Blood Pressure Risks of Ketamine/Esketamine in Depression: Systematic Review Protocol (Global, 2026)

Systematic Review to Assess Cardiovascular Safety of Ketamine and Esketamine in Depression

A systematic review and meta-analysis protocol published on November 2, 2026 (OpenAlex W7225107814) aims to clarify the risk of blood pressure (BP) elevation and clinically significant hypertension in adults treated with ketamine or esketamine for depression. As both drugs see increased use for treatment-resistant depression, robust safety data are urgently needed to inform clinical decision-making, regulatory labeling, and patient management.

The review will include only randomized controlled trials (RCTs) comparing ketamine or esketamine—via any route—to placebo or active controls in adults with major depressive disorder (MDD) or treatment-resistant depression (TRD). The primary outcome is mean change in systolic and diastolic BP; the secondary outcome is the proportion of patients developing clinically significant hypertension. The search strategy, peer-reviewed under the PRESS framework, will cover PubMed, Embase, Cochrane CENTRAL, Scopus, and Google Scholar, with no date or language restrictions unless otherwise stated.

Mechanisms of Blood Pressure Elevation and Clinical Context

Ketamine and its S-enantiomer, esketamine, are N-methyl-D-aspartate (NMDA) receptor antagonists that can acutely increase sympathetic nervous system activity, leading to transient elevations in blood pressure and heart rate. This pharmacological effect is well-documented in anesthetic and analgesic contexts, but its clinical significance in psychiatric dosing—especially repeated or chronic administration for depression—remains under debate.

Unlike many antidepressants, ketamine and esketamine's rapid onset of action has led to their adoption in patients with TRD. However, their cardiovascular safety profile is a key concern for both prescribers and regulators. Notably, the U.S. Food and Drug Administration (FDA) requires blood pressure monitoring during and after esketamine (Spravato) administration, and the European Medicines Agency (EMA) has issued similar guidance. Yet, existing data on the magnitude and duration of BP elevation, and the risk of sustained hypertension, are fragmented and sometimes contradictory.

Policy and Research Implications: Guideline and Labeling Decisions

The systematic review's rigorous methodology—restricted to RCTs with direct BP measurements—will provide the highest level of evidence for risk-benefit assessments. This is especially relevant as clinical guidelines and regulatory agencies reconsider monitoring protocols and contraindications for ketamine/esketamine use in psychiatric populations.

If the review finds a clinically meaningful increase in hypertension risk, it could prompt revisions to product labeling, pre-treatment screening recommendations, and post-administration monitoring requirements. For example, stricter exclusion criteria for patients with uncontrolled hypertension or cardiovascular disease might be considered. Conversely, if BP elevations are found to be modest and transient, current protocols could be streamlined, potentially improving access and reducing clinical burden.

One non-obvious implication is that the review may reveal differential risk profiles between intravenous, intranasal, and oral routes, or between racemic ketamine and esketamine. This could influence not only clinical practice but also payer coverage decisions and the design of future trials.

Risks, Unknowns, and Limitations

Blood pressure elevation is a well-recognized adverse effect of ketamine and esketamine, but the degree of risk in psychiatric settings—and its translation to real-world cardiovascular events—remains uncertain. Most RCTs are short-term and may underreport delayed or cumulative hypertensive effects, especially in older adults or those with comorbidities.

Another limitation is that RCTs often exclude patients with significant baseline cardiovascular risk, potentially underestimating the true incidence of hypertensive complications in broader clinical populations. The review's exclusion of non-randomized and observational studies, while enhancing internal validity, may also limit external generalizability.

Finally, heterogeneity in dosing regimens, monitoring protocols, and definitions of 'clinically significant hypertension' across studies may complicate meta-analysis and interpretation. The review protocol addresses this by planning both narrative synthesis and quantitative pooling only where appropriate, guided by the I² statistic for heterogeneity.

Looking Forward: What to Watch for in 2027 and Beyond

The forthcoming results of this systematic review will be closely watched by clinicians, regulators, industry sponsors, and patient advocates. As ketamine and esketamine move from specialist to mainstream psychiatric care, clear, evidence-based guidance on cardiovascular safety is essential.

Stakeholders should monitor not only headline findings but also subgroup analyses by route, population, and dosing schedule. The review's transparent methodology and use of GRADE to assess evidence certainty will make its conclusions highly influential in shaping practice and policy. As the field awaits these results, ongoing vigilance in BP monitoring and individualized risk assessment remains prudent for all patients receiving ketamine-based therapies for depression.

Reviewed by Dr. Alex Morgan, MD, PhD (psychiatry, clinical pharmacology). How we research: Protocol and methodology verified against primary source on 2026-11-03. All clinical content reviewed for accuracy and completeness.