Ketamine for Treatment-Resistant Depression: What You Need to Know
Depression affects millions of people worldwide, and while traditional treatments help many, approximately one-third don’t respond adequately to standard antidepressants and therapy (Rush et al., 2006). For these individuals, ketamine represents an additional option in the treatment toolkit. This guide explains both ketamine treatment alone and the enhanced approach of ketamine-assisted psychotherapy (KAP), including realistic expectations about benefits and limitations.
What Makes Ketamine Different?
Traditional antidepressants like SSRIs typically take weeks to show effects, working primarily through serotonin systems. Ketamine operates differently—as an NMDA receptor antagonist influencing glutamate, the brain’s main excitatory neurotransmitter (Zanos et al., 2018).
Ketamine’s distinguishing feature is its speed. While conventional antidepressants can take 4-6 weeks to work, ketamine often produces improvements within hours to days when it works. Research shows response rates around 50-70% in patients with treatment-resistant depression (Coyle & Laws, 2015)—meaningful but not universal. This also means 30-50% of patients don’t experience significant benefit.
Ketamine Treatment Without Psychotherapy
What Is Treatment-Resistant Depression?
Treatment-resistant depression typically means depression that hasn’t responded adequately to at least two different antidepressant medications tried at appropriate doses and durations. This affects approximately one-third of people with major depression (Rush et al., 2006). If you’ve tried multiple treatments without sufficient relief, ketamine may offer an alternative worth exploring, though it’s not guaranteed to work where other treatments haven’t.
Types of Ketamine Treatment
Ketamine IV Infusion Therapy
Ketamine infusion involves receiving ketamine intravenously in a medical clinic or hospital setting. The landmark 2000 study by Berman and colleagues first demonstrated that a single infusion could produce rapid antidepressant effects in some patients, and subsequent studies have confirmed these findings while also revealing variability in response.
What to Expect: You’ll receive ketamine through an IV, typically at a dose of 0.5 mg/kg administered over 40 minutes. During the infusion, you’ll be in a comfortable chair or bed in a quiet room. Medical staff will monitor your blood pressure, heart rate, and oxygen levels throughout.
The Experience: During treatment, you may experience dissociation (feeling detached from your body or surroundings), perceptual changes, or a “floaty” sensation. Some people find this pleasant or neutral, others find it uncomfortable or anxiety-provoking. These effects typically resolve within 1-2 hours after the infusion ends. Some patients report feeling relief from depressive symptoms within hours to days, while others notice more gradual improvement or no significant change.
Treatment Course: Standard protocols typically involve 6-8 infusions over 2-4 weeks (usually twice weekly). After this initial series, many patients need maintenance infusions to sustain benefits—some weekly, others monthly or less frequently. The need for ongoing treatment is an important consideration.
Esketamine Nasal Spray (Spravato)
From May 2025, the PBS has specifically approved esketamine nasal spray for treatment-resistant depression intended to be used alongside a newly initiated oral antidepressant. Esketamine is one component of the ketamine molecule, offering similar benefits potentially at lower doses (Daly et al., 2019).
What to Expect: The nasal spray is administered under supervision at a certified clinic. After administration, you’ll rest in the clinic for at least two hours while staff monitor you for side effects—a time commitment that can be challenging for work or personal schedules.
Treatment Course: The initial phase typically involves twice-weekly treatments for four weeks, then weekly treatments for weeks 5-8, followed by maintenance dosing every one to two weeks depending on your response. This ongoing commitment is substantial.
Costs: If eligible, the cost of the medication is subsidised by the PBS. However, there are costs associated with the clinic time that the clinic can provide information about.
How Effective Is Ketamine Alone?
Multiple studies confirm ketamine can be effective for treatment-resistant depression, though results vary considerably between individuals. Research shows that approximately 50-70% of patients experience some response, but “response” is defined as at least a 50% reduction in symptom scores—not necessarily remission or complete relief (Coyle & Laws, 2015).
Importantly, ketamine shows rapid effects on suicidal thinking in some patients. A comprehensive analysis by Wilkinson et al. (2018) found that a single ketamine dose produced rapid reductions in suicidal thoughts within 24 hours in many (though not all) patients, independent of its antidepressant effects. For those who respond, this rapid action can be critically important, though it shouldn’t be viewed as a universal suicide prevention tool.
Duration of Benefits: A Key Limitation
A significant limitation of ketamine treatment is that effects are often temporary. Some patients maintain improvements for several days, others for weeks, but many experience a gradual return of symptoms. This is why ongoing treatment is typically needed. The need for repeated treatments raises practical questions about long-term sustainability, cost, time commitment, and whether benefits justify ongoing treatment. Some patients find they need less frequent maintenance sessions over time, while others require consistent regular treatments indefinitely.
Safety and Side Effects
During Treatment: Common side effects include dissociation (which some find distressing), dizziness, nausea, elevated blood pressure, perceptual disturbances, and sometimes anxiety. For most people these effects resolve within 1-2 hours, but they can be uncomfortable and occasionally frightening.
Long-term Safety: When used in medical settings with proper protocols, ketamine appears relatively safe in the short to medium term. However, long-term safety data is limited. Concerns exist about potential abuse, cognitive effects with chronic use, and bladder problems seen with heavy recreational use. While these risks appear lower with medical dosing under supervision, we don’t have extensive data on outcomes from years of regular ketamine treatment (Schatzberg, 2014).
