Anxiety During Ketamine Infusions: Balancing Benefits and Challenges in Depression and Anxiety Treatment

Introduction

Ketamine, once primarily known as an anesthetic, has emerged as a groundbreaking treatment for major depressive disorder (MDD) and anxiety disorders due to its rapid antidepressant and anxiolytic effects. Unlike traditional antidepressants, which may take weeks to alleviate symptoms, ketamine can produce improvements within hours (Berman et al., 2000). Certainly, in our own clinic we have seen amazing and transformative responses to ketamine therapy, some that could reasonably and literally be described as 'life saving'. However, just like any man-made drug, not all patients respond positively to ketamine, and some experience negative effects, such as anxiety during infusions, which has been suggested to predict poorer treatment outcomes (Aust et al., 2019). This article explores the benefits of ketamine therapy, its responder rates for MDD and anxiety, and the evolving understanding of anxiety during infusions as a potential indicator of treatment response, drawing on current, peer-reviewed evidence.

Ketamine therapy, known for its rapid efficacy for major depressive disorder and anxiety, is entering a maturing field that appreciates that, like any drug, it may not be for everyone. Infusion-related anxiety, though rare, has been suggested to be associated with poorer treatment outcomes, emphasizing the need for further research to optimize outcomes.

Background on Depression with Concurrent Anxiety

Depression with concurrent anxiety is a common and challenging clinical presentation. Approximately 50–60% of individuals with MDD also experience significant anxiety symptoms, which can exacerbate functional impairment, increase suicide risk, and reduce response to standard treatments (Fava et al., 2008). This comorbidity is associated with greater symptom severity, longer illness duration, and higher rates of treatment resistance, defined as failure to respond to at least two adequate antidepressant trials (Rush et al., 2006). The overlapping neurobiological mechanisms, including dysregulation of the hypothalamic-pituitary-adrenal axis and glutamatergic systems, underscore the real need for novel treatments like ketamine that target these pathways (Ionescu et al., 2015).

Ketamine Therapy: Benefits and Responder Rates

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has shown remarkable efficacy in treating MDD, particularly treatment-resistant depression (TRD), and anxiety disorders. Administered intravenously (IV) at subanesthetic doses, ketamine has been demonstarted in numerous clinical studies, to produce rapid symptom relief, often within 24 hours (Zarate et al., 2006). Accordingly, its intranasal form, esketamine, was approved by the FDA in 2019 for TRD, further expanding its clinical use (FDA, 2019).

Responder Rates for Major Depression

Recent studies report robust responder rates for ketamine in MDD. A 2023 meta-analysis found that IV ketamine achieved a 50% response rate (≥50% reduction in depression scores) and a 20–30% remission rate (depression scores dropping to minimal levels) within 6 weeks of treatment (Nikayin et al., 2023). In a large community-based study of 424 patients with TRD, 50% showed a response and 20% achieved remission based on the Patient Health Questionnaire-9 (PHQ-9) after six IV infusions (Chisamore et al., 2023). For severe depression, a 2024 open-label study reported a 52% remission rate after three infusions over 11 days, with 67% of participants showing some response (Parikh et al., 2024).

Responder Rates for Anxiety

Ketamine’s efficacy in anxiety disorders, including generalized anxiety disorder (GAD) and social anxiety disorder (SAD), is also promising but less extensively studied. A 2023 systematic review reported that 50–80% of patients with treatment-refractory GAD or SAD experienced at least a 50% reduction in anxiety scores after IV ketamine (Walsh et al., 2023). A double-blind study found that 8 out of 12 patients with GAD/SAD achieved significant anxiety reduction (Shadli et al., 2023). However, the durability of these effects varies, with some studies noting symptom relapse within weeks without maintenance dosing (Glue et al., 2023).

Benefits

Ketamine’s rapid action is a key advantage, particularly for patients with suicidal ideation, where it can reduce thoughts of suicide within hours (Abbar et al., 2022). Its efficacy in TRD and anxiety offers hope for those unresponsive to conventional therapies. Additionally, ketamine’s glutamatergic modulation may enhance neuroplasticity, potentially sustaining effects when combined with psychotherapy (Wilkinson et al., 2018).

Anxiety During Ketamine Infusions

While ketamine is generally well-tolerated, even pleasant and enjoyable in some patients, some patients experience adverse psychological effects during infusions, including anxiety, (uncomfortable) dissociation, and confusion. These effects are typically transient, resolving within hours, but emerging evidence suggests they may influence treatment outcomes.

Findings from Aust et al. (2019)

A pivotal study by Aust et al. (2019) investigated the association between acute psychological effects during ketamine infusions and antidepressant response in 31 patients with TRD. Patients received six IV ketamine infusions over two weeks. Depression severity was assessed, and acute psychological effects were measured four hours after the first infusion. The study found that 55% of patients (17/31) responded (≥50% MADRS reduction), while 45% (14/31) did not. Notably, non-responders reported significantly higher anxiety-related experiences during infusions. Higher anxiety scores and early MADRS reduction at four hours predicted non-response by the end of treatment, suggesting that anxiety during infusions may be a phenotypic predictor of poor outcome (Aust et al., 2019).

Supporting Evidence

Subsequent studies have reinforced these findings. A 2023 retrospective analysis of 537 patients receiving IV ketamine found that 20% reported anxiety as a side effect, which was associated with a lower likelihood of response (McIntyre et al., 2023). A 2024 study noted that patients with pre-existing anxiety disorders were more likely to experience infusion-related anxiety, potentially exacerbating non-response (Parikh et al., 2024). However, the exact mechanisms remain unclear, with hypotheses including heightened glutamatergic activity or individual differences in emotional processing (Krystal et al., 2024).

Rarity of Negative Experiences

Negative experiences like anxiety are relatively rare, occurring in approximately 20–30% of patients, with severe anxiety reported in less than 10% (Phillips et al., 2019). Most side effects, including anxiety, are mild to moderate and resolve post-infusion. The low incidence underscores ketamine’s overall safety profile when administered under medical supervision (Ingrosso et al., 2025).

Implications and Future Directions

The correlation between anxiety during ketamine infusions and poor treatment response has significant clinical implications. At our own clinic, Neuregen in Scottsdale, Arizona, we are working to hone treatment protocols to account for acute psychological effects like anxiety, in some cases adjusting protocols for patients prone to anxiety, and including integrating psychotherapy and optimizing dosing schedules (Beaglehole et al., 2024). Until future research identifies more reliable biomarkers or psychological profiles that predict infusion-related anxiety and non-response, clinicians like us will have to rely on clinical experience and best judgment to attempt to more reliably produce positive outcomes.

So where does that leave us?

Ketamine therapy offers transformative potential for individuals with MDD and anxiety, with high responder rates and rapid symptom relief. However, the occurrence of anxiety during infusions, though relatively rare, may signal a reduced likelihood of treatment success, as evidenced by Aust et al. (2019) and supported by recent studies. By understanding and addressing these negative experiences, clinicians can optimize ketamine’s benefits, ensuring better outcomes for those battling these debilitating conditions. Continued research will be crucial to refining this promising treatment.

About the Author: David George is founder and lead clinician at Neuregen Integrative Psychiatry and Neurologic Health clinic, a ketamine clinic in Scottsdale, AZ. Dr. George and his team at Neuregen are exploring new ways to integrate ketamine therapy with other treatment approaches to drive a new approach to mental health, based on an emphasis in personal transformation and brain-based care. References

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