This open-label study (n=70) compared the effect of esketamine (28-84mg; 8x) in those with bipolar treatment-resistant depression (B-TRD, n=35) and those with unipolar TRD. There was no significant difference between the two groups on depression scores, and both responded to treatment. Those in the B-TRD group had more anxiety-reducing effects. This study is part of the REAL-ESK study.
Background
Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first-line therapeutic options, resulting in treatment-resistant bipolar depression (B-TRD). Esketamine, the S-enantiomer of ketamine, has recently been approved for treatment-resistant depression (TRD), but no data are available on its use in B-TRD.
Objectives
To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B-TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B-TRD, focusing on the average risk of an affective switch.
Methods
Thirty-five B-TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery-Asberg Depression Rating Scale/MADRS, Hamilton-depression scale/HAM-D, Hamilton-anxiety scale/HAM-A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up.
Results
A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B-TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B-TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment-emergent affective switch.
Conclusions
Our results supported the effectiveness and tolerability of esketamine in a real-world population of subjects with B-TRD. The low risk of manic switch in B-TRD patients confirmed the safety of this treatment.
Papers cited by this study that are also in Blossom
Zheng, W., Zhou, Y-L., Liu, W. et al. · Journal of Psychiatric Research (2018)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Wei, C., Wang, J., An, D. et al. · Frontiers in Psychology (2021)
Papers in Blossom that reference this study
Bipolar depression accounts for the majority of symptomatic time in both type I and type II bipolar disorder and is associated with high morbidity, suicidality, and limited effective treatment options. Conventional antidepressants have delayed onset, frequent poor tolerability, and risk provoking affective switches or rapid cycling in bipolar disorder. Brain stimulation techniques (ECT, rTMS, tDCS) offer alternatives for some patients, but a substantial proportion of people with bipolar depression remain partially responsive or treatment-resistant (B-TRD). Interest has therefore grown in glutamatergic agents such as ketamine and its S-enantiomer, esketamine, which have rapid antidepressant effects in unipolar TRD and a more favourable outpatient safety profile than intravenous ketamine; however, randomised data on esketamine in bipolar depression are lacking and regulatory guidance is cautious because of concerns about affective switching. This study aimed to provide preliminary real-world evidence on the antidepressant effectiveness, safety, and tolerability of esketamine nasal spray (ESK-NS) in patients with treatment-resistant bipolar depression, comparing outcomes with an age-matched sample of unipolar TRD. Secondary objectives included assessment of anxiolytic effects and the average risk of treatment-emergent affective switch in bipolar patients treated with ESK-NS. The investigation used retrospective multicentre data collected as part of an early access programme in Italy to address the current evidence gap regarding ESK-NS use in B-TRD.
The analysis used data from the REAL-ESK study, an observational, retrospective, multicentre dataset of patients with treatment-resistant depression treated with esketamine nasal spray as part of an early access programme. Thirty-five subjects with treatment-resistant bipolar depression (B-TRD) were identified and matched one-to-one by age with 35 subjects with unipolar TRD drawn from the same dataset, producing a total analysed sample of 70 patients. All B-TRD participants had a documented history of at least one hypomanic or manic episode according to DSM-5 criteria. Patients with comorbid organic conditions that the EMA lists as absolute contraindications to ESK-NS (for example, untreated hypertension or prior cerebrovascular disorders) were excluded. Retrospective anamnestic data and clinical ratings were extracted from medical records at baseline (T0) and psychometric assessments were recorded at baseline, one month (T1) and three months (T2). Depressive symptoms were measured with the Montgomery–Åsberg Depression Rating Scale (MADRS) and the 21-item Hamilton Depression Rating Scale (HAM-D-21); anxiety was assessed with the 21-item Hamilton Anxiety Rating Scale (HAM-A). Response was defined as a ≥50% reduction in MADRS or HAM-D-21 from baseline; remission was defined as MADRS <10 or HAM-D-21 <7. Adverse events and clinically relevant outcomes (hospitalisation, relapse, premature withdrawal) were documented by treating psychiatrists. Statistical analyses used SPSS and JASP. Normality was tested with Kolmogorov–Smirnov and, since distributions were normal, parametric tests were applied. Group comparisons used Student's t-tests for continuous variables and Pearson χ2 for categorical variables. Repeated-measures ANOVA (rm-ANOVA) assessed the interaction between group (B-TRD vs TRD) and time (T0, T1, T2) for MADRS and HAM-A scores, with Mauchly's test of sphericity and Greenhouse–Geisser correction as needed. Scheffé post-hoc tests controlled for multiple comparisons. Effect sizes reported included partial eta2 for rm-ANOVA and Cohen's d or Hedges' g for pairwise comparisons. Attrition reduced the analysed samples to 33 B-TRD and 32 TRD at T1, and 31 B-TRD and 28 TRD at T2. The extracted text notes that all B-TRD subjects were treated with mood stabilisers at ESK-NS initiation, while a smaller proportion of TRD subjects were on mood stabilisers.
