Introduction

Depression is a complex psychiatric disorder characterized by the presence of depressed mood, anhedonia, loss of interest, low energy, and fatigue for a minimum 2-week period. Other symptoms can be noted, such as insomnia or hyposomnia, diminished ability to concentrate, significant weight alteration, low self-esteem, and suicidal ideation [1]. Its etiology is not yet fully understood, and one of the pathophysiological mechanisms involved is the functional deficiency of the monoamine neurotransmitters serotonin, noradrenaline, and/or dopamine in the brain synapses. However, other multiple interactions with other brain systems are also involved [1, 2].

According to the World Health Organization, more than 300 million people of all ages suffer from depression, being considered a leading cause of disabling worldwide — 7.5% of all years lived with disability [3]. The economic burden of depression was estimated at $210.5 billion in the USA (increase of 21.5% between 2005 and 2010), with practically half of this amount being due to direct medical costs and the other half being attributed to indirect costs related to absenteeism, presentism, and suicide [4]. In addition, depression has an important impact on activities of daily living and quality of life and affects individuals, often in early life and for sustained periods, thereby causing many disease years [5]. Therefore, depression is a public health problem.

Treatment for depression includes the use of antidepressants, electroconvulsive therapy (ECT), and psychosocial interventions. Antidepressant medications, such as the selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors, can be used for treatment of mild, moderate, and severe depression [6]. However, current treatments require a considerable time to induce a response or remission of depression. The average time for antidepressant action of the standard antidepressants is 13 days, which can reach 20 days, considering the response criteria. Still, when patients have a clinical response, it is generally considered suboptimal [7].

At the beginning of this century, Berman et al. (2000) reported that ketamine was able to inhibit the N-methyl-d-aspartate (NMDA) receptor (i.e., the main receptor of the glutamatergic system that plays an important role in the antidepressant effect) [8]. In addition, current evidence suggests that ketamine’s acute antidepressant effect requires opioid system activation [9]. In this context, a growing number of clinical trials have shown that subanesthetic doses of esketamine (S-ketamine) and ketamine (RS-ketamine, a racemic mixture of R-ketamine and S-ketamine) have a rapid antidepressant effect [10, 11]. From that, the off-label use of ketamine and esketamine for depression (except for intranasal esketamine approved by FDA in the USA and EMA in Europe) has increased, giving great concern for the patient’s health and the healthcare system, since the efficacy and safety of these drugs are not yet fully established [12, 13].

In order to deliver accurate estimates of key outcomes of ketamine and esketamine in depression, some systematic reviews with meta-analyses have been published recently — considered the gold standard of evidence in health care [14]. In this sense, it is important to understand the diversity present in the extant systematic review literature. Also, the methodological quality of these systematic reviews is unknown, which is an indispensable step before treatment recommendations can be safely translated into clinical practice. Currently, there is no overview on the use of ketamine/esketamine in patients with depression. Therefore, this overview aimed to summarize the evidence of efficacy and safety of ketamine and esketamine for adult patients with depression from systematic reviews with meta-analyses.

Methods

The search strategy, eligibility criteria, and method of analysis for this overview were specified in advance and documented in a protocol available in Appendix 1.

Literature search

A comprehensive literature search was performed in the Medline (via PubMed), Latin American and Caribbean Health Sciences Literature (LILACS), Cochrane Library, and the Centre for Reviews and Dissemination (CRD) databases until November 29, 2020. The search strategy included the use of Medical Subject Headings (MeSH) terms and keywords related to the health condition (depression), intervention (ketamine and esketamine), and the study design (systematic reviews with meta-analysis). The detailed search strategy of all databases is shown in Appendix 2; keywords were searched in any fields unless otherwise specified. Also, we screened the reference lists of the appraised articles to identify any studies that might have been missed.

Study selection

The selection process was performed in three stages: (1) exclusion of repeated records, (2) analysis of the titles and abstracts, and (3) analysis of the full-text articles. The studies were independently selected by two authors (MBV and TML). Any disagreements were resolved by a third author (PMA). When the full-text article could not be obtained, the corresponding authors were contacted via ResearchGate (www.researchgate.net) or e-mail or both.

