Comparing Ketamine vs. Traditional Depression Treatments

For decades, depression has been treated with a combination of medications and psychotherapy, with varying degrees of success. While conventional antidepressants and talk therapy remain first-line treatments, they don’t work for everyone. Some individuals experience partial relief, intolerable side effects, or no meaningful improvement at all—especially those diagnosed with Treatment-Resistant Depression (TRD).

Ketamine represents a new frontier in depression treatment, working through a completely different mechanism than traditional antidepressants. But how does it compare to the most commonly used treatments for depression? In this article, we’ll take a deep dive into how ketamine stacks up against:

• Selective Serotonin Reuptake Inhibitors (SSRIs) – e.g., Prozac, Zoloft, Lexapro
• Tricyclic Antidepressants (TCAs) – e.g., Amitriptyline, Nortriptyline
• Cognitive Behavioral Therapy (CBT) – One of the most widely used psychotherapies for depression

We’ll explore how each treatment works, what patients typically experience, and why combining approaches is often the most effective strategy for long-term recovery.

SSRIs increase levels of serotonin, a neurotransmitter that plays a key role in mood regulation. They do this by blocking its reabsorption (or "reuptake") in the brain, making more serotonin available for communication between neurons.

SSRIs typically take 4–6 weeks to show noticeable effects. Some patients may feel mild improvements earlier, but full benefits often take months to materialize.

• Effects are gradual and subtle rather than immediate
• Some people experience early side effects (nausea, headaches, emotional blunting) before the benefits kick in
• Not everyone responds—about 30% of patients see little to no relief, leading to trials of different medications or higher doses

• Works within hours to days rather than weeks
• Targets glutamate, which is involved in neuroplasticity (the brain’s ability to form new connections)
• Can provide a dissociative experience, which some patients describe as mentally refreshing or perspective-shifting

For people who haven’t found relief with SSRIs, ketamine offers a new approach that works on different pathways in the brain.

TCAs increase both serotonin and norepinephrine, but unlike SSRIs, they also affect other neurotransmitters, leading to a broader range of effects and side effects.

• TCAs were widely used in the 1970s and 80s but have fallen out of favor due to their higher risk of side effects and overdose potential
• They are still prescribed in some cases—especially when SSRIs or SNRIs fail—but are not usually the first choice

• Can be highly sedating, often causing drowsiness and weight gain
• More likely to cause dry mouth, constipation, dizziness, and blurred vision
• Requires careful monitoring—they can be dangerous in overdose situations

• Works much faster than TCAs, with effects seen in hours or days
• Not taken daily—administered via IV or nasal spray in structured sessions
• No risk of overdose in clinical settings since it's administered under supervision

For patients who haven’t responded to SSRIs or newer antidepressants, TCAs may still be an option—but ketamine is an alternative with a more favorable side effect profile in many cases.

Unlike medications, CBT does not involve changing brain chemistry directly. Instead, it is a structured, evidence-based form of psychotherapy that helps people identify and reframe negative thought patterns that contribute to depression.

• Encourages active engagement in changing thought and behavior patterns
• Involves learning coping skills to manage depressive symptoms
• Typically structured as weekly sessions for a set period, though some people continue therapy long-term

• CBT does not provide immediate relief—progress happens over weeks or months
• Consistent participation is key; skipping sessions or disengaging can limit effectiveness
• Studies show CBT is most effective when paired with medication

1. Requires active effort—patients must practice techniques outside of sessions
2. Some resistance is normal—it can be difficult to challenge ingrained negative beliefs
3. Progress may feel slow, but long-term results can be highly sustainable

• Can provide rapid relief, which may help patients engage more fully in therapy
• Unlike therapy alone, directly alters brain function by promoting neuroplasticity
• Some patients describe ketamine as loosening rigid thought patterns, making CBT easier and more effective

Because ketamine can enhance neuroplasticity, some mental health professionals believe it works best in combination with psychotherapy—helping patients integrate new perspectives into lasting behavioral change.

• SSRIs are a standard first-line treatment, but don’t work for everyone and require patience
• TCAs are sometimes prescribed when other antidepressants fail but have more side effects
• CBT is highly effective, but works best when combined with another treatment
• Ketamine is a promising option for those who haven’t responded to traditional approaches and need faster relief

For many patients, the best strategy is combining ketamine with psychotherapy like CBT. This allows for both immediate symptom relief and long-term behavioral change, leading to the most sustained improvement over time.

If you’re struggling with Treatment-Resistant Depression, ketamine therapy may offer an alternative worth considering. Schedule a consultation with Therapeutic Infusions to explore your options and find out whether this treatment is right for you.