Baseline characteristics: Seventy patients were included (35 B-TRD, mean age 52.57 ± 12.77; 35 TRD, same mean age). The bipolar sample comprised 17 with BD type I and 18 with BD type II. Groups did not differ significantly in age, gender, employment, years of education, or overall illness duration. Lifetime suicide attempt rates and baseline suicidality (MADRS item 10: 2.75 ± 1.54 vs 1.73 ± 1.48) were higher in the B-TRD group (p = 0.007). Pharmacotherapy differed between groups: current SNRI use was higher in TRD (42.8% vs 20%, p = 0.032), while mood stabiliser treatment was universal in B-TRD versus 57.14% in TRD (p < 0.0001). Baseline total psychometric scores did not differ significantly between groups. Antidepressant effectiveness: Repeated-measures analyses found no significant interaction between group (TRD vs B-TRD) and time on MADRS scores (multivariate Wilks' Lambda = 0.938, F2,52 = 1.728, p = 0.188; univariate rm-ANOVA F1.723,91.334 = 2.445, ε = 0.862, p = 0.100). Mean MADRS reductions from T0 to T1 were reported as −13.03 in B-TRD and −12.21 in TRD, consistent with a rapid antidepressant effect. Response and remission rates increased from T1 to T2 in both groups: in B-TRD, responders were 9/35 (25.7%) at T1 and 24/35 (68.6%) at T2; remitters were 6/35 (17.1%) at T1 and 17/35 (48.6%) at T2. In TRD, responders were 9/35 (25.7%) at T1 and 20/35 (57.1%) at T2; remitters were 3/35 (8.6%) at T1 and 10/35 (28.6%) at T2. The authors note a marked increase in responders between one and three months, suggesting later responders after the induction phase. Anxiolytic effects: The rm-ANOVA interaction for HAM-A did not reach significance (Wilks' Lambda = 0.953, F2,42 = 1.027, p = 0.367). Nonetheless, the extract reports a larger within-group anxiolytic effect in B-TRD between T1 and T2 (p = 0.003, Cohen's d = 0.768) than in TRD (p = 0.330, Cohen's d = 0.489). HAM-A remission at T2 was higher in B-TRD (35%) compared with TRD (3%). Safety and tolerability: Reported side-effect rates were 57.14% in B-TRD versus 77.15% in TRD; types and frequencies are presented in the original tables (not fully reproduced in the extract). One affective switch was recorded in the B-TRD group; no statistically significant difference between groups was found for affective switch risk or development of manic symptoms. The authors state there was no overall increase in suicidality, need for acute hospitalisation, emergent hypomania, psychosis, or dissociation in B-TRD compared with TRD. The extract highlights that all B-TRD patients were on mood stabilisers when ESK-NS was started, which may have influenced the observed low rate of switches.
