Keywords
Major depressive disorder (MDD) encompasses a large number of psychobiological syndromes with the core features of depressed mood and/or loss of interest associated with cognitive and somatic disturbances, which causes significant functional impairment. Depressive disorders are classified as mood disorders and are distinguished from bipolar disorders by the absence of manic episodes. According to the American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision (DSM-IV-TR), depressive disorders include MDD (Box 1), dysthymic disorder (low-grade chronic depression occurring more than 50% of the days for at least 2 years), and minor depression (minimum of 2 depressive symptoms present for at least 2 weeks).
1
Box 1
Criteria for major depressive episode (DSM-IV-TR)
1
- •At least 5 of the following symptoms must be present continuously for 2 weeks; at least 1 should be either depressed mood or lack of interest:
- •depressed mood (or irritability in children and adolescents)
- •lack of interest or pleasure
- •appetite change or weight change
- •insomnia or hypersomnia
- •psychomotor agitation or retardation
- •fatigue or loss of energy
- •feelings of worthlessness or guilt
- •decreased concentration
- •recurrent thoughts of death and suicidal ideation
- •
- •No history of bipolar disorder (eg, manic or hypomanic episodes)
- •Symptoms should cause clinically significant functional impairment
- •Symptoms should not be secondary to a substance (eg, a drug of abuse, a medication) or a general medical condition (eg, hypothyroidism)
- •Symptoms are not better accounted for by bereavement
Large epidemiologic studies suggest that major depressive disorder is common,
2
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with a lifetime prevalence of 16.6%, occurring with approximately twofold higher frequency in women compared with men.2
, 3
MDD aggregates in families; it is 1.5 to 3 times more common in individuals with first-degree biologic relatives affected with MDD compared with the general population.4
The point prevalence of MDD has been reported to be 10% in the primary care setting, 15% to 20% in the nursing home population, and 22% to 33% in medically ill patients.5
, 6
, 7
Historically, MDD pathology has been associated with brain monoamine neurotransmitter or receptor abnormalities. Studies of cerebrospinal fluid chemistry, neuroreceptor, and transporter systems, as well as clinical response to monoaminergic agents, have suggested that serotonergic, noradrenergic, other neurotransmitter, and neuropeptide systems may be abnormal in MDD (reviewed in Refs.
8
, 9
). However, there has been an increasing focus on the interplay of environmental factors with genetic and neuroendocrine systems and the involvement of intracellular signaling pathways. The hypothalamic-pituitary-adrenal axis has been suggested to mediate environmental stress and contribute to neuronal atrophy. The common cellular abnormality in various forms of depression may be reduced cellular resilience caused by decreased expression of several neurotrophic factors (eg, brain-derived neurotrophic factor, Bcl-2).8
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, 10
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Evaluation
Diagnostic Evaluation
Clinical suspicion is key to the diagnosis of MDD. Patients should be asked about depressed mood and/or lack of interest or pleasure when they present with nonspecific symptoms suggestive of depression (Box 2). Clinicians should evaluate the patient for the following features: onset, duration, accompanying psychological symptoms, possible psychosocial precipitating factors (eg, relationship problems, work-related stressors, or living conditions), and the effect of these symptoms on the patient’s daily life and function. A key component of the evaluation is determining the absence or presence of suicidal ideations and/or homicidal ideations, in which case the clinician should also inquire whether the patient has intent to hurt self or others and whether a plan has been made.
Box 2
Common symptoms of depression
- Depressed mood
- Anxiety, excessive worrying
- Irritable mood
- Anger attacks
- Crying spells
- Loss of interest or pleasure
- Distractability
- Change in appetite
- Change in sleep
- Fatigue
- Pain (eg, headaches, back pain)
- Muscle tension
- Heart palpitations
- Guilt
- Feelings of worthlessness
- Recurrent thoughts of death or suicide
Detailed history of past depressive or manic episodes, other psychiatric disorders, and possible use of alcohol or other substances should be obtained because these can significantly influence diagnosis and treatment decisions.
Some depressive disorders may be secondary to medical conditions or medications (Box 3); the diagnosis will rest on physical signs and symptoms, medical history, and medication history.
