Practice Guidelines

APA Releases Guideline on Treatment of Patients with Major Depressive Disorder



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Am Fam Physician. 2011 May 15;83(10):1219-1227.

Guideline source: American Psychiatric Association

Evidence rating system used? Yes

Literature search described? Yes

Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx

The American Psychiatric Association (APA) recently updated its guideline on the treatment of major depressive disorder. The new evidence-based guideline summarizes recommendations on the use of antidepressants and other drug therapies; psychotherapy, including cognitive behavior therapy; and electroconvulsive therapy (ECT). Because many patients with major depressive disorder have co-occurring psychiatric disorders, including substance use disorders, physicians should also consider appropriate treatments for these diagnoses. Patients who have depressive symptoms in the context of another disorder but who do not meet the diagnostic criteria for major depressive disorder should be treated according to guidelines pertaining to the primary diagnosis.

Acute Phase

Treatment in the acute phase should be aimed at inducing remission of the depressive episode and achieving a full return to the baseline level of functioning. Patients with mild to moderate depression should be treated with antidepressants (Table 1) or psychotherapy. Combined pharmacotherapy and psychotherapy may be useful in patients with psychosocial or interpersonal problems, intrapsychic conflict, or a co-occurring axis II disorder. ECT can be used in select patients.

Table 1.

Medications for Treatment of Major Depressive Disorder

Drug Starting dosage (mg per day)* Usual dosage (mg per day)

Dopamine-norepinephrine reuptake inhibitors

Bupropion, immediate release (Wellbutrin)

150

300 to 450

Bupropion, sustained release

150

300 to 400

(Wellbutrin SR)

Bupropion, extended release

150

300 to 450

(Wellbutrin XL)

Monoamine oxidase inhibitors

Isocarboxazid

10 to 20

30 to 60

Moclobemide (not available in

150

300 to 600

the United States)

Phenelzine (Nardil)

15

45 to 90

Selegiline, transdermal (Emsam)

6

6 to 12

Tranylcypromine

10

30 to 60

Norepinephrine-serotonin modulator

Mirtazapine (Remeron)

15

15 to 45

Selective serotonin reuptake inhibitors

Citalopram (Celexa)

20

20 to 60§

Escitalopram (Lexapro)

10

10 to 20

Fluoxetine (Prozac)

20

20 to 60§

Paroxetine (Paxil)

20

20 to 60§

Paroxetine, extended-release (Paxil CR)

12.5

25 to 75

Sertraline (Zoloft)

50

50 to 200§

Serotonin modulators

Nefazodone

50

150 to 300

Trazodone∥

150

150 to 600

Serotonin-norepinephrine reuptake inhibitors

Desvenlafaxine (Pristiq)

50

50

Duloxetine (Cymbalta)

60

60 to 120

Venlafaxine, immediate release (Effexor)

37.5

75 to 375

Venlafaxine, extended release (Effexor XR)

37.5

75 to 375

Tricyclics and tetracyclics

Amitriptyline

25 to 50

100 to 300

Desipramine (Norpramin)

25 to 50

100 to 300

Doxepin

25 to 50

100 to 300

Imipramine (Tofranil)

25 to 50

100 to 300

Maprotiline

75

100 to 225

Nortriptyline (Pamelor)

25

50 to 200

Protriptyline

10 to 20

20 to 60

Trimipramine (Surmontil)

25 to 50

75 to 300


*—Lower starting dosages are recommended for older patients and for patients with panic disorder, anxiety, hepatic disease, and co-occurring medical conditions.

†—For some drugs (e.g., tricyclics), the upper dosage limit reflects the risk of toxicity or need for plasma level assessment, whereas for other drugs (e.g., selective serotonin reuptake inhibitors), higher dosages are safe but have not been proven more effective than lower dosages.

‡—These drugs are likely optimal in terms of safety, adverse effects, and quantity and quality of clinical trial data.

§—Dosage varies with diagnosis.

∥—Not typically used for this indication.

Adapted with permission from American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed January 27, 2011.

Table 1.   Medications for Treatment of Major Depressive Disorder

View Table

Table 1.