Martinotti and colleagues present this work as the first multicentre, real-world evaluation of esketamine nasal spray in a treatment-resistant bipolar depression sample, comparing outcomes with age-matched unipolar TRD patients. The investigators interpret the results as supporting good antidepressant effectiveness and tolerability of ESK-NS in both groups, with a rapid reduction in MADRS scores within the first month and further increases in response and remission rates by three months. Although the group-by-time interaction on MADRS was not statistically significant, the bipolar sample showed numerically higher remission rates at three months (48.6% vs 28.6%) and a larger within-group anxiolytic effect, leading the authors to suggest comparable or potentially greater benefit in some domains for B-TRD. The authors situate their findings within the broader glutamatergic hypothesis of mood disorders, noting neuroimaging evidence implicating glutamate dysfunction in regions such as the DLPFC and ACC and prior ketamine data in bipolar depression. They propose that ESK-NS and other glutamatergic interventions could be promising treatment options for bipolar depression, including mixed-features presentations, and that the observed anxiolytic signal may reflect efficacy on agitation/mixed symptoms as well as on comorbid anxiety disorders. Safety-wise, the low observed rate of affective switch and absence of increased severe adverse events are emphasised, but the authors acknowledge an important caveat: all B-TRD patients were concomitantly treated with mood stabilisers, which is appropriate in real-world practice but may reduce observable switch risk and thus bias safety conclusions. Key limitations acknowledged include the small sample size, retrospective observational design, and the absence of structured mania-rating scales (for example, YMRS) to systematically detect hypomanic/manic symptoms. The extracted text indicates the discussion of a further limitation was cut off; consequently, the full list of limitations and the authors' final recommendations are not completely reported in the provided extract. The authors call for randomised controlled trials with larger samples and placebo control to confirm these preliminary observations and better characterise both efficacy and switch risk of ESK-NS in bipolar depression.
Bipolar depression accounts for the majority of symptomatic periods in both type I and type II bipolar disorder (BD) and is associated with an elevated risk of suicide and high morbidity and mortality rates.In this context, depressive symptoms and major depressive episodes dominate the clinical course of BD, although manic/hypomanic episodes are required for the diagnosis of BD.However, while several treatments are available for the manic phase of BD, particularly antiepileptic agents, few are effective for bipolar depression.Indeed, a large 26-week study found that the use of antidepressants was not effective in the treatment of patients with type I or II BD.Moreover, currently available antidepressant medications are often poorly tolerated, associated with a delayed onset of action of several weeks, and, above all, capable of inducing an affective switch or rapid cycling in subjects with BD.Furthermore, brain stimulation techniques represent relevant therapeutic tools in this condition, with electroconvulsive therapy (ECT), historically recognized as a rapid antidepressant agent, able to significantly improve severe forms of bipolar depression.Nowadays, other brain stimulation techniques, for instance, repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), both targeting the dorsolateral prefrontal cortex (DLPFC), are employed as possible augmentation strategies for bipolar depressed patients.Indeed, these techniques act specifically on peculiar symptomatologic dominion, such as anhedonia.Furthermore, some studies have reported their ability to increase cortical excitability, positively modulating moodwith an extremely low risk of an affective switch, as reported by a recent meta-analysis on this matter.However, the role of rTMS and tDCS in treating bipolar depression may not have been explored enough, and further research in this area is still needed.
Although several treatment options for bipolar depression are emerging, many patients achieve only partial remission, not adequately responding to treatment, with residual symptoms persisting despite the use of several medications, even if there is good compliance, and the treatment has been taken long enough with an adequate dosage.Depression may be considered resistant to treatment when at least two trials with antidepressants from different pharmacological classes (adequate in dose, duration, and compliance) fail to produce significant clinical improvement.Treatment-resistant depression (TRD) is a condition historically considered peculiar to Major Depressive Disorder (MDD). Nevertheless, treatmentresistant depression in BD (B-TRD) represents a common and rapidly growing phenomenon in everyday practice and can occur even with evidence-based first-line treatments.Indeed, as no specific therapies have been approved for this condition, in clinical practice, the re-evaluation of the initial diagnosis and optimization of the initial regimen using switching to other antidepressants, augmentation strategies (e.g., combination therapy, lithium, and other mood stabilizers, thyroid hormones, atypical antipsychotics, etc.) or even monotherapy with second-generation antipsychotics have been considered within the psychopharmacologic options.For instance, several lines of evidence indicate that, among unipolar subjects with TRD, approximately 50% are misdiagnosed with BD when evaluated one year after the first diagnosis of TRD.In addition, BD in TRD appears to be twice as prevalent as in MDD.Finally, non-response in bipolar depression occurs in 40% of patients after eight weeks of treatment with quetiapine.Other first-line medications, such as lithium, lamotrigine, olanzapine, or the olanzapine-fluoxetine combination, may have similar or even less favorable outcomes.