Box 3
Examples of medical conditions causing depressive symptoms
- Autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis)
- Neurologic disorders (eg, stroke, dementias, multiple sclerosis, seizure disorder, Huntington disease, traumatic brain injury)
- Endocrine disorders (eg, hypercalcemia, hypercortisolism, hyperparathyroidism, hyperthyroidism, hypoparathyroidism, hypothyroidism)
- Malignancies (eg, gastrointestinal cancer, pancreatic cancer)
- Infectious disease (eg, hepatitis, human immunodeficiency virus, mononucleosis)
- Medications or substances: antihypertensive medications (eg, propranolol, thiazides, clonidine), anticholinergic agents, anticonvulsant agents, oral contraceptives, sedatives (eg, barbiturates, benzodiazepines), antiparkinsonian medications (eg, methyldopa, amantadine), and alcohol
Laboratory testing, including thyroid function tests, B12, and folate levels, may aid in reaching an accurate diagnosis and uncovering medical problems partially or fully responsible for the psychiatric presentation.
Measuring Depression Severity with Standardized Scales
Clinician-administered and self-rated scales allow a more objective assessment of depression severity but need to be interpreted in the context of patients’ symptoms and medical conditions. Such scales can also be useful in monitoring the effect of treatments. Because multiple well-established and validated scales are available, physicians can choose appropriate measures based on their patient populations and practice settings (Box 4).
Box 4
Examples of rating scales for depressive symptoms
- Hamilton Rating Scale for Depression (HAM-D)
- Montgomery-Asberg Depression Rating Scale (MADRS)
Clinician administered
- Beck Depression Inventory
- Quick Inventory of Depressive Symptoms–Self-report (QIDS-SR;12http://www.ids-qids.org)
- Geriatric Depression Scale (GDS; http://www.stanford.edu/∼yesavage/GDS.html)
Self-report scales
The Hamilton Rating Scale for Depression (HAM-D), the most widely used clinician-administered instrument, focuses on biologic and somatic symptoms of MDD; the 17-item version is the most frequently used subscale of the original 31-item HAM-D.
13
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The Montgomery-Asberg Depression Rating Scale (MADRS), has a lower number of items, less overlap with anxiety symptoms, and is one of the most user-friendly observer-rating scales.15
Self-administered instruments require less interaction with the clinician. The Quick Inventory of Depressive Symptomatology (QIDS-SR; http://www.ids-qids.org) overlaps well with the Diagnostic and statistical manual symptoms of MDD and has been extensively validated.
12
The Beck Depression Inventory (BDI), is an older self-rating scale that preferentially detects and rates cognitive aspects of depression, with an emphasis on self-esteem.16
The Geriatric Depression Scale (GDS) is a 30-item self-administered scale that includes questions about symptoms such as cognitive complaints, self-image, and loss; these symptoms are believed to be particularly relevant in late-life depression.17
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Safety Evaluation
Suicide is one of the most severe and potentially fatal mental health–related emergencies and is 20 times more common in patients suffering from MDD than in healthy populations. Clinicians play an important role in the screening and prevention of suicide because most suicidal patients have contact with their physicians within the month before suicide.
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Therefore, physicians should always ask about and document thoughts of death in patients with depression or other mental health problems (Box 5). Positive responses should be followed by assessment of the content of the thoughts (plans or intent), history of past attempts, triggering factors, and other associated risk factors. The physician should also work with both patient and family to limit access to lethal means (eg, firearms and large amounts of medications), and, when necessary, consider psychiatric consultation and/or hospitalization.Box 5
Suicidal thought item from Montgomery-Asberg Depression Rating Scale
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:- This last week have you had any thoughts that life is not worth living, or that you would be better off dead? What about thoughts of hurting or even killing yourself? If YES: What have you thought about? Have you actually made plans? (Have you told anyone about it?)
Clinician’s question
- 0: Enjoy life or take it as it comes
- 1
- 2: Weary of life. Only fleeting suicidal thoughts
- 3
- 4: Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible solution, but without specific plans or intention
- 5
- 6: Explicit plans for suicide when there is an opportunity. Active preparation for suicide
Responses (with anchor points for consistent rating of patient responses)
Differential diagnosis
Depression is a common symptom among many psychiatric conditions. Table 1 lists the most common psychiatric differential diagnoses of MDD.
