The effect of esketamine in patients with treatment-resistant depression with and without comorbid anxiety symptoms or disorder

This post-approval, double-blind, placebo-controlled study (n=223, TRANSFORM-2) finds that those with comorbid anxiety (72%) responded just as well as those without anxiety to esketamine (56-84mg, 4 weeks, combined with SSRI) treatment.


Background: Comorbid anxiety is generally associated with poorer response to antidepressant treatment. This post hoc analysis explored the efficacy of esketamine plus an antidepressant in patients with treatment-resistant depression (TRD) with or without comorbid anxiety.

Methods: TRANSFORM-2, a double-blind, flexible-dose, 4-week study (NCT02418585), randomized adults with TRD to placebo or esketamine nasal spray, each with a newly-initiated oral antidepressant. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (7-item Generalized Anxiety Disorder scale [GAD-7] score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening. Treatment effect based on change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and response and remission were examined by presence/absence of comorbid anxiety using analysis of covariance and logistic regression models.

Results: Approximately 72% (162/223) of patients had baseline comorbid anxiety. Esketamine-treated patients with and without anxiety demonstrated significant reductions in MADRS (mean [SD] change from baseline at day 28: -21.0 [12.51] and -22.7 [11.98], respectively). Higher rates of response and remission, and a significantly greater decrease in MADRS score at day 28 were observed compared to antidepressant/placebo, regardless of comorbid anxiety (with anxiety: difference in LS means [95% CI] -4.2 [-8.1, -0.3]; without anxiety: -7.5 [-13.7, -1.3]). There was no significant interaction of treatment and comorbid anxiety (p = .371). Notably, in the antidepressant/placebo group improvement was similar in those with and without comorbid anxiety.

Conclusion: Post hoc data support efficacy of esketamine plus an oral antidepressant in patients with TRD, regardless of comorbid anxiety.”

Authors: Ella J. Daly, Ibrahim Turkoz, Giacomo Salvadore, Maggie Fedgchin, Dawn F. Ionescu, H. Lynn Starr, Stephane Borentain, Madhukar H. Trivedi, Michael E. Thase & Jaskaran B. Singh


Comorbid anxiety and treatmentresistant depression are associated with poorer response to antidepressant treatment.


Major depressive disorder (MDD) commonly presents with co-morbid anxiety, and patients with MDD and comorbid anxiety have poorer response and remission rates to antidepressant medications than those without comorbid anxiety.

The diagnosis of anxious depression has been defined in many different ways in the literature, with no consensus as to the most appropriate approach.

Data with intravenous ketamine in patients with depression and comorbid anxiety are limited. A recent doubleblind, placebo controlled pilot study found intravenous ketamine to be equally efficacious in patients with or without baseline comorbid anxiety symptoms at days 1 and 3 after a single infusion.

To evaluate the effect of comorbid anxiety symptoms or disorder on the antidepressant effects of esketamine in TRD, post hoc analyses were conducted.

2.1 | Study design

This study investigated the effects of esketamine nasal spray on treatment-resistant depression in outpatients.

2.2 | Patients

TRANSFORM2 enrolled outpatients aged 18 – 64 years with recurrent MDD, without psychotic features, and a total score 34 on the clinicianrated Inventory of Depressive Symptomatology. Participants were adherent to an ongoing oral antidepressant for at least the most recent 2 weeks.

Patients with nonresponse to their ongoing oral antidepressant were randomized to receive twiceweekly, flexibledose esketamine nasal spray or placebo nasal spray in combination with a newlyinitiated openlabel oral antidepressant taken daily.

2.3 | Assessments

A standardized diagnostic interview was conducted at screening and on days 2, 8, 15, 22, and 28 of the doubleblind treatment phase to assess for presence of MDD and other comorbid disorders, including co-morbid anxiety disorder.

2.4 | Statistical analyses

Patients with comorbid anxiety disorders were included in the analysis if they received at least 1 dose of intranasal study drug and 1 dose of oral antidepressant. Adverse events and CADSS total scores were analyzed in a data set that included all patients who received at least one dose of either medication.

