Can Mirtazapine and Amitriptyline (tricyclic antidepressant) be used together?

From the Guidelines

Mirtazapine and amitriptyline can be used together, but this combination should only be done under careful medical supervision, as it may increase the risk of serotonin syndrome and other side effects, and should be considered early as part of a multidisciplinary treatment plan, particularly if pain is severe, chronic, or associated with functionally impairing anxiety or depression, as suggested by the most recent study 1. The combination of mirtazapine and amitriptyline may be prescribed in certain cases of treatment-resistant depression or when a patient needs the specific effects of both medications.

• Mirtazapine is a tetracyclic antidepressant, while amitriptyline is a tricyclic antidepressant, and both work in different ways to modulate the pain modulatory system in the brain and spinal cord, as mentioned in the study 1.
• The study 1 emphasizes that these medications are not targeted at treating mood- and emotion-related symptoms, but rather at modulating the pain modulatory system, and lower doses often suffice.
• However, using them together increases the risk of serotonin syndrome, a potentially serious condition characterized by agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and excessive sweating, as well as enhancing side effects like drowsiness, dry mouth, constipation, and blurred vision.
• Dosing would be individualized based on the patient's condition, typically starting with lower doses of each medication and gradually adjusting as needed, as suggested by the study 2, which provides guidance on treatment options for refractory gastroparesis symptoms.
• Patients taking this combination should report any unusual symptoms to their healthcare provider immediately and avoid alcohol and other central nervous system depressants, which could worsen side effects.
• The study 3 provides guidance on the use of psychotropic medication combinations, including the importance of developing a treatment and monitoring plan, educating the patient and family, obtaining assent/consent, and implementing the treatment trial.
• However, the most recent and highest quality study 1 provides the most relevant guidance on the use of mirtazapine and amitriptyline together, and should be prioritized in clinical decision-making.

From the FDA Drug Label

The concomitant use of mirtazapine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases Treatment with mirtazapine tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated The only drug overdose death reported while taking mirtazapine tablets was in combination with amitriptyline and chlorprothixene in a non-US clinical study.

Mortazapine and Amitryptiline can be used together, but with caution due to the potential increased risk of serotonin syndrome.

• The combination of these two drugs may increase the risk of serotonin syndrome, particularly during treatment initiation and dose increases.
• Patients should be monitored closely for signs and symptoms of serotonin syndrome, and treatment should be discontinued immediately if they occur.
• The use of mortazapine with amitriptyline has been associated with a reported overdose death in a non-US clinical study 4.
• Therefore, it is essential to weigh the benefits and risks of using mortazapine and amitriptyline together and to closely monitor patients for any adverse effects 5.

From the Research

Combination Therapy of Mirtazapine and Amitriptyline

• The combination of mirtazapine and amitriptyline has been studied in various contexts, including treatment-resistant depression and insomnia disorder 6, 7, 8.
• A study published in 2021 investigated the effectiveness of low-dose amitriptyline and mirtazapine for insomnia disorder, but it did not specifically examine the combination of the two medications 6.
• Another study from 1998 compared the efficacy of mirtazapine and amitriptyline in the long-term treatment of depression, but it did not explore the combination of the two medications 7.
• A 2018 study examined the addition of mirtazapine to SSRIs or SNRIs for treatment-resistant depression, but it did not investigate the combination of mirtazapine and amitriptyline 8.

Safety and Efficacy Considerations

• The safety and efficacy of combining mirtazapine and amitriptyline are not well established, and more research is needed to fully understand the potential benefits and risks of this combination 9, 10.
• A 2020 study protocol outlined a systematic review and meta-analysis to investigate the frequency and severity of adverse drug reactions associated with amitriptyline, but it did not specifically address the combination of mirtazapine and amitriptyline 9.
• A 2024 study compared the efficacy of mirtazapine, SSRIs, and amitriptyline in reducing core depression symptoms, but it did not examine the combination of mirtazapine and amitriptyline 10.

Key Findings and Implications

• The available evidence suggests that mirtazapine and amitriptyline have different mechanisms of action and side effect profiles, which may impact their potential use in combination therapy 7, 10.
• Further research is needed to fully understand the safety and efficacy of combining mirtazapine and amitriptyline, including the potential benefits and risks of this combination in different patient populations 6, 8, 9.