Medications for Treatment of Major Depressive Disorder

Drug Starting dosage (mg per day)* Usual dosage (mg per day)

Dopamine-norepinephrine reuptake inhibitors

Bupropion, immediate release (Wellbutrin)

150

300 to 450

Bupropion, sustained release

150

300 to 400

(Wellbutrin SR)

Bupropion, extended release

150

300 to 450

(Wellbutrin XL)

Monoamine oxidase inhibitors

Isocarboxazid

10 to 20

30 to 60

Moclobemide (not available in

150

300 to 600

the United States)

Phenelzine (Nardil)

15

45 to 90

Selegiline, transdermal (Emsam)

6

6 to 12

Tranylcypromine

10

30 to 60

Norepinephrine-serotonin modulator

Mirtazapine (Remeron)

15

15 to 45

Selective serotonin reuptake inhibitors

Citalopram (Celexa)

20

20 to 60§

Escitalopram (Lexapro)

10

10 to 20

Fluoxetine (Prozac)

20

20 to 60§

Paroxetine (Paxil)

20

20 to 60§

Paroxetine, extended-release (Paxil CR)

12.5

25 to 75

Sertraline (Zoloft)

50

50 to 200§

Serotonin modulators

Nefazodone

50

150 to 300

Trazodone∥

150

150 to 600

Serotonin-norepinephrine reuptake inhibitors

Desvenlafaxine (Pristiq)

50

50

Duloxetine (Cymbalta)

60

60 to 120

Venlafaxine, immediate release (Effexor)

37.5

75 to 375

Venlafaxine, extended release (Effexor XR)

37.5

75 to 375

Tricyclics and tetracyclics

Amitriptyline

25 to 50

100 to 300

Desipramine (Norpramin)

25 to 50

100 to 300

Doxepin

25 to 50

100 to 300

Imipramine (Tofranil)

25 to 50

100 to 300

Maprotiline

75

100 to 225

Nortriptyline (Pamelor)

25

50 to 200

Protriptyline

10 to 20

20 to 60

Trimipramine (Surmontil)

25 to 50

75 to 300


*—Lower starting dosages are recommended for older patients and for patients with panic disorder, anxiety, hepatic disease, and co-occurring medical conditions.

†—For some drugs (e.g., tricyclics), the upper dosage limit reflects the risk of toxicity or need for plasma level assessment, whereas for other drugs (e.g., selective serotonin reuptake inhibitors), higher dosages are safe but have not been proven more effective than lower dosages.

‡—These drugs are likely optimal in terms of safety, adverse effects, and quantity and quality of clinical trial data.

§—Dosage varies with diagnosis.

∥—Not typically used for this indication.

Adapted with permission from American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed January 27, 2011.

In patients with severe depression without psychotic features, pharmacotherapy, combined pharmacotherapy and psychotherapy, or ECT can be used; however, psychotherapy should not be used alone. In patients with severe depression with psychotic features, antidepressant and antipsychotic agents should be used, with or without psychotherapy. ECT is also an option.

Selection of an initial treatment modality should be influenced by clinical features, such as severity of symptoms and presence of co-occurring disorders, as well as other factors, such as patient preferences and prior treatment experiences. Because the effectiveness of antidepressants is generally comparable between and within drug classes, the initial selection will be based largely on anticipated adverse effects, safety and tolerability, pharmacologic properties (e.g., half-life, drug interactions), and cost. For most patients, optimal treatments include a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, mirtazapine (Remeron), or bupropion (Wellbutrin). The use of nonselective monoamine oxidase inhibitors should be restricted to patients who do not respond to other treatments. In patients who prefer complementary and alternative therapies, S-adenosylmethionine (SAM-e) or St. John's wort can be considered. However, patients who take St. John's wort should be monitored carefully for drug interactions.

Once an antidepressant has been selected, it should be titrated based on the patient's age, the treatment setting, and the presence of co-occurring disorders, concomitant pharmacotherapy, or adverse effects of medication. If adverse effects occur, the dosage can be lowered or the patient should be switched to a different medication.

An incomplete response to treatment is associated with poor functional outcomes; therefore, the acute phase of treatment should not be concluded prematurely in patients who do not fully respond. If a moderate improvement in symptoms does not occur within four to eight weeks after treatment initiation, the diagnosis should be reconsidered, adverse effects and adherence to therapy assessed, comorbidities and psychosocial factors reviewed, and the treatment plan adjusted. For patients who are being treated with psychotherapy, the frequency of sessions and the specific approach to psychotherapy should be reassessed. If minimal or no improvement is noted after an additional four to eight weeks, the treatment plan should be readjusted, and consultation should be considered.

Continuation Phase

In the continuation phase, management is aimed at preventing relapse. Systematic assessment of symptoms and monitoring for adverse effects of medications (Table 2), adherence to therapy, and functional status are essential. To reduce the risk of relapse, patients in whom pharmacotherapy has been successful should continue treatment at the same dosage for four to nine months. Depression-focused cognitive behavior therapy is also recommended in the continuation phase.

Table 2.