To be included in the present overview, the articles had to meet the following criteria: (1) be a systematic review with pairwise meta-analysis of randomized controlled trials (RCT); (2) be published in English, Spanish, or Portuguese; (3) have evaluated the use of ketamine or esketamine or both (monotherapy or associated with other drugs, any route of administration and frequency of use) in comparison with placebo or other drugs; (4) report any efficacy and safety outcomes; and (5) in adults with major depressive disorder or bipolar disorder. Articles were excluded if they were (1) narrative reviews; (2) systematic reviews without meta-analysis; (3) meta-analyses not from systematic reviews; (4) network meta-analysis; (5) systematic reviews including concomitant use of ECT and ketamine or esketamine as intervention; (6) systematic reviews with meta-analysis including another target population, intervention, or primary study design; (7) systematic reviews that did not have the full-text article available.

Data extraction

Data extraction was using a spreadsheet preformatted in Microsoft Excel® by two independent researchers (MBV and TML), and any disagreement was resolved by a third author (PMA). The following information was collected: author(s), year of publication, literature search period, databases used in literature search, target population, intervention (dose and route of administration), comparators, outcome measures, number of RCTs and patients included in the meta-analysis, statistical model for meta-analysis, pooled effect size, heterogeneity, publication bias, quality of evidence by the GRADE approach [15], and funding source.

Quality assessment

The methodological quality of included systematic reviews was assessed using the AMSTAR-2 (Assessment of Multiple Systematic Reviews) tool [16]. The AMSTAR-2 is a 16-item questionnaire, with the majority of questions being judged as “yes,” “partial yes,” or “no.” The overall rating was based on weaknesses in critical domains (items: 2, 4, 7, 9, 11, 13, and 15) as following: “high,” no or one non-critical weakness; “moderate,” more than one non-critical weakness but no critical flaws; “low,” one critical flaw with or without non-critical weaknesses; and “critically low,” more than one critical flaw with or without non-critical weaknesses. One investigator (TML) conducted the evaluation of the studies, and a second one (PMA) verified this evaluation.

Data synthesis

The characteristics of systematic reviews and their methodological quality were descriptively summarized using systematically structured tables. The estimates of effect size from meta-analyses (and their 95% confidence intervals [95% CI]) were expressed as mean difference (MD), standardized mean difference (SMD), relative risk (RR), and odds ratio (OR), depending on what the authors had reported.

Results

Search results

The electronic search identified 118 potentially relevant records. After removing duplicates and screening titles and abstracts, 21 studies were selected for full-text reading. Of these, 11 systematic reviews with pairwise meta-analysis on use of ketamine or esketamine or both for treatment depression fully met the eligibility criteria and were included in the present overview [17,18,19,20,21,22,23,24,25,26,27]. All included systematic reviews were found for full-text examination. A flowchart of the literature search is shown in Fig. 1. The excluded studies and the reasons for their exclusion are detailed in Appendix 3.

Fig. 1
figure 1

Study selection flowchart through literature search. RCT randomized controlled trials

Full size image

Characteristics of systematic reviews

Characteristics of the 11 reviews included in this overview are shown in Table 1. All included systematic reviews were published in English between 2015 and 2020. Most reviews included primary studies evaluating patients with major depression disorder or bipolar disorder [18, 20,21,22, 24, 26]. Two reviews included patients with bipolar depression [19, 23], and three reviews included patients with major depression disorder [17, 25, 27].

Table 1 Characteristics of systematic reviews with meta-analyses on ketamine and esketamine for depression
Full size table

Almost all reviews involved ketamine as monotherapy in the intervention arm [17,18,19,20,21,22,23,24,25]. One review involved ketamine or esketamine [26], and another review involved only esketamine in the intervention arm [27]. Seven reviews included studies whose comparator was placebo or active-control [18, 20,21,22, 24,25,26], and four reviews included studies that used placebo as comparator [17, 19, 23, 27].

Nine reviews assessed clinical remission or clinical response or both [17, 19,20,21,22,23,24,25, 27], and all of them assessed the severity of depressive symptoms through validity scales, except the review by Fornaro et al. (2020) [23]. Most reviews used the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS/HAM-D) [17, 18, 20, 22, 24,25,26,27], two reviews used the Brief Psychiatric Rating Scale (BPRS) and Clinician-Administered Dissociative States Scale (CADSS) [20, 21], two reviews used MADRS [19, 27], and one review used 9-Item Patient Health Questionnaire (PHQ-9) [27]. Six reviews assessed other outcomes, such as suicidality [22, 26], acceptability [19, 23, 27], disability [27], and adverse events [25, 27].

Three reviews did not report a source of support [18, 21, 22], four received research funding from institute organization [17, 19, 26, 27], and four declared no support from any organization [20, 23,24,25].

