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Best Antidepressants for Preventing Depression Relapse & Maintenance Treatment (Study)

Depression is a complex, often long-term condition requiring careful management.

Recent research has shed light on the effectiveness of various antidepressants during the maintenance phase of major depressive disorder (MDD).


  • Extensive Study: The meta-analysis included 34 double-blind, placebo-controlled trials with a total of 9,384 participants.
  • Multiple Drugs Analyzed: 20 different antidepressants were compared for their long-term effectiveness and safety.
  • Outcome Measures: The study focused on relapse rates, drug discontinuation rates, adverse events, and individual side effects.
  • Top Performers: Amitriptyline, citalopram, desvenlafaxine, and several others showed superior efficacy in preventing relapse compared to placebo.

Source: Molecular Psychiatry (2023)

Depression Relapse During Antidepressant Treatment

Depression is a recurrent condition, and even with ongoing treatment, some individuals may experience a relapse.

Understanding the frequency, causes, and underlying mechanisms is crucial for both patients and healthcare providers to manage expectations, tailor treatment, and develop strategies to minimize the risk.

Prevalence of Depression Relapse

High Recurrence Rate: Studies indicate that more than 50% of individuals who have one major depressive episode will have at least one more in their lifetime, and the risk increases with the number of past episodes.

During Treatment: Even during maintenance therapy designed to prevent relapse, a significant proportion of patients (approximately 20-50%) may experience a relapse within a year.

Causes of Depression Relapse on Medications

Incomplete Response to Treatment: Patients who do not achieve full remission are at a higher risk of relapse. Residual symptoms, even if mild, can be a potent predictor of a future episode.

Non-Adherence to Medication: Discontinuation or irregular use of antidepressants significantly increases the risk of relapse. Patients might stop their medication due to side effects, perceived lack of efficacy, or a misunderstanding of how long they need to continue treatment.

Psychosocial Stressors: Life stressors, traumatic events, and ongoing relational or work-related problems can precipitate a relapse, particularly if coping mechanisms are inadequate.

Neurobiological Factors: Changes in brain structure and function, neurotransmitter imbalances, and genetic factors can all influence the risk of relapse.

Comorbid Mental Health Conditions: The presence of other mental health disorders, like anxiety or substance use disorders, can complicate treatment and increase relapse risk.

Tolerance to Medication: Over time, some patients might develop tolerance to their antidepressant medication, where the drug loses its effectiveness despite continuous use.

Comparing 20 Antidepressants for Maintenance Treatment of Depression (Meta-Analysis)

A robust systematic review and network meta-analysis were conducted to compare 20 antidepressants’ efficacy, acceptability, tolerability, and safety.

The analysis was based on double-blind, randomized, placebo-controlled trials, ensuring a high standard of evidence.

The study focused on adults with MDD in the maintenance phase of treatment, where preventing relapse is the primary goal.

Rigorous Selection and Analytical Approach

Literature Review: Extensive searches were conducted across PubMed, Cochrane Library, and Embase databases.

Inclusion Criteria: Only studies with a specific design focusing on patients stabilized on antidepressants followed by randomization were included.

Outcome Measures: Primary outcomes included the 6-month relapse rate, with secondary outcomes covering all-cause discontinuation, discontinuation due to adverse events, and individual adverse events.

Top Antidepressants for Preventing Depression Relapse

The meta-analysis provided a comprehensive comparison of 20 antidepressants, evaluating them based on their efficacy in preventing relapse, acceptability, and tolerability.

1. Amitriptyline

  • Efficacy: Strongly outperformed placebo.
  • Considerations: Higher side effects might limit its use.

2. Citalopram

  • Efficacy: Significantly better than placebo.
  • Considerations: Well-tolerated with a balanced profile.

3. Desvenlafaxine

  • Efficacy: Notably effective.
  • Considerations: Higher incidence of nausea/vomiting.

4. Duloxetine

  • Efficacy: Demonstrated solid performance.
  • Considerations: Well-regarded for treating co-morbid pain symptoms.

5. Fluoxetine

  • Efficacy: Consistently effective.
  • Considerations: Long half-life can be an advantage or drawback depending on the scenario.

Antidepressants with Low All-Cause Discontinuation (Higher Acceptability)


  • Acceptability: Lower discontinuation rates.
  • Considerations: Nausea/vomiting were more common.