Treatment of Adverse Effects Associated with Antidepressants

Effect Associated antidepressant Treatment

Anticholinergic

Constipation

TCAs

Adequate hydration; bulk laxative

Delirium

TCAs

Assess for other causes

Dry mouth

TCAs, SNRIs, bupropion (Wellbutrin)

Use of sugarless gum or candy

Urinary hesitancy

TCAs

Bethanechol

Visual changes

TCAs

Pilocarpine eye drops

Cardiovascular

Arrhythmias

TCAs

Avoid TCA use in patients with cardiac instability or ischemia; attend to interactions with antiarrhythmic drugs

Hypertension

SNRIs, bupropion

Monitor blood pressure; keep dosage as low as possible; add antihypertensive drug

Hypertensive crisis

MAOIs

Seek emergency treatment; if hypertension is severe, intravenous antihypertensive agents (e.g., labetalol, nitroprusside [Nitropress]) may be needed

Increased cholesterol levels

Mirtazapine (Remeron)

Statin drugs

Orthostatic hypotension

TCAs, trazodone, nefazodone, MAOIs

Fludrocortisone; add salt to diet

Neurologic

Headache

SSRIs, SNRIs, bupropion

Assess for other causes (e.g., caffeinism, bruxism, migraine, tension headache)

Myoclonus

TCAs, MAOIs

Clonazepam (Klonopin)

Seizures

Bupropion, TCAs, amoxapine

Assess for other causes; add anticonvulsant drug, if indicated

Sexual

Arousal, erectile dysfunction

TCAs, SSRIs, SNRIs

Sildenafil (Viagra), tadalafil (Cialis), buspirone (Buspar), bupropion

Orgasm dysfunction

TCAs, SSRIs, venlafaxine, desvenlafaxine, MAOIs

Sildenafil, tadalafil, buspirone, bupropion

Priapism

Trazodone

Obtain emergency urologic evaluation

Other

Activation

SSRIs, SNRIs, bupropion

Administer in morning

Akathisia

SSRIs, SNRIs

Beta blocker or benzodiazepine

Bruxism

SSRIs

Obtain dental consultation, if indicated

Diaphoresis

TCAs, some SSRIs, SNRIs

Alpha 1-adrenergic antagonist, central alpha2-adrenergic antagonist, or anticholinergic

Fall risk

TCAs, SSRIs

Monitor blood pressure for evidence of hypotension or orthostasis; assess for sedation, blurred vision, or confusion; modify environment to reduce risk

Gastrointestinal bleeding

SSRIs

Determine whether other medications may affect clotting

Hepatotoxicity

Nefazodone

Provide education about and monitor for evidence of hepatic dysfunction; order hepatic function testing, if indicated

Insomnia

SSRIs, SNRIs, bupropion

Administer in morning; add sedative-hypnotic drug at bedtime; add melatonin; provide cognitive behavior therapy or sleep hygiene education

Nausea, vomiting

SSRIs, SNRIs, bupropion

Administer after a meal or in divided doses

Osteopenia

SSRIs

Monitor bone mineral density and treat, if indicated (e.g., calcium and vitamin D supplement, bisphosphonates, selective estrogen receptor agents)

Sedation

TCAs, trazodone, nefazodone, mirtazapine

Administer at bedtime; add modafinil (Provigil) or methylphenidate (Ritalin)

Severe serotonin syndrome

MAOIs

Obtain emergency evaluation; consider admission to a critical care unit

Weight gain

SSRIs, mirtazapine, TCAs, MAOIs

Encourage exercise; consult with dietician; if changing antidepressants, consider a secondary amine (if a TCA is required) or antidepressant with less effect on weight (e.g., bupropion)


MAOI = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Adapted with permission from American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed January 27, 2011.

Table 2.   Treatment of Adverse Effects Associated with Antidepressants

View Table

Table 2.

Treatment of Adverse Effects Associated with Antidepressants

Effect Associated antidepressant Treatment

Anticholinergic

Constipation

TCAs

Adequate hydration; bulk laxative

Delirium

TCAs

Assess for other causes

Dry mouth

TCAs, SNRIs, bupropion (Wellbutrin)

Use of sugarless gum or candy

Urinary hesitancy

TCAs

Bethanechol

Visual changes

TCAs

Pilocarpine eye drops

Cardiovascular

Arrhythmias

TCAs

Avoid TCA use in patients with cardiac instability or ischemia; attend to interactions with antiarrhythmic drugs

Hypertension

SNRIs, bupropion

Monitor blood pressure; keep dosage as low as possible; add antihypertensive drug

Hypertensive crisis

MAOIs

Seek emergency treatment; if hypertension is severe, intravenous antihypertensive agents (e.g., labetalol, nitroprusside [Nitropress]) may be needed

