As ketamine therapy gains ground as a rapid-acting antidepressant, one of the most common clinical questions is: Can patients safely continue their antidepressants while receiving ketamine?
The short answer: yes—usually. But the longer, more nuanced answer lies in understanding pharmacodynamics, patient selection, and vigilant monitoring.

1. Why combination therapy is common

In most clinical settings, ketamine is used as an augmentation strategy rather than a standalone treatment. The reasoning is simple—most patients seeking ketamine therapy are already on antidepressants and haven’t achieved sufficient response.

Stopping antidepressants abruptly before ketamine may risk relapse or withdrawal symptoms. Hence, current protocols, including those used in esketamine trials, recommend continuing the baseline antidepressant while ketamine is introduced.

2. What the evidence says

• IV and SC ketamine studies: Trials of racemic ketamine generally allowed participants to stay on stable doses of SSRIs or SNRIs. No significant safety signals or serotonin-related toxicities emerged.
• Esketamine trials: The FDA-approved intranasal esketamine is mandated to be used alongside an oral antidepressant—most often sertraline, duloxetine, or venlafaxine.
• Meta-analyses: Pooled data show combination use enhances response rates without increasing serious adverse events. Dissociation, transient hypertension, and nausea remain the commonest side-effects, regardless of antidepressant co-use.

3. Class-specific considerations

Antidepressant Class	Compatibility with Ketamine	Notes & Cautions
SSRIs (e.g., sertraline, escitalopram)	Generally safe	May enhance response; watch for agitation or anxiety early on
SNRIs (e.g., venlafaxine, duloxetine)	Safe	Both can raise BP—monitor for additive hypertensive effects
TCAs (e.g., nortriptyline)	Use with caution	Risk of arrhythmia; baseline ECG advisable
MAOIs (e.g., tranylcypromine)	Avoid or use only under expert supervision	Rare risk of hypertensive crisis; insufficient data
Atypical antidepressants (e.g., mirtazapine, bupropion)	Generally safe	Minimal pharmacokinetic overlap
Lithium, mood stabilisers	Usually safe	Monitor renal function and neurotoxicity if used long term

4. Mechanistic harmony, not conflict

Ketamine primarily acts via NMDA antagonism and glutamate-BDNF-mTOR activation, distinct from the monoaminergic modulation of SSRIs or SNRIs. This complementary action explains why co-administration often produces synergistic rather than antagonistic effects.

While SSRIs increase synaptic serotonin, ketamine enhances synaptic plasticity—offering a “bottom-up” and “top-down” approach to restoring mood regulation.

5. Practical guidance for clinicians

• Continue the antidepressant if it has been tolerated and stable for several weeks.
• Monitor closely for BP spikes, dissociative symptoms, or mood switching.
• Avoid abrupt withdrawal of baseline antidepressants; tapering destabilises mood.
• Document informed consent explaining off-label use and possible additive effects.
• Space sessions to once or twice weekly during induction; antidepressant coverage supports baseline mood between sessions.

6. The clinical art of timing

In practice, ketamine and antidepressants are allies, not adversaries. The challenge is synchronising their rhythms: ketamine provides rapid relief, while antidepressants maintain it. Over time, some patients may sustain improvement and taper one or both under supervision.

The ideal strategy isn’t “ketamine or antidepressants” but “ketamine with careful continuation”—a bridge between biological innovation and long-term stability.

Author:
Dr. Srinivas Rajkumar T, MD (AIIMS Delhi), DNB, MBA (BITS Pilani)
Consultant Psychiatrist, Mind & Memory Clinic
Apollo Clinic Velachery (opposite Phoenix MarketCity), Chennai
📞 +91 85951 55808 | 🌐 srinivasaiims.com