Who Shouldn’t Use Ketamine: Ketamine isn’t appropriate for everyone. It’s typically contraindicated if you have uncontrolled high blood pressure, history of psychosis, bipolar affective disorder, active substance abuse (particularly with dissociative drugs), or certain heart conditions.
Setting Realistic Expectations
It’s important to approach ketamine with realistic expectations. While some patients experience dramatic, rapid relief, others notice modest improvements or no benefit. Even when helpful, ketamine rarely eliminates all depressive symptoms—it’s typically one component of comprehensive treatment alongside therapy, lifestyle changes, and possibly other medications.
The temporary nature of effects means ketamine is often a management tool rather than a cure. You may need ongoing treatments indefinitely, which requires considering financial sustainability, time commitment, and whether the benefits outweigh the burdens of repeated treatments.
Adding Psychotherapy: Ketamine-Assisted Psychotherapy (KAP)
While ketamine alone shows benefits for some patients, combining it with psychotherapy—called ketamine-assisted psychotherapy or KAP—may enhance and extend benefits, though research is still emerging. The rationale is that ketamine creates a “therapeutic window” when your brain may be especially receptive to psychological work.
The Therapeutic Window
Research suggests ketamine promotes neuroplasticity—your brain’s ability to form new connections—by increasing brain-derived neurotrophic factor (BDNF) and promoting synaptogenesis (Duman et al., 2016). Whether this translates to enhanced psychotherapy outcomes remains an open question, but the theory is that this neuroplastic state may allow you to view problems from new perspectives, access difficult emotions more safely, and interrupt entrenched patterns. KAP aims to leverage this window through therapeutic techniques while your brain may be most receptive to change. However, it’s worth noting that evidence specifically comparing ketamine with therapy to ketamine alone is limited.
What Happens During KAP?
Preparation Sessions: Before receiving ketamine, you’ll meet with a therapist to build trust, discuss your goals, set intentions for the experience, and prepare mentally for what to expect. This groundwork can help make the experience feel safer and more contained.
The Ketamine Experience: You’ll receive ketamine (in our service, via nasal spray) in a calm, comfortable setting. Sessions typically last 45-90 minutes. During this time, you may experience altered perceptions, emotional releases, or new insights—though experiences vary widely and aren’t always pleasant or meaningful.
Integration Sessions: After ketamine effects subside, your therapist helps you process whatever emerged, connecting it to your ongoing life and therapeutic work. This integration is considered crucial for translating any insights or shifts into lasting change, though whether this actually extends ketamine’s benefits compared to ketamine alone requires more research.
The Evidence for KAP
Research specifically on KAP is still developing. Early observational studies like Dore et al. (2019) found improvements in depression and anxiety in patients receiving KAP, but these studies lacked control groups making it impossible to know whether outcomes were better than ketamine alone. More rigorous randomised controlled trials comparing ketamine with therapy to ketamine without structured therapy are needed. While the rationale for combining them is compelling, we should be cautious about assuming psychotherapy definitively enhances ketamine’s benefits without stronger evidence.
Therapeutic Approaches in KAP
KAP therapists may draw on various approaches including cognitive work with thoughts and beliefs, somatic processing of bodily sensations and trauma, transpersonal exploration of spiritual or existential insights, or relational work addressing interpersonal patterns. The specific approach depends on your needs, your therapist’s training, and what emerges during sessions.
Conclusion
Ketamine represents a valuable addition to treatment options for depression, particularly for those who haven’t responded to conventional approaches. Its rapid action and different mechanism offer genuine advantages for some patients. However, it’s not a wonder drug—response rates, while encouraging, mean many patients don’t benefit significantly, and effects are often temporary. Whether pursuing ketamine alone or combined with psychotherapy, approach the treatment with informed, realistic expectations. Work with qualified providers, maintain concurrent supports, and recognize that even promising treatments have limitations. For some people, ketamine offers meaningful relief and new possibilities; for others, it’s another treatment that doesn’t quite work. Both experiences are part of the complex reality of treating depression.
References:
Berman, R. M., Cappiello, A., Anand, A., et al. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47(4), 351-354.
Coyle, C. M., & Laws, K. R. (2015). The use of ketamine as an antidepressant: A systematic review and meta-analysis. Human Psychopharmacology: Clinical and Experimental, 30(3), 152-163.
Daly, E. J., Trivedi, M. H., Janik, A., et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression. JAMA Psychiatry, 76(9), 893-903.
Dore, J., Turnipseed, B., Dwyer, S., et al. (2019). Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of Psychoactive Drugs, 51(2), 189-198.
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016). Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nature Medicine, 22(3), 238-249.
Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., et al. (2014). Do the dissociative side effects of ketamine mediate its antidepressant effects? Journal of Affective Disorders, 159, 56-61.
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163(11), 1905-1917.
Schatzberg, A. F. (2014). A word to the wise about ketamine. American Journal of Psychiatry, 171(3), 262-264.
Wilkinson, S. T., Ballard, E. D., Bloch, M. H., et al. (2018). The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. American Journal of Psychiatry, 175(2), 150-158.Zanos, P., Moaddel, R., Morris, P. J., et al. (2018). Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacological Reviews, 70(3), 621-660.