Betweengroup differences for baseline demographics and disease characteristics were analyzed by paired t test and analysis of covariance (ANCOVA) with fixed effects for treatment group, comorbid anxiety condition, and baseline value as a covariate.

Response and remission rates were compared between treatment groups using the Cochran – Mantel – Haenzsel (CMH) test, and multiple logistic regression models were used to examine whether observed treatment differences at day 28 were dependent on the presence or absence of comorbid anxiety.


227 patients were randomized to doubleblind treatment; 223 patients received esketamine plus antidepressant and 109 received antidepressant plus placebo. Most patients completed 28 days of treatment.

At baseline, 72.6% of patients had comorbid anxiety symptoms, and 13.5% had a current anxiety disorder. Patients with comorbid anxiety had more chronic depressive symptoms than patients without comorbid anxiety.

Esketamine/antidepressant group received similar median daily doses of duloxetine, escitalopram, sertraline, and venlafaxine XR as antidepressant/placebo group.

Patients with comorbid anxiety and those without comorbid anxiety demonstrated significant reductions in MADRS at day 28. Patients with comorbid anxiety demonstrated a greater improvement in MADRS scores than those without comorbid anxiety.

Patients with comorbid anxiety had a greater likelihood of meeting response criteria with esketamine/antidepressant versus antidepressant/placebo, and a greater likelihood of achieving remission with esketamine/antidepressant compared with antidepressant/placebo.

Esketaminetreated patients experienced anxiety, blurred vision, dissociation, dizziness, dysgeusia (metallic taste), headache, nausea, paresthesia, somnolence, and vertigo, with a higher incidence in the esketamine/antidepressant group than the antidepressant/placebo group. Two patients experienced a serious adverse event.

Esketamine/antidepressant group patients had higher incidence of dissociative symptoms than antidepressant/placebo group patients, but comorbid anxiety was unrelated to incidence of dissociation.


These posthoc data support the efficacy of esketamine plus an oral antidepressant in patients with TRD regardless of comorbid anxiety. Esketamine treatment demonstrated a clinically meaningful improvement compared to antidepressant/placebo in patients with TRD and comorbid anxiety symptoms or disorder(s).

After 4 weeks of treatment, esketamine/antidepressant showed a significantly greater decrease in MADRS total score and higher response and remission rates than antidepressant/placebo in patients with TRD and comorbid anxiety symptoms. However, there are several limitations to comparing findings between studies.

Patients with MDD and comorbid anxiety had a reduced rate of response or remission following treatment with monoaminergic antidepressants and a greater risk for side effects compared to patients without comorbid anxiety.

Esketamine treatment was well tolerated, with few serious adverse events. Patients with comorbid anxiety experienced higher rates of anxiety, dissociation, nausea, and paresthesia, but not higher rates of dissociation based on the CADSS.

4.1 | Study limitations

The TRANSFORM2 study was not designed to evaluate efficacy or safety in patients with comorbid anxiety. The data may not necessarily reflect the true prevalence of comorbid anxiety in the overall TRD population.

The definition of anxiety does impact findings. For example, patients who met criteria for anxiety disorder based on the MINI may have met criteria for state anxiety, even after treatment effects, allowing them to still meet criteria for being included in the analysis.

The design of the TRANSFORM2 study may have an impact on the interpretability of the findings. Patients with anxiety were not more likely to respond to monoaminergic oral antidepressants than those without anxiety.

The generalizability of these findings is limited because patients with moderatetosevere substance and alcohol use disorder and those taking highdose benzodiazepines were excluded.


In this post hoc analysis, esketamine nasal spray was more effective than placebo nasal spray in treating TRD in adults, regardless of the presence of comorbid anxiety.


Janssen Research and Development, LLC, Titusville, NJ, funded the study and provided medical writing assistance. Ellen Baum, PhD, provided additional editorial support and was not compensated.

Study details

Compounds studied

Topics studied
Anxiety Depression

Study characteristics
Placebo-Controlled Double-Blind Randomized



Institutes associated with this publication

Johnson & Johnson
One of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant
This posthoc analysis of the TRANSFORM-2 trial assessed the effects of esketamine plus an oral antidepressant (AD) using the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS). The odds of improving in those treated with esketamine plus AD were at least two times greater than with placebo plus AD.

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