Historically, available treatments for depressive disorders were based on the monoaminergic hypothesis, which linked MDD to a significant depletion of the neurotransmitters dopamine, noradrenaline, and serotonin.This hypothesis, over the years, has proven to be insufficient, given the failure of a significant proportion of patients to monoaminergic agents. Thus, by engaging other targets together with them, physicians can help patients with residual symptoms and TRD cases.In this context, the interest of the scientific community in the role of glutamate in unipolar and bipolar depression has increased in recent years, with the aim of developing potential new therapeutic agents for these disorders.The glutamatergic hypothesis for depressive disorders has been supported by the antidepressant efficacy of ketamine, an antagonist of the ionotropic N-methyl-D-aspartate (NMDA) receptor.Ketamine has shown good efficacy in both bipolarand unipolarTRD, with response rates ranging from 50-70%.Furthermore, in the various studies conducted,no cases of manic switch after ketamine use in B-TRD have been shown, with preliminary data supporting effectiveness and safety among those patients.However, its clinical use is severely limited by the numerous side effects and the intravenous administration.Besides, the use of Ketamine and derivates in bipolar depression represents a promising field, with a recent international expert consensus pointing to the urgency of further investigation in this area.Esketamine, the S-enantiomer of ketamine, has recently emerged as a potential treatment for TRD. Its rapid antidepressant action and good efficacy (approximately 40%-50% in the maintenance phase, as demonstrated in several randomized controlled trials, RCTs)have led to its approval by several medical agencies as a new therapeutic tool for unipolar TRD. Furthermore, esketamine-nasal spray (ESK-NS) exhibits a more favorable safety profile than ketamine, thus confirming its potential use in outpatient settings.The excellent safety profile was confirmed by the SUSTAIN-2 study, in which no manic symptoms were reported among adverse events; furthermore, no other ESK-NS RCT reported manic symptoms or affective switches.Currently, the approval of ESK-NS for B-TRD is limited by two main factors: firstly, the absence of studies focused on bipolar depression, apart from a single case report that indicated the potential effectiveness of ESK-NS in combination with mood stabilizer therapy in a patient with BD; secondly, the considerable concerns raised regarding possible affective switches induced by ESK-NS, although studies in unipolar TRD have not reported this evidence. Indeed, the European Medicines Agency (EMA) ESK-NS Summary of Product Characteristics (SPCs) does not contraindicate ESK-NS use among subjects with BD, suggesting a careful evaluation between the risk and benefits of its application in this condition.
Considering the previous findings and the growing need for antidepressant agents for BD, the main objective of our research is to compare ESK-NS antidepressant action in two samples of unipolar and bipolar TRD, providing preliminary insights on its effectiveness among subjects with B-TRD. Secondarily, this study will address the safety and tolerability of ESK-NS in bipolar subjects, focusing on the average risk of an affective switch.
Data presented in this manuscript are part of the REAL-ESK study, an observational, retrospective, and multicentric study of subjects with TRD treated with ESK-NS.Treatment was carried out as part of an early access program that supplied ESK-NS to the main mental health centers in Italy. Thirty-five subjects affected by B-TRD and treated with ESK-NS were included in the B-TRD group. Subsequently, to create a control group composed of TRD subjects, B-TRD subjects were matched one to one for age to extract from the REAL-ESK study,thus generating a TRD sample (n = 35). Furthermore, TRD and B-TRD groups were compared and did not statistically differ for sociodemographic data and baseline severity symptoms. Subjects enrolled in the B-TRD group were carefully evaluated by qualified psychiatrists, investigating the previously documented history of manic or hypomanic episodes (all B-TRD had at least one hypomanic or manic episode in their clinical history, according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders /DSM-5).Several Italian mental health facilities were involved in this study, the coordination centers being both the 'G. Patients with comorbid organic pathologies that represent an absolute contraindication to ESK-NS according to the EMA (i.e., untreated arterial hypertension or previous cerebrovascular disorders) were excluded from the study.
Anamnestic data were retrospectively collected and included information on sociodemographic factors, the history of the disease, the treatment history for the current depressive episode, antidepressant trials experienced during the current episode, augmentation strategies (combined use of mood stabilizers / antipsychotic medications or not) and other therapeutic tools applied to treat TRD. Data were also collected in cases of premature study withdrawal or the occurrence of clinically relevant events, such as admission to or discharge from inpatient care, symptom relapse, or remission of major depressive episodes. Anamnestic data were collected from patients' medical records at baseline (T0), while psychometric assessments were collected at T0, after one month (T1), and three months (T2) from the start of treatment. The Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Scale (HAM-D-21 items) were used by clinicians to characterize depressive symptoms. The Hamilton Anxiety Rating Scale (HAM-A-21 items) was used to assess the severity of anxiety symptoms. Patients were defined as responders with an overall 50% reduction in the MADRS or HAM-D-21 score compared to the baseline assessment,while remission was defined as a MADRS score <10 or a HAM-D-21 score <7.A qualified psychiatrist carefully evaluated adverse events related to ESK-NS administration and reported in the patient medical records.
