Antidepressant combination
Combining Antidepressants: A Review of Evidence
Overview of Antidepressant Use
Despite the rise in antidepressants, many patients experience inadequate responses.
At least one-third do not respond adequately to their first treatment.
Optimization involves ensuring adequate dosage and adherence over time.
Treatment Strategies for Incomplete Response
Initial recommendations include:
Higher doses of the current antidepressant.
Switching to another antidepressant of the same or different class.
Augmenting with psychotherapy or non-antidepressant medications (like lithium).
Combining with another antidepressant.
Limited evidence exists for treatment-refractory cases.
STAR*D Study Highlights
STAR*D (Sequenced Treatment Alternatives to Relieve Depression) includes evidence for those who fail up to four treatment trials.
No definitive superior antidepressant combinations were identified.
Research Methodology
Literature search in MEDLINE since 1950 using keywords related to antidepressants.
Reviewed randomized controlled trials (RCTs), open-label studies, case series, and reports.
Excluded bupropion due to lack of licensing as an antidepressant in the UK.
Antidepressant Combinations by Class
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRI Combinations with SSRIs
Limited evidence from open-label studies (e.g., citalopram + fluvoxamine).
Clinical improvement noted; however, risks include nausea and potential for serotonin syndrome.
SSRI Combinations with Tricyclic Antidepressants (TCAs)
SSRIs may enhance TCA efficacy potentially through increased plasma levels.
Three key studies show varying results in efficacy for non-responders.
Side effects may include dry mouth, gastrointestinal distress, and cardiovascular risks.
SSRI Combinations with Monoamine Oxidase Inhibitors (MAOIs)
Combining SSRIs with irreversible MAOIs poses serious risks, including serotonin syndrome.
A period of washout is crucial when switching medications.
SSRI Combinations with Moclobemide
Increased efficacy observed in open-label trials with good tolerability at low doses.
However, still some risk for serotonin toxicity.
SSRI with NaSSAs
This combination is common; evidence supports enhanced response due to differences in mechanisms.
Studies show rapid onset of effects and good tolerance compared to monotherapy.
Side effects include sedation and weight gain.
SSRI Combinations with SNRIs
SSRIs combined with SNRIs (e.g., venlafaxine) are increasingly practiced but irrational due to redundant mechanisms.
Low doses of both can lead to increased side effects risk, including serotonin toxicity.
SSRI with Trazodone
Trazodone provides dual activity and has been successfully used in combination with SSRIs to manage insomnia and anxiety associated with SSRIs.
Caution advised due to the potential for serotonin syndrome at higher doses.
Tricyclic Antidepressants (TCAs)
TCA with MAOIs:
Theoretical basis exists for combining TCAs and MAOIs, but evidence largely shows negative results in controlled studies.
Risks include increased occurrence of severe side effects (e.g., serotonin syndrome).
TCA with SNRIs:
No strong rationale exists to combine both, yet anecdotal evidence suggests efficacy in specific cases.
Summary of Evidence Challenges
The literature lacks robust RCTs to definitively establish the efficacy of combinations versus monotherapy.
Broader treatment strategies (e.g., augmentation therapy) may be more beneficial in treatment-resistant cases.
Many combinations need to be closely monitored for risks and effectiveness.
Clinical Implications
Evidence indicates a cautious approach in clinical practice regarding antidepressant combinations.
Consider monotherapy before combinations due to the risk of toxicity.
Assess the clinical status of patients and keep them informed about treatment risks and benefits.
Best considered protocols include combination of SSRI with NaSSAs or trazodone when applicable.