Major depressive disorder medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Overview

The mainstay of treatment for major depressive disorder is pharmacologic therapy with serotonergic agents.

Medical Therapy

Pharmacologic medical therapies for Major Depressive Disorder include:

Serotonin reuptake inhibitors

• SSRIs are effective, well-tolerated medications used as a first-line treatment for MDD.
• Possible adverse effects with SSRIs: serotonergic symptoms including nausea, diarrhea, anxiety or nervousness, insomnia, sexual dysfunction, withdrawal syndrome, and hyponatremia in elderly. Most side effects are transient and self-limited; however, sexual dysfunction is usually persistent and may respond to a change in drug (for example to mirtazapine or bupropion) or dosage.
• During the early few weeks of initiation of SSRI therapy, anxiogenic effects of SSRI may aggravate suicidal ideation in patients with MDD. This can be managed by reducing the dose or adjunctive therapy with an anxiolytic, for example, a benzodiazepine.
• Co-administration with monoamine oxidase inhibitors is contraindicated due to the risk of serotonine syndrome.
• Fluoxetine (Effective dose range: 20-80mg)
  • Benefits: It is associated with a low risk of withdrawal symptoms upon tapering due to its long half-life.
  • Adverse effects: See SSRIs side effects
• Sertraline (Effective dose range: 50-200mg): has a dual mechanism of action, i.e., serotonine and dopamine reuptake inhibitor
  • Benefits: Low transplacental transmission during pregnancy; relatively low concentrations in breast milk
  • Adverse effects: Transient diarrhea during first few weeks of initiation of therapy
• Paroxetine (Effective dose range: 20-50mg)
  • Benefits: Low transplacental transmission during pregnancy; relatively low concentrations in breast milk
  • Adverse effects: higher risk of withdrawal symptoms than other SSRIs, weight gain, potential higher risk of teratogenic effects (FDA pregnancy category D)
• Citalopram (Effective dose range: 20-40mg)
  • Benefits: Few drug-drug interactions
  • Adverse effects: May prolong QTc interval, in particular at higher doses. It is not recommended in patients with congenital long QT syndrome or acute cardiac conditions (e.g. acute decompensated heart failure). It should be discontinued in patients with QTc interval >500ms. Doses of >20 mg are not recommended in the elderly or in patients with hepatic dysfunction.
• Escitalopram (Effective dose range: 10-20mg)
  • Benefits: Few drug-drug interactions
  • Adverse effects: Modest effects on QTc interval

Serotonin-norepinephrine reuptake inhibitors

• Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also considered first-line medications for the treatment of MDD. SNRIs have a dual mechanism of action. They may be effective in treating concomitant pain conditions.
• Adverse effects: Neuradrenergic symptoms (hypertension, dry mouth, constipation, insomnia, decreased appetite), serotonergic side effects ([[nausea, diarrhea, nervousness, insomnia, sexual dysfunction, withdrawal symptoms, and hyponatremia).
• Duloxetine (Effective dose range 60-120 mg)
  • May be effective in treating neuropathic pain and other pain condition. Smoking decreases the plasma levels of duloxetine.
• Venlafaxine (Effective dose range 75-350 mg)
  • Adverse effects: Compared to other serotonergic antidepressants, is associated with a slightly increased incidence of nausea and vomiting, higher risk of withdrawal symptoms, and hypertesnion.
• Desvenlafaxine (Effective dose range 50-100 mg)
  • Benefit: may reduce neuropathic pain
• Levomilnacipran (Effective dose range 40-120 mg)

Other antidepressants

• Bupropion XR (Effective dose range 300--450 mg)
  • Atypical antidepressant
  • A noradrenergic, dopaminergic drug with stimulat-like effects
  • Approved for smoking cessation
  • Benefits: Weight neutral, minimal to no risk of sexual dysfunction, minimal withdrawal symptoms.
  • Adverse effects: Lowers seizure threshold, particularly at higher doses.
• Mirtazapine (Effective dose range 15-45 mg)
  • Atypical antidepressant
  • Benefits: faster onset of action than SSRIs, minimal sexual dysfunction, minimal withdrawal symptoms.
  • Adverse effects: increased appetite and sleep (may be beneficial in patients with reduced appetite and insomnia as symptoms of MDD), higher risk of weight gain
• Trazodone
• Vilazodone (Effective dose range 10-40 mg):
  • Serotonin partial agonist and reuptake inhibitor.
  • Benefits: May have a lower risk of [[sexual dysfunction[]] than other serotonergic antidepressants
  • No generic formulation is currently available.
• Vortioxetine (Effective dose range 10-20 mg):
  • Serotonin reuptake inhibitor and serotonin modulator
  • Benefits: May have a lower risk of sexual dysfunction than other serotonergic antidepressants. A long half-life may reduce the risk of withdrawal symptoms upon tapering.
  • Adverse effects: Despite 5-HT3 receptor antagonism, it has high rates of nausea.