Statistical analyses were performed using SPSS 20.0 software (SPSS Inc.) and JASP for Mac (JASP version: 0.16.4; JASP Team, 2022). All tests were two-tailed, with a statistical significance level set at p < 0.05. Continuous variables are expressed as mean ± standard deviation (SD), while categorical variables are reported as average numbers and percentages. The Kolmogorov-Smirnov normality test was used to verify the normality distribution of our data in both groups (B-TRD and TRD). Subsequently, parametric tests were used since the data distribution was found to be normal. The student t-test was conducted to assess changes in continuous variables, whereas the Pearson χ 2 test was performed for categorical variables. Furthermore, a general linear model approach was used to analyze the "between factor" × "within factor" interaction effect (between factor: TRD vs. B-TRD; within factor, treatment time: baseline/pre-treatment/T0 vs. at the end of the 1st month of treatment/ T1 vs. at the end of the 3rd month of treatment/T2) on MADRS and HAM-A total scores. Two separate models of repeated measures analysis of variance (rm-ANOVA) were employed with MADRS and HAM-A as dependent variables to investigate the interaction effect. The sphericity of the covariance matrix was tested with Mauchly's test of sphericity; in the case of violation of the sphericity assumption, Greenhouse-Geisser epsilon (ε) adjustment was used. For strict control of the type I error, post-hoc pairwise comparison tests were performed using Scheffé's method for multiple comparisons. Measures of effect size were partial eta2 ( 2 p ) in rm-ANOVA and Cohen's d or Hedges' g in pairwise comparisons, respectively, if groups had the same sample size or different sample sizes.
The final set of patients consisted of 70 subjects, 35 from the TRD group (mean age: 52.57 ± 12.77) and 35 from the B-TRD group (mean age: 52.57 ± 12.77) B-TRD group consisted of 17 subjects with a BD type 1 and 18 Subjects with a BD type 2. As mentioned above, B-TRD and TRD groups did not differ statistically in age, gender, occupancy level, years of education, or duration of the disease. Subjects with B-TRD subjects showed higher lifetime suicide attempt rates than subjects with TRD, consistent with previous evidence indicating higher suicidality in those affected by BD.Concerning pharmacotherapy, both groups had a history of different antidepressant trials experienced in their lifetime (TRD group: 3.00 ± 0.98; B-TRD group: 3.28 ± 0.85); TRD group had significantly higher levels of SNRI as actual therapy versus the B-TRD group (42.8% vs. 20%; χ 2 = 4.619 df = 1 p = 0.032), while more B-TRD than TRD subjects were treated with mood stabilizers (100% vs. 57.14%; χ 2 = 14.885 df = 1 p < 0.0001). No significant differences in the psychometric baseline scores were found between the TRD and B-TRD groups. However, the B-TRD group showed higher baseline suicidality levels than the TRD group (MADRS ITEM-10: 2.75 ± 1.54 vs. 1.73 ± 1.48, t = -2.766, df = 65 p = 0.007). All sociodemographic and clinical data are extensively reported in In total, 33 subjects in the B-TRD group and 32 subjects in the TRD group were included in the data analysis at T1, while 31 subjects with B-TRD and 28 with TRD were included at T2.
In the rm-ANOVA, the multivariate test showed a not significant effect of the "TRD vs. B-TRD" × "T0 vs. T1 vs. T2" interaction factor (Wilks' Lambda = 0.938, F 2,52 = 1.728, p = 0.188, 2 p = 0.062) on MADRS. Mauchly's test of sphericity was significant: W = 0.839, 2 2 = 9.102, p = 0.011. The univariate rm-ANOVAs for MADRS confirmed this not significant interaction factor effect (F 1.723,91.334 = 2.445, ε = 0.862, p = 0.100, 2 p = 0.044). As shown in Tableand FigureIn general, in the B-TRD group, nine subjects (25.7%) responded in T1 and 24 subjects (68.57%) in T2, while six patients (17.14%) were remitters in T1 and 17 (48.57%) in T2. Furthermore, in the TRD group, nine subjects (25.7%) responded in T1, 20 subjects (57.14%) in T2, while 3 (8.57%) were remitters in T1 and 10 (28.57%) were remitters in T2.
