Treatment-resistant depression (TRD) remains one of the most challenging mental health conditions in modern psychiatry. Affecting nearly 30% of individuals diagnosed with depression, TRD is characterized by a poor response to at least two different antidepressants. This condition not only prolongs suffering but is also linked to a higher suicide risk, increased illness severity, and considerable personal and societal costs. Despite its prevalence and impact, historically, few effective treatments have been available for adults with TRD—until now.
Over the past two decades, ketamine and its derivative esketamine (offered in nasal form under the brand name Spravato) have emerged as treatment options for individuals afflicted with TRD and major depressive disorder (MDD). These treatments differ from conventional antidepressants in both speed and mechanism of action, providing rapid symptom relief, often within hours.
The FDA granted approval for intranasal esketamine in 2019 to treat treatment-resistant depression (TRD). In 2020, its use was extended to include depression characterized by acute suicidal ideation or behaviors. Most recently, in 2025, the indication expanded further to allow esketamine to be used as monotherapy for major depressive disorder. This change marks a significant shift, enabling patients to begin esketamine therapy without enduring the trial-and-error of oral antidepressants. Research has shown that both ketamine and esketamine act more quickly than traditional antidepressants and are effective long-term, even surpassing the efficacy of medications like quetiapine XR (brand name Seroquel).
Intravenous ketamine, widely regarded as the safest and most effective method of administration, has shown remarkable potential in rapidly reducing depressive symptoms and suicidal ideation, making it a critical tool in acute psychiatric care. But beyond symptom relief, what does this mean for real-world outcomes? Specifically, how does ketamine impact the quality of life for individuals living with depression?
While research has demonstrated the clinical efficacy of ketamine and esketamine—with response rates for depression reaching up to 80% in some cases with IV administration—their effect on quality of life (QoL), a key patient-reported outcome, remains less well understood.
People living with MDD or TRD often emphasize that improvements in day-to-day functionality, emotional well-being, and life satisfaction are as important as symptom reduction. Unfortunately, these aspects are frequently underrepresented in clinical studies.
To address this gap, a systematic review including five high-quality studies with a combined sample of 1,688 patients was conducted to examine how ketamine and esketamine affect quality of life outcomes in adults (18+) diagnosed with MDD or TRD.
In all five studies, the improvements in QoL were consistent and statistically significant—demonstrating not only symptom relief but also a tangible increase in daily functioning and perceived well-being.
Quality of life in depression isn't simply a “nice-to-have” metric—it's crucial for recovery. It reflects how effectively individuals can reintegrate into their personal, professional, and social roles. While all reviewed studies confirmed that ketamine and esketamine enhance QoL, they also indicate that much of this improvement likely stems from alleviating core depressive symptoms. However, researchers still don’t fully understand the mechanistic pathways linking symptom relief to improved daily functioning. Potential contributors could include:
Anhedonia is one of the most disabling symptoms of depression, referring to a reduced ability to experience pleasure from activities that were once enjoyable. It's also one of the most resistant symptoms to traditional antidepressant treatments. Ketamine and esketamine, however, have shown promising effects in reversing anhedonia rapidly.
These medications work through NMDA receptor antagonism, enhancing glutamatergic activity and stimulating neuroplasticity in brain regions associated with reward processing. As a result, patients often report a renewed interest in hobbies, relationships, and meaningful experiences, restoring a core component of emotional health that directly contributes to quality of life.
Cognitive dysfunction is common in both MDD and TRD, including problems with concentration, memory, and decision-making. These impairments don’t just impact academic or professional tasks; they also interfere with routine responsibilities and social engagement.
Ketamine and esketamine may help reverse these impairments by promoting synaptic connectivity and supporting neuroplastic changes in brain circuits involved in executive functioning. Improvements in cognitive flexibility and attentional control can lead to better task completion, increased independence, and a greater sense of personal competence—all of which contribute to quality of life improvements.
Depression is characterized not only by sadness but also by emotional volatility, numbness, and low motivation. These symptoms impair interpersonal relationships and reduce a person's ability to engage meaningfully with life.
Ketamine and esketamine have been shown to stabilize mood fluctuations and enhance emotional regulation. By restoring balance to disrupted neural circuits, patients may find it easier to process emotions in healthier, more adaptive ways. With greater emotional stability often comes enhanced motivation. Furthermore, patients treated with ketamine or esketamine frequently report a newfound ability to envision the future more optimistically and engage in life with a sense of purpose and direction.
The findings from this new systematic review offer a renewed sense of hope and direction for both patients and mental health providers. As clinicians, it can be incredibly frustrating when traditional treatments for depression, such as oral antidepressants or electroconvulsive therapy (ECT), fail to produce a sustained response. For patients, the experience of cycling through medication after medication, often with little or no relief, can be disheartening and demoralizing, especially when accompanied by intolerable side effects and potential long-term health implications.
Ketamine and esketamine represent a paradigm shift in our approach to treatment-resistant depression (TRD). Not only are they revolutionizing clinical outcomes by providing rapid and robust symptom relief, but they are also demonstrating meaningful improvements in quality of life—an area often overlooked in traditional psychiatric care.
These treatments should be viewed as significant additions to the psychiatric toolkit. While they are not a universal solution, they may provide a critical lifeline for carefully selected patients, delivering the lasting, transformative results that many have long awaited.
Innerbloom Ketamine Therapy, located in San Luis Obispo, is dedicated to highlighting emerging treatments and wellness innovations. Follow our blog for more in-depth insights into breakthroughs in mental health, lifestyle strategies, and therapeutic advancements.
About the Author
Dr. Ray Rivas, a former general and trauma surgeon with over a decade of experience utilizing ketamine, became a ketamine therapy specialist to treat mental health and pain after witnessing its profound impact on his hospital trauma patients and his own mental health. As the founder and medical director of Innerbloom Ketamine Therapy in San Luis Obispo, California, Dr. Rivas applies his extensive medical expertise to provide safe, evidence-based ketamine treatments for mood disorders, including depression, anxiety, PTSD, and chronic pain. His passion lies in helping patients find relief and rediscover hope through personalized, compassionate care.
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