Tricyclic antidepressants

• Tricyclic antidepressants (TCAs) are considered second-line or third-line medications in the treatment of MDD due to greater side effects compared to SSRIs and SNRIs, in particular in the elderly.
• they work by inhibiting serotonin and norepinephrine reuptake.
• Common side effects of TCAs include sedation, orthostatic hypotension, anticholinergic effects, GI distress, weight gain, cardiac arrhythmias, and QTc prolongation.
• TCAs include:
• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Clomipramine
• Doxepin
• Amoxapine

Monoamine oxidase inhibitors

• Monoamine oxidase inhibitors (MAOIs) are considered second-line or third-line medications in the treatment of MDD due to greater side effects compared to SSRIs and SNRIs, in particular in the elderly.
• Combination of MAOIs with other serotonergic drugs, i.e., TCAs, SSRIs, or SNRIs are contraindicated due to increased risk of serotonin syndrome.
• MAOIs include:
  • Phenelzine
  • Tranylcypromine

Treatment in primary care

Trails of medications and multifactorial interventions show benefit.

A systematic review by the Cochrane Collaboration found benefit from medications in primary care.

Measurement-based care (STAR*D and VAST-D trials)

Treatment after SSRI (citalopram) failure
(STAR*D Studies)

Intervention		Outcome
Medication	Mean final dose	Remision %	Quit 2˚ ADRs (%)
Switch meds (NEJM 2006; PMID: 16554525)
Bupropion SR	283 mg	21%	27%
Sertraline (SSR)	136 mg	18%	21%
Venlafaxine ER (SNRI)	194 mg	25%	21%
Augment meds (NEJM 2006; PMID: 16554526)
Bupropion SR	268 mg	30%	13%
Buspirone	41 mg	30%	21%

When treated with monotherapy for depression, approximately 30% of patients have remission of symptoms while 50% have a response to medications. For patients with inadequate response, either adding sustained-release bupropion ("bupropion was 200 mg per day during weeks 1 and 2, increasing to 300 mg per day by week 4 and to 400 mg per day (the final dose) during week 6") or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients (bupropion may be more effective than buspirone), while switching medications can achieve remission in about 25% of patients. Alternatively, "extended-release venlafaxine, the starting daily dose of 37.5 mg for 7 days was increased to 75 mg from day 8 to 14, to 150 mg from day 15 to 27, to 225 mg from day 28 to 41, to 300 mg from day 42 to 62, and to 375 mg from day 63 onward."

In level 3 of the STAR*D trials, patients who had failed two trials of a second-generation antidepressant, tended to better with nortriptyline than mirtazapine.

For patients failing anti-depressants, buproprion has been compared to aripiprazole in the VAST-D trial; while aripiprazole was "modestly' better, it had more adverse drug reactions.

Clinical Hints

When treating patients with major depressive disorder the following clinical hints should be taken into consideration:

• Initiation of SSRIs may be associated with early transient anxiety, aggravating suicidal ideation. Reducing the dose or adding a benzodiazepine may be helpful in these patients.
• In MDD patients with insomnia, benzodiazepines, zolpidem, trazodone, or mirtazapine are helpful. A systematic review in 2022 concluded that in the treatment of chronic insomnia, "eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce"
• In addition, when depressed patients begin to clinically improve, their physical energy also improves, enabling them to carry out suicidal acts that they did not have the power to perform before. This is known as paradoxical suicide.
• Antidepressants may take as long as 6-8 weeks to take effect.
• The goal of treatment is achieving complete remission of symptoms and return to normal functioning.
• In patients who fail to respond to an SSRI, or experience intolerable side effects, another medication in this class may be tried. However, some physicians prefer to switch to another medication with a different mechanism of action.
• Psychotherapy may be added in the treatment of patients with a partial response to pharmacotherapy alone.
• In patients with the first episode of major depression, maintenance treatment for at least months may be helpful in preventing relapse. In patients with recurrent major depressive episodes, long-term treatment may be beneficial.
• In patients experiencing intolerable sexual side effects with SSRIs, bupropion or mirtazapine may be considered.
• Bupropion may be beneficial in patients with anergy and psychomotor retardation due to its stimulant-like effects.
• Hospitalization may be considered in patients with significant suicidal ideation or intent without adequate family support or safe-guards at home. Patients who express intent to hurt others or those who are not able to care for themselves may also be hospitalized.
• Pharmacogenomic testing to guide dosing may slightly improve remission (17% vs 16%).