Increased cholesterol levels

Mirtazapine (Remeron)

Statin drugs

Orthostatic hypotension

TCAs, trazodone, nefazodone, MAOIs

Fludrocortisone; add salt to diet

Neurologic

Headache

SSRIs, SNRIs, bupropion

Assess for other causes (e.g., caffeinism, bruxism, migraine, tension headache)

Myoclonus

TCAs, MAOIs

Clonazepam (Klonopin)

Seizures

Bupropion, TCAs, amoxapine

Assess for other causes; add anticonvulsant drug, if indicated

Sexual

Arousal, erectile dysfunction

TCAs, SSRIs, SNRIs

Sildenafil (Viagra), tadalafil (Cialis), buspirone (Buspar), bupropion

Orgasm dysfunction

TCAs, SSRIs, venlafaxine, desvenlafaxine, MAOIs

Sildenafil, tadalafil, buspirone, bupropion

Priapism

Trazodone

Obtain emergency urologic evaluation

Other

Activation

SSRIs, SNRIs, bupropion

Administer in morning

Akathisia

SSRIs, SNRIs

Beta blocker or benzodiazepine

Bruxism

SSRIs

Obtain dental consultation, if indicated

Diaphoresis

TCAs, some SSRIs, SNRIs

Alpha 1-adrenergic antagonist, central alpha2-adrenergic antagonist, or anticholinergic

Fall risk

TCAs, SSRIs

Monitor blood pressure for evidence of hypotension or orthostasis; assess for sedation, blurred vision, or confusion; modify environment to reduce risk

Gastrointestinal bleeding

SSRIs

Determine whether other medications may affect clotting

Hepatotoxicity

Nefazodone

Provide education about and monitor for evidence of hepatic dysfunction; order hepatic function testing, if indicated

Insomnia

SSRIs, SNRIs, bupropion

Administer in morning; add sedative-hypnotic drug at bedtime; add melatonin; provide cognitive behavior therapy or sleep hygiene education

Nausea, vomiting

SSRIs, SNRIs, bupropion

Administer after a meal or in divided doses

Osteopenia

SSRIs

Monitor bone mineral density and treat, if indicated (e.g., calcium and vitamin D supplement, bisphosphonates, selective estrogen receptor agents)

Sedation

TCAs, trazodone, nefazodone, mirtazapine

Administer at bedtime; add modafinil (Provigil) or methylphenidate (Ritalin)

Severe serotonin syndrome

MAOIs

Obtain emergency evaluation; consider admission to a critical care unit

Weight gain

SSRIs, mirtazapine, TCAs, MAOIs

Encourage exercise; consult with dietician; if changing antidepressants, consider a secondary amine (if a TCA is required) or antidepressant with less effect on weight (e.g., bupropion)


MAOI = monoamine oxidase inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Adapted with permission from American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed January 27, 2011.

Patients who respond to ECT should continue treatment with medication; a combination of lithium and nortriptyline (Pamelor) is recommended. Alternatively, continuation ECT can be given, especially if medication and psychotherapy have been ineffective.

Maintenance Phase

Patients who have had three or more episodes of major depression or who have chronic major depressive disorder should proceed to the maintenance phase of treatment after completing the continuation phase. Maintenance therapy should also be considered for patients with additional risk factors for recurrence (e.g., residual symptoms, ongoing psychosocial stressors, early age at onset). Additional considerations include patient preference, the type of treatment received, adverse effects, comorbid conditions, frequency and severity of previous depressive episodes (including psychosis and suicide risk), and the persistence of depressive symptoms after recovery. In many patients—particularly those with chronic and recurrent major depressive disorder or co-occurring medical or psychiatric disorders—some form of treatment will be required indefinitely. Because of the risk of recurrence, patients should be monitored at regular intervals during the maintenance phase.

The antidepressant that produced symptom remission during the acute phase should be continued at the full therapeutic dosage. If depression-focused psychotherapy was used during the acute and continuation phases, maintenance therapy should be considered, with less frequent sessions. Maintenance ECT can be considered in patients with depressive episodes that have not responded to medications or depression-focused psychotherapy, but that have responded to ECT.

Discontinuation

Pharmacotherapy should be tapered over the course of at least several weeks. Before discontinuation of active treatment, patients should be counseled about the potential for relapse, and a plan should be established for seeking treatment if symptoms recur. Patients should be monitored for several months after medications are discontinued, and they should receive another course of acute-phase treatment if symptoms recur.

Coverage of guidelines from other organizations does not imply endorsement by AFP or the AAFP.

A collection of Practice Guidelines published in AFP is available at http://www.aafp.org/afp/practguide.



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