What are non-SSRI (Selective Serotonin Reuptake Inhibitor) treatment options for depression?

Non-SSRI Treatments for Depression

Several effective non-SSRI treatment options exist for depression, including SNRIs, bupropion, mirtazapine, psychotherapy (particularly CBT), complementary treatments, and exercise, all of which have demonstrated efficacy comparable to SSRIs with different side effect profiles. 1

Pharmacological Non-SSRI Options

First-Line Medication Alternatives

• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine

• Atypical Antidepressants

  • Bupropion: Affects dopamine and norepinephrine; useful for depression with fatigue or low energy; fewer sexual side effects 2, 3
  • Mirtazapine: Enhances serotonin and norepinephrine; helpful for depression with insomnia or appetite loss 1
  • Nefazodone: Beneficial for patients with anxiety but requires monitoring for hepatotoxicity 2

• Other Options

  • Tricyclic antidepressants: Effective but have more anticholinergic effects; use with caution, especially in elderly or patients with dementia 2
  • Buspirone: Partial 5HT1A agonist; effective for depression with anxiety 2

Second-Step Treatments

For patients who fail to respond to initial treatment:

• Switching strategies: Switching to a non-SSRI antidepressant (bupropion, mirtazapine, venlafaxine) shows modestly higher remission rates (28%) compared to switching to another SSRI (23.5%) 4

• Augmentation strategies:

  • Adding psychotherapy to medication
  • Combining medications (e.g., adding bupropion to an SSRI)
  • Adding lithium or thyroid hormone 5
  • Atypical antipsychotics (e.g., aripiprazole, olanzapine with fluoxetine) 5

Non-Pharmacological Options

Psychotherapy

• Cognitive Behavioral Therapy (CBT): Shows similar response and remission rates to antidepressants (moderate-strength evidence) 1
• Interpersonal Therapy
• Psychodynamic Therapy
• Acceptance and Commitment Therapy
• Behavioral Activation

Complementary and Alternative Medicine (CAM)

• St. John's Wort: Effective for mild to moderate depression 1
• S-adenosyl-L-methionine (SAMe)
• Omega-3 fatty acids
• Acupuncture
• Meditation and mindfulness practices

Exercise

• Regular physical activity has demonstrated antidepressant effects 1, 2
• Various forms of aerobic exercise show benefit

Other Non-Pharmacological Interventions

• Electroconvulsive Therapy (ECT): Highly effective for severe or treatment-resistant depression 5
• Transcranial Magnetic Stimulation (TMS): For treatment-resistant cases 5
• Vagus Nerve Stimulation: FDA-approved for treatment-resistant depression 5

Combination Approaches

Recent evidence shows that combining psychotherapy with medication may be more effective than medication alone:

• Dynamic interpersonal therapy or general supportive therapy combined with antidepressants showed significantly higher response rates (78.7% and 78.1%) compared to antidepressant monotherapy (45.2%) 1

Important Considerations

• Side effect profiles differ among non-SSRI options, which can guide selection based on patient-specific factors:

  • Bupropion: Lower risk of sexual dysfunction and weight gain; may increase seizure risk 3
  • SNRIs: May cause higher rates of nausea, increased blood pressure
  • Mirtazapine: May cause sedation and weight gain

• Drug interactions: Be aware of potential interactions, particularly with bupropion which inhibits CYP2D6 and can interact with many medications 3

• Contraindications:

  • Avoid bupropion in patients with seizure disorders 3
  • Avoid MAOIs within 14 days of other antidepressants 3
  • Screen for bipolar disorder before initiating any antidepressant to avoid triggering manic episodes 2

The evidence suggests that many non-SSRI treatments have comparable efficacy to SSRIs for depression, with the choice between options often guided by side effect profiles, patient comorbidities, and treatment history.