Results on clinical response

Ketamine produced a significant clinical response compared to placebo at 40 min, 80 min, 2 h, and 4 h after intervention [21]. Seven reviews showed a significant effect of ketamine in the clinical response at 24 h compared to placebo or active-control or both [17, 19,20,21,22,23,24]. However, very-low-dose ketamine for patients with major depression disorder did not show significant difference in the clinical response at the same time compared to placebo and active-control [22]. In addition, one review reported that ketamine was significantly better than placebo and active-control in the clinical response at 48 h [21].

Regarding clinical response at 72 h, ketamine produced a significant clinical response compared to placebo or active-control or both in four reviews [17, 20,21,22]. On the other hand, one study did not show a significant effect of ketamine in the clinical response at the same time compared to placebo for patients with bipolar disorder (very low-quality evidence) [19]. In addition, very-low-dose ketamine for patients with major depression disorder was not significantly better than placebo and active-control in the clinical response at 72 h [22].

Four reviews showed significant effect of ketamine in the clinical response at 1 week compared to placebo or active-control or both [20,21,22, 24]. However, it is important to note that there was no significant difference between ketamine and placebo at the same time in patients with bipolar depression [22]. One review showed a tendency to significant difference between ketamine and placebo in the clinical response at 2 weeks [21]. In addition, one systematic review showed a significant effect of ketamine in the clinical response overall compared to placebo and active-control [24]. The only review that evaluated oral ketamine did not present a significant result [25].

Finally, esketamine was statistically superior compared to placebo in the clinical response at 2 h, 1 week, 4 weeks, by 2 to 28 days and by 8 to 28 days (high-quality evidence) [27]. The results on clinical response are displayed in Table 2.

Table 2 Results on clinical response in systematic reviews with meta-analyses on ketamine and esketamine for depression
Full size table

Results on clinical remission

Ketamine produced a significant clinical remission of symptoms compared to placebo at 80 min, 2 h, and 4 h after intervention [21]. Regarding the clinical remission at 24 h, four reviews showed significant effect of ketamine compared to placebo or active-control or both [20,21,22, 24]. On the other hand, two reviews involving a smaller number of patients did not report significant differences in the clinical remission of symptoms between groups at the same time [17, 19]. In addition, ketamine was significantly better than placebo and active-control in the clinical remission at 48 h [21].

Data on clinical remission of symptoms at 72 h was presented by five reviews. Ketamine produced a significant clinical remission compared to placebo or active-control or both in most of them [17, 20,21,22]. However, very-low-dose ketamine for patients with major depression disorder did not show significant difference in the clinical remission at the same time compared to placebo and active-control [22].

Two reviews showed significant effect of ketamine in the clinical remission of symptoms at 1 week compared to placebo and active-control [20, 22], and two reviews did not present a significant difference between groups [21, 24]. One review assessed the clinical remission of symptoms at 2 weeks and did not show a significant difference between ketamine and placebo [21]. In addition, two reviews did not show a significant difference between ketamine versus placebo and active-control in the clinical remission overall [24, 25].

Finally, esketamine was statistically superior compared to placebo in the clinical remission at 2 h, 4 h, 24 h, 1 week, 4 weeks, and by 8 to 28 days (high-quality evidence) [27]. The results on clinical remission are displayed in Table 3.

Table 3 Results on clinical remission in systematic reviews with meta-analyses on ketamine and esketamine for depression
Full size table

Results on depression scales

Four reviews showed significant beneficial effects of ketamine in the HAM-D/HDRS and MADRS scores at 24 h compared to placebo or active-control or both [17, 18, 20, 22]. However, one systematic review did not show significant effect in the same time compared to placebo and active-control [24]. Two reviews showed a beneficial effect at 72 h [17, 22]. However, Xu et al. (2016) reported that very-low-dose ketamine did not improve the HAM-D/HDRS and MADRS scores at the same time compared to placebo and active control [22].

Three reviews showed data of HAM-D/HDRS and MADRS scores at 1 week [18, 22, 24]. All of them showed significant beneficial effects of ketamine compared to placebo or active-control or both. However, Lee et al. (2015) did not show significant difference between ketamine and placebo for patients with bipolar depression [18], and Xu et al. (2016) did not show significant difference between ketamine (normal or very-low-dose) compared to placebo and active-control [22]. In addition, Nuñez et al. (2020) showed a significant effect of oral ketamine compared to placebo or active-control or both at 2 and 3 weeks [25], and two studies showed superior effect of ketamine compared to placebo and active-control in the overall scores [24, 25].

