What is the mechanism by which depression worsened and suicidal thoughts developed in a patient taking Zepbound (Escitalopram)?

From the Guidelines

Tirzepatide (Zepbound) may worsen depression and trigger suicidal thoughts, and immediate action is necessary to ensure the patient's safety. The medication's effects on neurotransmitter systems, appetite, weight, and hormone levels can contribute to mood disturbances. According to the American College of Physicians, SSRIs are associated with an increased risk for suicide attempts compared with placebo 1.

Mechanism of Action

The potential mechanisms by which Zepbound may worsen depression and trigger suicidal thoughts include:

• Affecting neurotransmitter systems in the brain, particularly serotonin and dopamine pathways that regulate mood
• Impacting body image and psychological well-being through its effects on appetite and weight
• Altering hormone levels due to rapid weight loss, potentially affecting mood regulation
• Causing increased anxiety or mood disturbances as the body adjusts to metabolic changes

Recommendations

If your patient is experiencing worsened depression and suicidal thoughts while on Zepbound, consider the following:

• Temporarily discontinue the medication and provide appropriate mental health support
• Conduct a psychiatric evaluation to assess the patient's mental health status
• Discuss alternative weight management approaches with the patient
• Monitor the patient closely, as suicidal ideation represents a medical emergency requiring prompt intervention
• Weigh the benefits of continued treatment against the serious psychological risks, prioritizing the patient's safety above all else, as recommended by the American College of Physicians 1.

From the FDA Drug Label

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

The mechanism by which antidepressants like venlafaxine may worsen depression and increase suicidal thoughts is not fully understood. However, it is thought that these medications may increase the risk of suicidality in certain patients, particularly children, adolescents, and young adults.

• Key symptoms to monitor for include anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania.
• If a patient's depression is worsening or they are experiencing suicidal thoughts, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication 2.

From the Research

Mechanism of Worsened Depression and Suicidal Thoughts

• The exact mechanism of worsened depression and suicidal thoughts in patients taking antidepressants, such as zepbound, is not fully understood, but several studies have investigated the relationship between antidepressant use and suicidal behavior 3, 4, 5.
• A cohort study using a primary care database found that the risk of suicide and attempted suicide or self-harm was significantly increased during periods of treatment with certain antidepressants, such as mirtazapine, venlafaxine, and trazodone 3.
• Another study found that the risk of suicidal behavior was increased in the first month after starting antidepressants, especially during the first 1 to 9 days 4.
• A reanalysis of randomized placebo-controlled studies of fluoxetine and venlafaxine found that suicidal thoughts and behavior decreased over time for adult and geriatric patients, but no differences were found for youths 5.

Risk Factors for Suicidal Thoughts and Behavior

• Several risk factors for suicidal thoughts and behavior have been identified, including:
  • Previous suicide attempts or self-harm 6
  • Presence of comorbid psychiatric illness or substance abuse 6
  • Availability of social support 6
  • Intent, plan, and means of suicidal ideation 6
• A study found that asking high-risk patients about suicidal intent leads to better outcomes and does not increase the risk of suicide 6.

Management of Suicidal Patients

• Evaluation and treatment of suicidal patients are challenging tasks for physicians, and clinical judgment guides the decision-making process 6.
• Important elements of the history that permit evaluation of the seriousness of suicidal ideation include the intent, plan, and means; the availability of social support; previous suicide attempts; and the presence of comorbid psychiatric illness or substance abuse 6.
• Care plans for patients with chronic suicidal ideation include ensuring patient safety and medical stabilization, activating support networks, and initiating therapy for psychiatric diseases 6.