Table 1Psychiatric differential diagnoses of major depression
| Differential Diagnoses | Characteristic Feature |
|---|---|
| Nonpathologic periods of sadness | Short duration, few associated symptoms, and lack of significant functional impairment or distress |
| Bereavement | In response to the loss of a loved one, usually ameliorating within 2 months and not lasting more than 6 months |
| Adjustment disorder with depressed mood | In response to an immediate stressor; does not meet full criteria for a major depressive episode |
| Seasonal depression | Recurrent episodes with clear seasonal pattern (onset in fall or winter and full remission usually by the spring) |
| Premenstrual dysphoric disorder | Characterized by significant depressed mood, anxiety, and irritability during the 1–2 weeks before menses and resolving with menses |
| Postpartum depressive disorder | Full depressive episode with an onset within a few months after delivery. To be differentiated from postpartum blues (fewer symptoms, onset shortly after delivery, and subsides usually within 3 weeks) |
| Bipolar I or bipolar II disorder | History of 1 or more manic, mixed, or hypomanic episodes |
| Mood disorder caused by a general medical condition | Direct physiologic effect of a general medical condition |
| Substance-induced mood disorder | Caused by the direct physiologic effect of a substance (including medication); symptoms develop within a month of substance use |
| Dysthymic disorder | Depressed mood present more than 50% of days in a 2-year period, in the absence of major depressive episodes |
| Schizoaffective disorder | Recurrent periods of at least 2 weeks of delusions or hallucinations; at least some of these periods occur in the absence of prominent mood symptoms |
| Schizophrenia, delusional disorder, psychotic disorder not otherwise specified | Depressive symptoms are brief relative to the total duration of the psychotic disturbance (eg, delusions, hallucinations) |
| Posttraumatic stress disorder | Occurs within the 6 months following a stressful event; characterized by hyperarousal, episodes of flashbacks, nightmares, detachment, numbness, maladaptive coping responses, and excessive use of alcohol and drugs |
| Dementia | Characterized by a progressive history of declining cognitive functioning (usually before depressive symptoms). Low scores (usually <23) on the mini–mental status examination |
Special MDD populations
Depression in Patients with General Medical Conditions
Depression is more prevalent among patients with medical illness (including cardiovascular disease, diabetes, and other conditions listed in Box 3) and has been suggested to increase mortality by as much as 4.3 times.
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Major depression itself is harder to treat in medically ill patients.21
It is important to understand the relationship between depressive symptoms and the underlying medical conditions. For example, in patients with depression and chronic pain, controlling the pain often results in significant improvement of mood symptoms. Treating both medical and depressive symptoms can improve the outcome of medical treatment and adherence to medical therapy and rehabilitation. Atypical depressive symptoms and associated positive laboratory findings for a nonprimary depressive disorder warrant a full medical work-up.Depression in Patients with Stroke
About one-third of all patients with stroke develop poststroke depression (PSD).
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PSD can contribute to the disability caused by the stroke and can increase mortality. A meta-analysis of 51 population-, hospital-, and rehabilitation-based stroke studies conducted between 1977 and 2002 showed that depression was associated with physical disability, stroke severity, and cognitive impairment.22
A prospective, randomized controlled trial of 448 patients with stroke evaluated for depression 1 month after stroke and followed up at 12 and 24 months showed that mood symptoms were associated with increased 12- and 24-month mortality after adjustment for other identified risk factors.23
The incidence of PSD peaks 3 to 6 months after the stroke; risk factors include severity of disability, poor social support, personal and family history of depression, and the development of aphasia. Numerous studies have reported increased risk of PSD in left anterior hemisphere strokes or basal ganglia (reviewed in Refs.24
, 25
).Although multiple studies support the use of selective serotonin reuptake inhibitors (SSRIs) and tri/tetracyclic antidepressants (TCAs) in PSD, there are no well-designed studies that guide therapeutic decision making for patients with PSD.
26
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More than 60% of patients with PSD respond to antidepressants, with no particular class of antidepressant showing a clear advantage in treatment efficacy. The data are less conclusive regarding psychostimulants because of a lack of randomized controlled trials. Overall, antidepressants and stimulants are well tolerated in patients with stroke (reviewed in Ref.28
). In a recent randomized controlled study both the SSRI escitalopram and problem-solving therapy (a form of cognitive-behavioral therapy [CBT]) were more effective than placebo in preventing development of PSD in 176 at-risk patients.29
Depression in Patients with Multiple Sclerosis
Cross-sectional studies estimate that almost half of patients with multiple sclerosis (MS) develop depression during the course of their disease.