Regarding the MADRS score, one review showed that ketamine produced a significant beneficial effect compared to placebo at 24 h and 72 h [19]. However, the superior result was not observed at 1 and 2 weeks (very low-quality evidence) [19]. In addition, Zheng et al. (2020) showed a significant beneficial effect of esketamine compared to placebo (high-quality evidence) [27].

Finally, two reviews assessed the use of ketamine through BPRS and CADSS score [20, 21] and one assessed the use of esketamine through PHQ-9 score (high-quality evidence) [27]. All reviews showed the intervention arm was significantly better than placebo or active-control or both to improve these scores. The results on depression scales are shown in Table 4.

Table 4 Results on depression scales score in systematic reviews with meta-analyses on ketamine and esketamine for depression
Full size table

Results on suicidality, acceptability, disability, and adverse events

One review presented the results of the suicidal ideation at 4 h, 24 to 72 h, 2 to 4 weeks, and more than 4 weeks, observing a significant difference between ketamine or esketamine or both compared to placebo and active control at 4 h and 24 to 72 h (low-quality evidence) [26]. Xu et al. (2016) presented a significant difference between ketamine versus placebo and active control at 24 and 72 h. However, this result was not observed at 1 week [22].

Three reviews did not show a significant difference between ketamine or esketamine versus placebo in the acceptability of the treatment (total dropout and dropout due to lack of efficacy) [19, 23, 27]. In contrast, Zheng et al. (2020) showed a significant difference between esketamine and placebo on acceptability (dropout due to adverse events) (high-quality evidence) [27]. In addition, only one review evaluated disability and showed a significant difference between esketamine and placebo (high-quality evidence) [27].

In terms of adverse events, one systematic review on oral ketamine reported this outcome and did not show a significant difference between ketamine versus placebo and active-control [25]. Finally, Zheng et al. (2020) showed significant difference between esketamine and placebo in the dissociation, dissociative disorder, dizziness postural, feeling abnormal, feeling drunk, hypoesthesia, oral hypoesthesia, lethargy, nausea, paresthesia, sedation, somnolence, throat irritation, vertigo, vision blurred, and vomiting (high-quality evidence) [27]. The results on suicidality, acceptability, disability, and adverse events are displayed in Table 5.

Table 5 Results on suicidality, acceptability, disability, and adverse events in systematic reviews with meta-analyses on ketamine and esketamine for depression
Full size table

Methodological quality of systematic reviews

Methodological quality of 11 systematic reviews based on the AMSTAR-2 tool is shown in Table 6. Three reviews presented “low quality” [17, 19, 24] while eight reviews presented “critically low quality” [18, 20,21,22,23, 25,26,27].

Table 6 The quality assessment results of systematic reviews with meta-analyses included using the AMSTAR-2 tool
Full size table

All reviews included the components of PICO (Population, Intervention, Control, and Outcomes) in their research questions. Moreover, only three reviews did not perform study selection and data extraction in duplicate [20, 21, 25], two reviews did not provide a satisfactory explanation for any heterogeneity observed in their results [21, 25], and one review did not use a satisfactory technique for assessing the risk of bias (RoB) in primary studies, did not use appropriate methods for statistical combination of their results, and did not report any potential sources of conflict of interest [21].

In contrast, no review reported on the sources of funding for the studies included in their review and assessed the potential impact of risk of bias in individual studies on their results. Five reviews did not report an “a priori” design and indicated the existence of a protocol [18, 20,21,22, 27]. Furthermore, only five reviews provided a list of excluded studies and justify their exclusions [17, 19, 20, 23, 24], four of the reviews conducted an adequate investigation of publication bias and discuss its likely impact on the results of the review [18, 20, 24, 26], and two of them considered the risk of bias in individual studies when interpreting/discussing their results [17, 19].

