What is the interaction between Sertraline (Zoloft), Mirtazapine, and Promethazine (Phenergan)?

From the Guidelines

I strongly advise against taking Zoloft (sertraline), mirtazapine, and Phenergan (promethazine) together without close medical supervision due to the high risk of serotonin syndrome and other serious drug interactions. When considering the combination of these medications, it is crucial to weigh the potential benefits against the risks, particularly the risk of serotonin syndrome, which can be life-threatening 1. The combination of an SSRI like Zoloft, a tetracyclic antidepressant like mirtazapine, and an antihistamine with sedative properties like Phenergan can lead to excessive serotonin levels in the body, causing symptoms such as agitation, confusion, rapid heart rate, and hyperthermia 1. Additionally, the sedative effects of these medications can compound each other, leading to excessive drowsiness, impaired coordination, and potentially life-threatening respiratory depression. Key considerations include:

• The potential for drug-drug interactions, particularly with SSRIs and MAOIs, which are contraindicated due to the risk of serotonin syndrome 1.
• The importance of medical education, training, and experience in safely prescribing antidepressant medications, including the need for careful dose titration and monitoring for adverse effects 1.
• The recommendation to start with a subtherapeutic dose as a “test” dose and to systematically assess treatment response using standardized symptom rating scales 1. Given these considerations, it is essential to consult with a healthcare provider before taking Zoloft, mirtazapine, and Phenergan together, as they can help determine if the benefits outweigh the risks and suggest alternative treatments or dosing schedules to minimize adverse effects 1.

From the FDA Drug Label

Table 5: Clinically Important Drug Interactions with Mirtazapine Tablets Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with mirtazapine tablets increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases If serotonin syndrome occurs, consider discontinuation of mirtazapine tablets and/or concomitant serotonergicdrugs Examples SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John’s Wort, tramadol, tryptophan, buspirone

The combination of Zoloft (SSRI), mirtazapine, and Phenergan may increase the risk of serotonin syndrome.

• Zoloft is an SSRI, which is a type of serotonergic drug.
• Mirtazapine also has serotonergic properties.
• The concomitant use of these serotonergic drugs increases the risk of serotonin syndrome.
• It is recommended to monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases.
• If serotonin syndrome occurs, consider discontinuation of mirtazapine and/or concomitant serotonergic drugs 2.

From the Research

Medication Combinations

The combination of Zoloft, mirtazapine, and Phenergan is not directly mentioned in the provided studies. However, the studies do discuss the use of combination pharmacotherapy for bipolar disorder and depression:

• The study 3 discusses the complexity of combination pharmacotherapy for bipolar disorder and the need for a rational approach to ensure that each component of the treatment regimen has a defined role.
• The study 4 mentions the use of olanzapine/fluoxetine combination, quetiapine, and lurasidone as approved treatments for bipolar depression, but does not discuss the combination of Zoloft, mirtazapine, and Phenergan.
• The study 5 reports on the use of various psychotropic drugs, including mirtazapine, in combination with other medications for the treatment of bipolar depression, but does not specifically mention the combination of Zoloft, mirtazapine, and Phenergan.
• The study 6 compares the efficacy of two antidepressant medication combinations, including venlafaxine plus mirtazapine, with selective serotonin reuptake inhibitor monotherapy, but does not discuss the combination of Zoloft, mirtazapine, and Phenergan.

Key Findings

Some key findings from the studies include:

• The use of combination pharmacotherapy for bipolar disorder is common, but often lacks a clear rationale 3.
• The choice of medication for bipolar depression should be individualized, taking into account the potential benefits and risks of each medication 4.
• Combinations of antidepressants, mood stabilizers, and atypical antipsychotics are commonly used in clinical practice, but the efficacy of many of these combinations has not been studied 5.
• The combination of venlafaxine plus mirtazapine may have a greater risk of adverse events compared to other medication combinations 6.

Medication Safety and Efficacy

The safety and efficacy of the combination of Zoloft, mirtazapine, and Phenergan cannot be determined based on the provided studies. However, the studies do highlight the importance of careful consideration of the potential benefits and risks of each medication, as well as the need for individualized treatment approaches:

• The study 4 discusses the use of number needed to treat (NNT) and number needed to harm (NNH) to quantify the benefits and risks of different medications for bipolar depression.
• The study 6 reports on the adverse events associated with different medication combinations, including the combination of venlafaxine plus mirtazapine.