30
Based on a large-scale Canadian national survey, the 12-month prevalence of MDD is 15% in this population of patients with MS.31
, 32
, 33
Multiple studies have shown a lower quality of life, increased risk of suicidal ideation, and impaired cognitive function in patients with MS with depression (reviewed in Ref.31
).The consensus from research suggests that the development of depression in patients with MS is multifactorial: psychosocial stress related to the diagnosis and exacerbation or progression of disability, as well as MS-related brain changes (eg, neuroinflammatory and neurodegenerative changes) and underlying preexisting psychiatric comorbidities, can predispose patients to depression (reviewed in Ref.
34
). A recent multicenter, observational study of 798 patients suggested that past history of depression (rather than specific MS treatments, ie, interferon or glatiramer acetate) predicted emergence of depressed mood.35
Screening and detection of depression in patients with MS is particularly important because depression has also been identified as one of the 3 most significant factors contributing to noncompliance with immune-modulatory treatment.
36
A follow-up study of 85 patients with MS who developed depression after initiation of interferon therapy showed improved treatment adherence with both psychotherapy and antidepressants.37
The general consensus is that the combination therapy is the best approach to treatment of depression in this population.38
, 39
SSRIs are often the first-line treatment option because of their safer side effect profile, fewer contraindications, and significantly lower chance of negative drug interactions. Based on tolerability rather than any evidence for differences in efficacy, TCAs and monoamine oxidase inhibitors (MAOIs) are generally used in patients in whom SSRIs have been ineffective. However, for patients experiencing chronic pain or sleep disturbance, TCAs (eg, nortriptyline, amitriptyline) may be the treatment of choice because of their ability to reduce pain and because of their sedative effects.
40
Counseling and social support have also been found to be helpful in the treatment of depression in these chronically ill patients.34
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Depression in Patients with Parkinson Disease
Depression is the most common psychiatric disturbance in patients with Parkinson disease (PD) and, although the prevalence varies across different studies, depression is estimated to occur in approximately half of all patients with PD.
42
, 43
Despite its high prevalence, depression is frequently underdiagnosed and undertreated in these patients. This is most likely because of the challenge of distinguishing PD symptoms, such as psychomotor slowing and blunted affect, from depressive symptoms. Degeneration of monoaminergic neurotransmitter systems and frontocortical dysfunction have been suggested as the underlying mechanism of depression in PD.44
, 45
Randomized controlled studies have shown that TCAs and bupropion are efficacious for the treatment of depression in Parkinson disease.
46
, 47
, 48
SSRIs have shown similar efficacy compared with TCAs, but show a different profile of adverse effects, which may be particularly favorable in elderly patients.49
A recent double-blind, randomized, placebo-controlled study showed that desipramine and citalopram each improved depressive symptoms after 30 days, but that mild adverse events were twice as frequent in the desipramine-treated group.50
A randomized multicenter national study showed that pramipexole improved motor symptoms but also had antidepressant efficacy that was comparable with sertraline and specifically improved anhedonia.49
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Although based on this single study, pramipexole could be recommended as a first-line treatment in patients with PD and depression. Lithium, a commonly used augmentation agent with antidepressant drugs, should be avoided in patients with PD because of the risk of tremor induction.49
Treatment of MDD
Useful treatments for depression include pharmacotherapy, focused psychotherapies, somatic treatments, and lifestyle changes.
Pharmacotherapy
Commonly used antidepressants and doses are listed in Table 2. Although several pharmacologic agents are approved by the US Food and Drug Administration (FDA), none are clearly superior in efficacy. They differ in pharmacologic and side effect profile (Table 3). Although onset of antidepressant efficacy may vary for individual patients, onset of efficacy may require 4 to 6 weeks of treatment with most currently available agents, whereas full efficacy may require 8 to 12 weeks.
