Can you take venlafaxine (Effexor) and mirtazapine (Remeron) together?

Can You Take Venlafaxine and Mirtazapine Together?

Yes, venlafaxine and mirtazapine can be taken together, and this combination is increasingly used in clinical practice for treatment-resistant depression, with evidence showing response rates of 44-81% and acceptable tolerability. 1, 2

Evidence for Combined Use

Efficacy in Treatment-Resistant Depression

The combination of venlafaxine (an SNRI) and mirtazapine (a NaSSA) has demonstrated substantial clinical benefit in patients who have failed previous antidepressant trials:

• Response rates of 44% at 4 weeks and 50% at 8 weeks were observed in patients with persistent depressive illness who had failed an average of 2.5 previous antidepressant trials 1
• At 6 months, 56% of the original cohort responded, representing 75% of those still receiving treatment 1
• A prospective case series showed 81.8% response rate and 27.3% remission rate after approximately 8 weeks of combination treatment in patients with moderate to severe depression 2

Mechanism and Rationale

The combination works through synergistic pharmacological actions:

• Venlafaxine inhibits both serotonin and norepinephrine reuptake (SNRI mechanism) 3
• Mirtazapine enhances noradrenergic and serotonergic neurotransmission through alpha-2 antagonism while blocking certain serotonin receptor subtypes 3
• This dual mechanism is sometimes referred to as "California rocket fuel" in clinical practice 4

Combination from Treatment Initiation

Emerging evidence suggests starting with combination therapy may be superior to monotherapy:

• Mirtazapine combined with venlafaxine from treatment initiation produced a 58% remission rate compared to 25% with fluoxetine monotherapy 5
• Combination treatments doubled the likelihood of remission compared to single medication use 5
• Among responders, discontinuing one agent led to relapse in approximately 40% of cases, suggesting both medications contribute to efficacy 5

Safety and Tolerability Profile

Common Adverse Effects

The combination is generally well-tolerated, though side effects occur in approximately 44% of patients:

• Sedation (19%) and weight gain (19%) are the most frequent adverse effects 1
• Only 5% discontinued treatment due to adverse effects in one study 1
• Nearly half of patients experienced significant side effects during treatment, though most continued therapy 2
• No serious adverse effects were directly linked to the combination 1

Important Safety Considerations

Monitor carefully for hypomanic switching, particularly in patients with unrecognized bipolar disorder, as this combination can induce profound alterations in mental state 4

Both medications are metabolized by CYP2D6, which shows genetic polymorphism affecting 5-8% of Caucasians (poor metabolizers) and 1-7% (ultrarapid metabolizers) 3

Dosing Strategy

Clinical response typically occurs at moderate to high doses of both agents:

• Venlafaxine is commonly used at 75-225 mg/day 3, 5
• Mirtazapine is typically dosed at 15-30 mg/day 3, 5
• Titration should occur over approximately 2 weeks for venlafaxine to minimize side effects 5

Clinical Context

While the American College of Physicians guidelines note that second-generation antidepressants generally do not differ significantly in efficacy for acute-phase major depressive disorder 3, these guidelines primarily address monotherapy. The combination strategy is specifically indicated for:

• Patients who have failed initial antidepressant trials (38% do not respond to 6-12 weeks of monotherapy) 3
• Treatment-resistant depression where switching alone may only help 1 in 4 patients 3

Common Pitfalls to Avoid

Do not assume this combination is first-line therapy—it is best reserved for patients who have failed adequate trials of monotherapy 1, 2

Do not overlook the potential for weight gain and sedation, which may significantly impact quality of life and adherence 1

Do not fail to screen for bipolar disorder before initiating this combination, as the risk of hypomanic switching is real 4

Do not discontinue abruptly—venlafaxine particularly requires gradual tapering to prevent discontinuation symptoms 3