What Works Better for Depression–Ketamine or SSRIs?

A Side-by-Side Comparison

This chart makes it crystal clear: ketamine therapy is significantly better at treating depression than SSRIs.

But even these numbers dramatically understate ketamine’s effectiveness. Here’s why: research on ketamine is almost exclusively focused on treatment-resistant depression—the toughest, most entrenched cases, where patients have failed multiple therapies and face the highest hurdles to recovery. Meanwhile, SSRI studies include the full spectrum of depression—mild, moderate, and severe—where the symptoms are often less entrenched and far easier to treat.

Ketamine is very different than SSRIs. It’s like comparing runners on two very different tracks. Ketamine is forced to compete on the steepest uphill climb—treatment-resistant depression—and yet it still outperforms SSRIs in remission and response rates. SSRIs, by contrast, are most often tested on flat, straightforward tracks—milder forms of depression—and they still can’t match ketamine’s performance.

Now imagine unleashing ketamine on that same flat track. If ketamine outperforms SSRIs on the hardest terrain, how far behind would it leave them in a less challenging race?  In a head-to-head comparison across all types of depression, ketamine wouldn’t just win—it’d make SSRIs look like they never showed up.

Below the chart, you’ll find citations that substantiate the effectiveness rates presented, along with notes that delve into the complexities of making direct, apples-to-apples comparisons between two fundamentally different treatment approaches.

What about costs? See my Ketamine Therapy vs SSRIs cost comparisons here.

NOTES

Creating a chart comparing ketamine therapy to SSRIs for depression is deceptively complex. On the surface, metrics like remission rates, adherence, persistence, and response rates seem straightforward, but they’re anything but. The core issue lies in how these outcomes are measured, the populations being studied, and the vastly different ways these treatments are used.

For starters, ketamine is almost exclusively studied in treatment-resistant depression (TRD)—patients who’ve failed to respond to at least two other treatments. These are some of the hardest cases to treat, with entrenched symptoms and high rates of comorbid conditions like anxiety or PTSD. On the other hand, many SSRI studies include patients with a much broader range of depression severities, from mild to severe, and often focus on people experiencing their first depressive episode. Comparing these two groups is like comparing sprinters to marathon runners—they’re running very different races.

Adding to the challenge, the definitions of success—like remission or response rates—differ across studies. One study might define remission as “minimal depression symptoms on a specific scale,” while another uses a completely different scale or threshold. Similarly, adherence and persistence are tricky to pin down. Ketamine, administered in clinics, ensures short-term adherence but involves logistical hurdles that could impact long-term persistence. SSRIs, taken daily at home, rely entirely on patient consistency, often hindered by side effects like weight gain or sexual dysfunction.

Even with decades of SSRI data, studies show wildly different results depending on the population, methodology, and duration of follow-up. Ketamine, as a newer therapy, has fewer long-term studies, which further muddies comparisons. As someone steeped in ketamine research, I’ve seen how its rapid-acting nature often leads to dramatic early improvements, but this doesn’t always translate into the same long-term outcomes seen with SSRIs.

In short, putting this chart together is like assembling a puzzle where half the pieces are missing or don’t fit together. The data isn’t flawed—it’s just coming from different frameworks, making direct comparisons nearly impossible without a lot of context. This highlights not only the promise of ketamine but also the need for more nuanced discussions about how and why these treatments work in such different ways.

REMISSION RATES

Comparing remission rates between ketamine therapy and SSRIs is challenging due to:

• Timeframe Differences: Ketamine shows rapid effects (within hours to days), while SSRIs typically take weeks to months.

• Study Populations: Many ketamine studies focus on treatment-resistant depression, whereas SSRI studies often include broader populations–patients with a wide range of depression severities, from mild to severe.

• Dosing and Protocols: Ketamine’s effects depend on specific dosing regimens (e.g., IV, intranasal), making standardization difficult compared to oral SSRIs.

• Measurement Tools: Variations in how remission is defined and measured across studies can skew comparisons.

• Study Design: Ketamine studies often lack long-term data, while SSRIs have extensive longitudinal research.

ADHERENCE RATES

Comparing adherence rates between ketamine therapy and SSRIs is challenging due to:

• Dosing and Administration: Ketamine therapy always requires clinic-based administration, ensuring short-term adherence but adding logistical barriers. SSRIs are self-administered daily, making long-term adherence harder to monitor.

• Treatment Duration: SSRIs are prescribed for months or years, while ketamine is a short-term or intermittent treatment, complicating direct comparisons.

• Study Follow-Up: Most ketamine studies are short-term, making long-term adherence data scarce compared to extensive SSRI research.

RESPONSE RATES

The problem with comparing response rates is that studies don’t always define “response” the same way. For example:

• One study might say a patient has responded if their symptoms improve by 50%.
• Another study might use a stricter or looser definition, like a smaller improvement or even just feeling better overall.

These definitions usually rely on questionnaires, but different studies use different ones—or interpret them differently. So, a patient who feels “much better” after ketamine might not meet the same criteria as someone who responds to an SSRI, even if both are improving. The lack of a universal standard means we’re often comparing apples to oranges when looking at response rates. Two other factors make a comparison a little tricky:

• Patient Populations: Ketamine studies often focus on treatment-resistant cases, while SSRIs include a broader range of depression severities.

• Study Design: Ketamine trials are typically shorter, while SSRI studies often assess longer-term responses.

SIDE EFFECTS

I did not mention dissociation as a side effect of ketamine therapy as you may find in the literature because scientists consider it a direct pharmacological effect of the drug rather than a side effect or symptom. It’s an inherent part of ketamine’s mechanism of action in the brain.

KETAMINE CITATIONS

Remission Rates

Pubmed

NIH

University of Michigan

National Library of Medicine

Response Rates

Translational Psychiatry

NIH

National Library of Medicine

Persistence Rates

Ketamine Academy Training

SSRI CITATIONS

Remission Rates

British Medical Journal

Biomed Central

American Academy of Family Physicians

Response Rates

Agency for Healthcare Research

NIH

The Lancet

Adherence & Persistence Rates

BMC Psychiatry