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As a general rule, antidepressant side effects can be minimized by slowly increasing dosage (especially in the elderly), although this strategy may also delay the onset of efficacy.Table 2Recommended dosages for commonly prescribed antidepressants
| Drug | Usual Dose (mg/d) | Initial Dose (mg/d) | Notes |
|---|---|---|---|
| SSRIs | |||
| Citalopram (Celexa) | 20–60 | 10–20 | Few drug interactions |
| Escitalopram (Lexapro) | 10–20 | 5–10 | Few drug interactions |
| Paroxetine (Paxil and Paxil CR) | 10–50 | 10–20 | Short half-life |
| Sertraline (Zoloft) | 25–200 | 25–50 | |
| Fluvoxamine (Luvox) | 50–300 | 25–50 | |
| Fluoxetine (Prozac) | 10–60 | 10–20 | Longest half-life |
| SNRIs | |||
| Venlafaxine (Effexor and Effexor XR) | 75–225 | 37.5 | |
| Desvenlafaxine (Pristiq) | 50–100 | 50 | |
| Duloxetine (Cymbalta) | 40–120 | 20–40 | |
| Tricyclic/Tetracyclic Antidepressants | |||
| Amitriptyline (Elavil) | 100–300 | 10–50 | |
| Clomipramine (Anafranil) | 100–250 | 25 | |
| Doxepin (Adapin) | 100–300 | 25–50 | |
| Imipramine (Tofranil) | 100–300 | 10–25 | |
| Trimipramine (Surmontil) | 100–300 | 25–50 | |
| Desipramine (Norpramin) | 100–300 | 25–50 | Favorable tolerability |
| Nortriptyline (Pamelor) | 50–150 | 10–25 | Favorable safety, tolerability |
| Protriptyline (Vivactil) | 15–60 | 10 | Activating |
| Amoxapine (Asendin) | 100–400 | 50 | |
| Maprotiline (Ludiomil) | 100–225 | 50 | |
| MAOIs | |||
| Phenelzine (Nardil) | 45–90 | 15 | |
| Tranylcypromine (Parnate) | 30–60 | 10 | |
| Isocarboxazid (Marplan) | 30–60 | 20 | |
| Selegiline (Eldepryl) | 30–40 | 10 | Selective MAO-B Inhibitor at low doses |
| Selegiline transdermal (Emsam) | 6–12 | 6 | |
| Other Antidepressants | |||
| Bupropion (Wellbutrin) | 300–450 | 75–150 | Available as SR and XL/XR |
| Mirtazapine (Remeron) | 15–45 | 15 | |
Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Table 3Important side effects of antidepressants
| Drug Class | Important Side Effects |
|---|---|
| SSRIs and SNRIs | Nausea, decreased appetite, weight loss, diaphoresis, insomnia, sedation, nervousness, sexual dysfunction, headache, dizziness |
| TCAs | Anticholinergic: dry mouth, constipation, hyperthermia, sinus tachycardia, blurred vision, urinary retention, cognitive/memory impairment Antihistaminic: sedation, increased appetite, weight gain, hypotension Antiadrenergic: postural hypotension, dizziness, tachycardia Reduced seizure threshold, sexual dysfunction, cardiac conduction effects similar to class 1A antiarrhythmics, cardiotoxicity in overdose |
| MAOIs | Insomnia, sedation, weight gain, orthostatic hypotension, sexual dysfunction Less common: pyridoxine deficiency with parasthesias, tremor, anticholinergic effects Hypertensive crisis: occurs with tyramine ingestion (eg, aged cheese and meats, fava beans, soy sauce) Serotonin syndrome: life threatening with rapid onset of hyperthermia, hypertension, tachycardia, shock |
| Bupropion (Wellbutrin) | Agitation, dry mouth, insomnia, nausea, constipation, tremor, headache Increased seizure risk |
| Mirtazapine (Remeron) | Antihistaminic: sedation, increased appetite, weight gain, hypotension, dry mouth, constipation, dizziness |
SSRIs
SSRIs are frequently used as a first-line treatment of depressive disorders because their specificity results in fewer drug-drug interactions, safety in overdose, and a favorable side effect profile.
54
They also effectively treat anxiety disorders and other psychiatric comorbidities frequently associated with depression.55
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Serotonin and norepinephrine reuptake inhibitors
Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also effective in treating depression and anxiety. They may be particularly useful in SSRI nonresponders and in specific chronic pain conditions.
57
However, they tend to be more expensive.TCAs
TCAs are older, inexpensive agents that also act primarily by inhibiting serotonin and norepinephrine reuptake, are effective as antidepressants, and effectively treat chronic pain.