  • Acceptability: Favored for continued use.
  • Considerations: Possible weight gain and withdrawal issues.


  • Acceptability: Generally well-received.
  • Considerations: Higher discontinuation due to adverse events, mainly gastrointestinal.


  • Acceptability: Good retention rates.
  • Considerations: Must be tapered due to withdrawal risks.


  • Acceptability: Good overall profile.
  • Considerations: Balances efficacy with tolerability but watch for nausea.

Least Effective Antidepressants for Preventing Depression Relapse

These medications did not show a statistically significant advantage over placebo in reducing the 6-month relapse rate or had less robust data supporting their efficacy:


  • Efficacy: Did not significantly outperform the placebo in some analyses.
  • Considerations: Unique mechanism but may not be as effective for maintenance.


  • Efficacy: While effective in other contexts, it did not demonstrate superiority in this setting.
  • Considerations: Often appreciated for its activating effects and lower sexual side effects.


  • Efficacy: Generally well-regarded but didn’t stand out in this particular analysis for maintenance.
  • Considerations: Known for its tolerability and effectiveness in acute treatment.


  • Efficacy: Insufficient evidence to demonstrate a significant advantage over placebo.
  • Considerations: A newer medication with less long-term data available.


  • Efficacy: Did not show a significant benefit in this context.
  • Considerations: More commonly used for fibromyalgia in some regions.

Antidepressants with Higher Discontinuation Due to Adverse Events

These medications were associated with a higher rate of discontinuation due to adverse effects, indicating tolerability issues for some patients:


  • Tolerability: Despite its efficacy and lower all-cause discontinuation rates, it had a higher rate of discontinuation due to adverse events, primarily gastrointestinal issues like nausea and vomiting.
  • Considerations: Often chosen for its balanced profile but may not be suitable for everyone.

Mixed or Limited Data in Depression Relapse Prevention

Some medications had mixed results, limited data, or wider confidence intervals in the analysis, making it harder to draw definitive conclusions about their long-term maintenance efficacy:

Reboxetine, Tianeptine, Vilazodone

  • Efficacy: These drugs had less robust or mixed data in the context of this study.
  • Considerations: While they may be effective for some individuals, there wasn’t enough compelling evidence in this meta-analysis to rank them higher for maintenance treatment.

Study Limitations: Antidepressant Maintenance Efficacy

Limited Data for Some Drugs: The analysis for certain antidepressants was based on a small number of studies, which might affect the reliability of the results.

Population Representation: Most studies included outpatients and a majority female population, which may not represent all demographics equally.

Real-World Application: The study’s findings need to be interpreted in the context of real-world clinical settings, where patients might have co-existing health conditions or be on multiple medications.

Longer Follow-up Needed: As the study focused on a 6-month period, longer-term studies are required to understand the sustained efficacy and safety of these treatments.

Antidepressants in Relapse Prevention

  • Maintenance Therapy: Continuing antidepressants after achieving remission is a standard strategy to prevent relapse. The length of this maintenance phase can vary depending on individual risk factors but is generally recommended for at least 6-12 months, and often longer for those with recurrent or severe episodes.
  • Tapering Off: Gradual reduction of antidepressants, rather than abrupt cessation, is advised to minimize the risk of relapse. The tapering process should be individualized and closely monitored.

Strategies to Reduce the Risk of Depression Relapse

  • Psychoeducation: Teaching patients about the nature of depression, the importance of adherence to medication, and strategies to cope with stress can empower them and reduce relapse rates.
  • Psychotherapy: Combining antidepressants with psychological therapies like Cognitive Behavioral Therapy (CBT) or Interpersonal Therapy (IPT) has been shown to reduce the risk of relapse.
  • Lifestyle Modifications: Regular physical activity, adequate sleep, a healthy diet, and stress management techniques can all support mental health and reduce the risk of relapse.
  • Monitoring and Follow-Up: Regular check-ins with healthcare providers are crucial. They allow for early detection of symptoms and adjustment of treatment plans.

Antidepressant Selection Remains Nuanced

It’s essential to remember that while this ranking offers a snapshot based on specific criteria like relapse prevention and acceptability, the choice of an antidepressant is deeply personal and should be tailored to the individual’s unique medical history, side effect profile, and specific symptoms.

What might be a top performer for one person could be less effective or tolerable for another.

As always, treatment decisions should be made in close consultation with healthcare providers, considering the full spectrum of each medication’s effects.


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