Regarding the anxiolytic effect of ESK-NS, the rm-ANOVA showed a not significant effect of the "TRD vs. B-TRD" × "T0 vs. T1 vs. T2" interaction factor (Wilks' Lambda = 0.953, F 2,42 = 1.027, p = 0.367,and Figure.
TRD and B-TRD groups did not differ in terms of the percentage of subjects reporting side effects (57.14% of B-TRD vs. 77.15% of TRD; The type and percentage of side effects in both groups are extensively reported in Table. Only one case of the affective switch was reported in the B-TRD group, and there was no significant difference with the TRD group in terms of affective switch risk or maniacal symptom development
To our knowledge, this is the first multicentric, real-world study to evaluate the effectiveness, safety, and tolerability of ESK-NS in a B-TRD sample. ESK-NS showed good effectiveness in terms of response and remission rates in both TRD and B-TRD groups. Our findings are consistent with previous studies on both intravenous ketamineand esketamine; the latter, in particular, highlighted the effectiveness of intravenous esketamine in anhedonic features in both MDD and BD patients,thus suggesting a potential comparable effectiveness in the two conditions. Besides, our results confirmed the rapid antidepressant action of ESK-NS (MADRS mean score reduction from T0 to T1, B-TRD group:-13.03, TRD group:-12.21; see Table), in line with results of previous RCT studiesindicating a rapid antidepressant action of ESK-NS, with a reduction in MADRS scores within the first day of treatment and significant response rate in the first month, when the clinical response to ESK-NS is expected.Furthermore, we found a dramatic increase in ESK-NS effectiveness from T1 to T2 (responders increased in the B-TRD group from 25.7% to 68.57%, in the TRD group from 25.7% to 57.14%), suggesting the presence of later responders. Practically, although the induction phase is often considered a critical point for evaluating ESK-NS effectiveness, our study indicates that continuing ESK-NS beyond this phase could result in a later successful response. Secondarily, ESK-NS appeared to be effective in subjects affected by bipolar depression. Indeed, although our primary endpoint was set to demonstrate similar effectiveness of ESK-NS in B-TRD patients compared to TRD, our results went far beyond this goal. Although without statistical significance, the number of B-TRD remitters was higher than TRD subjects at T2 (48.57% and 28.57%, respectively). Interestingly, the general linear model showed a higher effect size in B-TRD subjects compared to TRD ones: in particular, comparing MADRS variations between T1 and T2, the
Two lines of evidence support the critical role of glutamatergic dysfunction in BD. Firstly, different neuroimaging studies indicate the impairment of glutamate neurotransmission in the different stages of BD,specifically involving the DLPFC and the anterior cingulate cortex (ACC), two areas of the brain with a critical role in mood disorders.Secondly, ketamine, another glutamatergic agent, showed a good clinical efficacy and tolerability as antidepressant in BD.Furthermore, as already mentioned, one of the main factors contributing to treatment resistance in depression is represented by BD, which is often misdiagnosed as MDD.Considering these last pieces of evidence and our main findings, we can speculate that glutamatergic dysfunction may be a 'trait' feature of BD. Thus, ESK-NS and other glutamatergic agents may be primary options for treating mood swings in BD. Nevertheless, to validate our hypothesis, these findings should be confirmed by RCT with larger samples of patients and placebo control.
Regarding the safety and tolerability of ESK-NS in subjects with BD, the B-TRD and TRD groups did not differ statistically in terms of the percentage of reported side effects. However, BD subjects showed lower levels of reported side effects (57.14% of B-TRD subjects vs. 77.15% of TRD subjects). Furthermore, ESK-NS-related adverse effects were reduced after the treatment without leading to any significant sequelae. Moreover, no differences were found in affective switches between the TRD and B-TRD groups, with only one case in the B-TRD group of discontinuation related to manic symptoms and psychomotor agitation. In addition to the very low risk of manic switch, the safety of ESK-NS in bipolar patients is TA B L E 4 Reported adverse events in the TRD and B-TRD groups confirmed by the absence of the increase in suicidality or need for acute hospitalization. Overall, there was no increased risk of treatment-emergent hypomania or psychosis or dissociation in subjects with B-TRD compared to those with TRD, in line with previous evidence reported in studies on ketamine in BD,a finding which is very relevant, considering the previous concerns about possible risks of ESK-NS use in BD. However, B-TRD subjects in our study were all treated with mood stabilizers when starting ESK-NS. While the use of mood stabilizers is expected in real-world settings, it could be an essential study bias for assessing the overall risk of ESK-NS-induced affective switch.