58
They also interact with many other receptors, which may contribute to their efficacy, but produces side effects that may limit tolerability and compliance.59
TCAs block muscarinic acetylcholine receptors, leading to anticholinergic side effects (see Table 3). The risk of confusion and disorientation is most significant in elderly patients, and delirium has been reported in 5% of elderly patients taking TCAs.60
TCAs also antagonize histamine H1 receptors and α1 adrenergic receptors; caution is advised in patients with narrow angle glaucoma, prostatic hypertrophy, or low blood pressure. Because TCAs prolong cardiac repolarization, they can act similarly to class I antiarrhythmic agents. Their toxic effects on cardiac conduction, which make TCAs potentially lethal in overdose, can be detected by QTC prolongation. Therefore, obtaining an electrocardiogram is advisable before and 4 weeks after initiating TCA treatment.61
Plasma levels can help guide dosage adjustments.62
In PD, a controlled trial showed superiority of TCA treatment, with a response rate of 53%.63
MAOIs
MAOIs are most often used in patients with atypical depression or in treatment-resistant patients who fail trials of other medications. In patients with atypical depression, MAOI response rates of 59% to 71% have been reported.
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MAOIs can also be effective in PD, and may be particularly suited for treating depression in these patients. They act by inhibiting monoamine oxidase (MAO)-A and -B, enzymes that break down monoamines including serotonin, dopamine, and norepinephrine. These MAO enzymes are widely distributed throughout the body and can be found throughout the gastrointestinal tract and liver, and in platelets, as well as in neurons and glia. Several MAOIs available in the United States (eg, phenelzine, tranylcypromine) irreversibly inhibit both MAO-A and MAO-B, so their effects persist through several drug-free days until enzyme stores are replenished. Intake of foods containing the sympathomimetic amine tyramine can result in potentially lethal hypertensive crises. Serotonin syndrome is also possible with MAOIs, TCAs, and SSRIs; it involves cognitive changes such as confusion or agitation, autonomic dysregulation such as fever, changes in blood pressure, diarrhea, flushing, and diaphoresis, as well as hyperreflexia, myoclonus, and tremor.66
Tryptophan-containing foods also pose a risk for serotonin syndrome. To avoid serotonin syndrome, a washout period of at least 2 weeks (5 weeks for fluoxetine, because of its longer half-life) is recommended when switching to or from an MAOI.67
Other medications that may react with MAOIs to cause hypertensive crises or serotonin syndrome include meperidine, tramadol, dextromethorphan, and SSRIs.Other agents
Additional antidepressants include bupropion and mirtazapine. These agents are generally safer in overdose than TCAs, and mirtazapine has a particularly favorable safety profile, with a large study reporting no fatalities in 2599 suicidal ingestions.
68
Bupropion has dopaminergic properties and energizing effects; it is used as an aid for smoking cessation and has few sexual side effects. Because of increased seizure risk, bupropion is contraindicated in patients with seizure disorders or bulimia. Mirtazapine can be easily combined with other agents because of limited drug-drug interactions. Its side effects, such as weight gain and sedation, result mainly from histamine H1 receptor blockade.69
Augmenting standard antidepressants with atypical antipsychotics is the best shown augmentation strategy in treatment-resistant depression.
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Many high-quality studies also support antidepressant augmentation with lithium72
or thyroid hormones,73
although most of those studies were carried out with tricyclic antidepressants, and few of those studies included modern antidepressants.74
Smaller studies also support the role of certain natural remedies (eg, S-adenosyl-methionine),75
and psychostimulants as augmentation strategies in cases of partial or nonresponse to an antidepressant agent.Psychotherapy
CBT (including mindfulness and relaxation techniques), behavioral therapy, and interpersonal therapy are efficacious in treating MDD. Although short-term dynamic and emotion-focused psychotherapies may also be efficacious, less evidence supports these strategies for the treatment of depressed patients.
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Although remission rates with cognitive therapy or medication alone have been reported to reach 40% to 46%, patients with moderate or severe depression may benefit more from a combination of pharmacotherapy and psychotherapy.77
Somatic Treatments
Electroconvulsive therapy (ECT) is well established and highly effective in resistant depression.
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Electrical stimulation is applied bilaterally or unilaterally to the head to induce a seizure. ECT requires anesthesia and can cause transient cognitive side effects or amnesia and is therefore generally used after patients have failed pharmacologic trials and/or in very severe forms of depression.80
Hypertension and arrhythmias have also been noted, but these complications occur more frequently in patients with preexisting cardiac complications and can be well managed in clinical contexts.81
Hence, there are no absolute contraindications, although relative contraindications include coronary artery disease, arrhythmia, and increased intracranial pressure or lesions.Other FDA-approved treatments for resistant depression include transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS). TMS (a noninvasive brain depolarization induced by a magnetic field) has shown modest efficacy (14% remission rates) but few adverse effects in subjects with MDD with mild to moderate levels of treatment resistance.
