry, Vice Chairman, Psychiatry Department, Director, Psychiatric Residency Program, University of Kansas School of Medicine; Director, Psychiatric Outpatient Clinic, The University of Kansas Medical Center
Barry I Liskow, MD is a member of the following medical societies: American Academy of Clinical Psychiatrists, American Academy of Psychiatrists in Alcoholism and Addictions, American Medical Association, American Psychiatric Association, and Research Society on Alcoholism
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Iqbal Ahmed, MBBS, Professor, Department of Psychiatry, John A Burns School of Medicine, University of Hawaii
Iqbal Ahmed, MBBS is a member of the following medical societies: Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry, American Neuropsychiatric Association, and American Psychiatric Association
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Speaking and teaching; Northstar Grant/research funds Research; Novartis Grant/research funds research; Pfizer  Speaking and teaching; Sanofi-avetis Grant/research funds research; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration and American Psychosomatic Society
Disclosure: Nothing to disclose.

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