Along with the antidepressant effectiveness, the anxiolytic effect of ESK-NS recorded here deserves to be considered. As well described in the literature, anxiety symptoms or comorbidity with a general anxiety disorder (GAD) are common in both unipolar and bipolar depression.The close relationship between MDD and GAD is due, on the one hand, to common symptoms and, on the other hand, to common genetic risk factors.Anxiety symptoms also have high comorbidity in BD: epidemiological studies have shown that patients with BD and co-occurring anxiety symptoms or anxiety disorders are susceptible to higher rates of depressive episodes and increased suicidal behavior.Furthermore, in the phenomenology of MDD, anxiety symptoms have often been included as part of socalled 'agitated depression,' which has been questioned about being a 'mixed-features' depression and part of the bipolar spectrum rather than the unipolar depression itself.In this regard, the more significant decrease of anxious symptoms in the B-TRD group compared to TRD appear noteworthy, with a stronger effect size in the former (T1 vs. T2, p = 0.003, Cohen's d = 0.768) and a lower in the latter (T1 vs. T2, p = 0.330, Cohen's d = 0.489), in addition to a considerable higher remission rate at T2 in B-TRD subjects (35% against 3%, respectively). As detected by the HAM-A psychometric scale, anxiety symptoms could be related, from a phenomenological point of view, to different psychopathological domains. Several items of the HAM-A, in fact, refer to a wide range of symptoms (e.g., general anxiety, insomnia, pronounced psychomotricity, emotional tension, etc.) that could, on the one hand, be interpreted as characteristics of an anxiety disorder, but, on the other, could be symptoms of a manic/hypomanic affective state. Speculating on this, the anxious symptoms in both TRD and B-TRD groups could express different clinical conditions, which explained the differences in anxiolytic effectiveness. On the one hand, anxious symptoms in the TRD group could be interpreted as genuine symptoms of GAD in the context of a depressive episode. On the other hand, the more severe anxious symptoms in the B-TRD group could be the clinical manifestation of 'agitated depression' or 'depression with mixed-features,' in which anxiety symptoms refer to symptoms such as psychic akathisia, hyperactivity, or tension that are part of a hypomanic/manic clinical presentation. Furthermore, mixed features have been described as frequent in the context of both (BD) type I and type II, affecting approximately 30% of the subjects during a depressive episode.Therefore, the anxiolytic effect of ESK-NS in subjects with BD could be consistent with its specific action on the 'mixed-features' domain of bipolar depression. In line with our findings, a recent study revealed the efficacy of intravenous ketamine in the rapid treatment of mixed features in subjects with TRD, hypothesizing glutamatergic agents as possible therapeutic alternatives in these states.Consistently, the role of ketamine/esketamine in treating mixed features/anxiety symptoms could be related to brain dysfunction in glutamate/gamma-aminobutyric acid (GABA) homeostasis, which has been often implicated in the pathophysiology of both mood and anxiety disorders.Furthermore, several preclinical and clinical studies indicate the ability of glutamatergic drugs to 'stabilize' this homeostatic system,probably acting on brain networks that are often impaired in subjects with BD, independently of the affective episode.Clearly, this possible explanation is speculative and should be considered as a starting point for further studies on this topic, perhaps using specific scales to assess mixed features in the context of TRD.
As previously mentioned, further studies are needed to substantiate the efficacy of ESK-NS in B-TRD, as our work has some limitations. Firstly, our sample size is small; RCT studies on this topic with a larger number of participants are needed. Secondly, the use of psychometric scales to assess manic switches in patients with BD (such as the Young Mania Rating Scale / YMRS) would be worth considering. In our study, a careful clinical assessment was performed by expert psychiatrists who, however, could have benefited from the use of structured scales to assess manic symptoms. Thirdly, the short
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