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A recent meta-analysis of more than 34 randomized, sham-controlled trials, including more than 1000 patients, supports the efficacy of TMS as both monotherapy and as an adjunctive treatment to pharmacotherapy.83
VNS requires a surgically implanted device sending electrical impulses to ascending fibers of the vagus nerve, and has shown no significant efficacy compared with placebo after 3 months, but increasing efficacy in open treatment up to 1 year in populations with severe treatment-resistant depression.84
Phototherapy, which involves the application of bright light, may be particularly useful in seasonal depression.85
Lifestyle changes and alternative remedies with some efficacy in the treatment of depression include physical exercise, and some dietary supplements (eg, ω-3 fatty acids, S-adenosyl methionine, St John’s wort).
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Phases of treatment
The recently published APA Practice guidelines for the treatment of patients with major depressive disorder, 3rd edition
87
incorporates insights from large studies in MDD in the last decade, including the large National Institute of Mental Health–sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. According to the APA guidelines, management of the patient with MDD can be framed in the context of 3 phases.The acute phase of treatment is focused on the acutely depressed patient and begins with tailoring a strategy that is based on the severity of the symptoms, history of prior positive responses, presence of other psychiatric symptoms, side effect profile of the medication, and the patient’s preference (eg, pharmacotherapy without/with psychotherapy for the mild/moderate symptoms, ECT for severe depression, and presence of psychotic features or catatonia). In cases of treatment failure (ie, no improvement after 4–8 weeks of treatment), raising antidepressant doses to the optimal tolerable level (optimization) should be considered before switching to another drug within the same class or in another class of drugs. For partial responders, combination of antidepressant medications (adding buproprion, low-dose TCA, mirtazapine, or buspirone) or augmentation strategies (with atypical antipsychotics, lithium, triiodothyronine, psychostimulants, or dopaminergic agents) can be used before switching medications.
The continuation treatment refers to the phase after the initial remission of symptoms. The antidepressant treatment that led to remission in the acute phase should be continued for an additional 6 to 9 months with full antidepressant doses to decrease the risk of relapse.
The maintenance treatment is the phase during which patients with high risk of relapse (ie, patients with a history of 3 or more major depressive episodes) might benefit from indefinite maintenance therapy to prevent the risk of recurrence.
Summary
MDD is a common illness associated with significant morbidity and mortality. The prevalence of MDD is even higher in medically ill patients. It is important for clinicians to suspect the diagnosis of MDD in patients with suggestive symptoms or risk factors. Such suspicion should be followed by a review of diagnostic symptoms (possibly through the administration of standardized scales) with an emphasis on the presence of suicidal thinking, and by laboratory tests to differentiate from medical causes of depression. Although several pharmacotherapies, psychotherapies, and somatic treatments have been shown to effectively treat MDD, a large number of patients do not improve sufficiently with any single treatment and can benefit from switching or combining different antidepressant modalities. Patients with severe depression and/or suicidal ideation, and those having failed several antidepressant treatments, would benefit from consultation with, or referral to, a psychiatrist (Box 6).
Box 6
Helpful clinical recommendations
- •Explain depression as an illness associated with neurochemical dysregulation in the brain, rather than a personal weakness or fault
- •More than 60% of patients with MDD are at risk for recurrence; patients with recurrent depression should be educated about the early signs of depression; some may require lifelong antidepressant therapy
- •Education about the anticipated side effects of the medications will improve patient compliance
- •Significant risk for suicide or homicide (acute suicidal risk may require a psychiatric hospitalization)
- •Current or plans for future pregnancy
- •Poor social support
- •Disability caused by depression
- •Suboptimal response to 1 or 2 adequate treatments
- •Comorbid psychiatric problems (psychosis, mania, severe anxiety, substance abuse, panic attacks, posttraumatic stress disorder, dementia)
- •Need for alcohol or illicit drug detoxification
When to refer to, or consult with, a psychiatrist:
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Footnotes
L. Soleimani and K.A.B Lapidus contributed equally (ie, shared first authorship).
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© 2011 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