Overlap of primary studies across the systematic reviews

In this overview, there are two pairs of systematic reviews on ketamine that included the same RCT (Appendix 4). McGirr et al. [20] (critically low-methodological quality) and Newport et al. [21] (critically low-methodological quality) included the same seven RCT; however, in common comparisons on clinical response and remission at 24 h, 72 h, and 1 week as well as BPRS score and CADSS score, they did not use the same RCT or considered different sample sizes. Other than that, they performed other comparisons that did not overlap, either by outcome, time measured, or subgroup analyses. Moreover, McCloud et al. [19] (low-methodological quality) and Fornaro et al. [23] (critically low-methodological quality) included the same two RCT, performed meta-analyses for response rate at 24 h and drop-out rate with both RCT, and used the same statistical model for meta-analyses (random effects model); however, the number of events they reported for the outcomes was different and, therefore, they showed slightly distinct results. In both cases, it was not possible to identify whether there was an error in data extraction by the review authors or whether data were extracted from different sources for the same primary study (e.g., different reports, unpublished data). There was no overlap of RCT across the systematic reviews that evaluated esketamine (Appendix 5).

Discussion

Main findings

To the best of our knowledge, this is the first overview of systematic reviews with meta-analyses evaluating efficacy and safety of ketamine and esketamine in adult patients with depression. Ketamine showed a significantly greater clinical response compared to control in most results between 24 h and 1 week post-intervention, except for very low doses for patients with major depression disorder at 24 h and 72 h, for patients with bipolar disorder at 72 h and 1 week, and for oral ketamine. Esketamine was statistically superior compared to placebo in the clinical response at all results evaluated between 2 h and 4 weeks.

For clinical remission, ketamine was significantly superior compared to control in most results between 80 min and 72 h post-intervention. The findings were inconsistent from 1 week after the intervention and not significant for oral ketamine. In addition, esketamine showed significant beneficial effects compared to placebo in the clinical remission at all results evaluated between 2 h and 4 weeks. When compared to control, ketamine showed significant reduction on scores of BPRS, CADSS, MADRS until 72 h, and in most results between at 24 h and 3 weeks post-intervention for the HAM-D/HDRS and MADRS depression scales. Esketamine was significantly better than placebo to improve the PHQ-9 score.

A recent systematic review with network meta-analysis compared the efficacy of 21 antidepressants for the acute treatment of adults with major depressive disorder [28]. The analyses were performed about 8 weeks post-intervention and the pooled effect size for clinical response, and clinical remission for antidepressants was frequently smaller than reported by the systematic reviews on the efficacy of ketamine and esketamine included in this overview. Therefore, ketamine and its isomer produce a rapid, powerful, and persistent action in adult patients with depression. Despite ketamine and esketamine presenting a faster onset of action and more likely to sustain it having clear therapeutic advantages [11, 29, 30], it is important to note that little is known about their long-term efficacy.

The effects of ketamine and esketamine on suicidal ideation were apparent up to 72 h post-intervention, but not at longer time points compared to control. According to the recent literature, there is no scientific evidence to support the use of suicide risk assessment tools to predict suicidal acts. However, they can complement the clinical assessment and be the starting point of the suicide prevention process [31]. Considering that patients using antidepressants have a higher risk of suicide in the first week of treatment compared to subsequent weeks, the use of medications with antidepressant effects within hours or a few days might have a positive impact on the patient's prognosis [32, 33].

Finally, only two systematic reviews with meta-analysis reported adverse events. Compared to control, the use of oral ketamine did not cause more adverse events, while intranasal esketamine showed significantly more dropouts due to adverse events and any events, such as dissociative disorder, dizziness, oral hypoesthesia, and vertigo. The main justification for not pooling data on ketamine used in different routes of administration is that many RCTs did not present data on adverse events; then, acute (up to 2 weeks) and long-term adverse events are lacking. In the absence of data, it would be imprudent to assume that there are no serious safety concerns [12]. Even because a systematic review (including different types of study designs) showed a qualitative summary of the adverse events from the use of ketamine. According to Short et al. (2018), acute adverse events associated with ketamine are common and include mainly psychiatric, psychotomimetic, cardiovascular, and neurological changes. Moreover, these authors suggest a selective reporting bias with limited assessment of long-term safety [34].

Methodological quality of systematic reviews

All systematic reviews included in this overview were classified as “low quality” or “critically low quality” according to the AMSTAR-2 critical appraisal criteria. This result is consistent with overviews that also used the AMSTAR-2 instrument to assess the methodological quality of systematic reviews on various treatments for depression [35, 36].

About the items of the AMSTAR-2 tool, all reviews did not report on the sources of funding for the studies included in their study (item 10). This finding is very worrying, since studies that receive industry funding can favor sponsored products, and they are less likely to be published compared to financially independent studies [37,38,39]. The failure to evaluate this item seems to be common in systematic reviews on treatments for mental disorders [35, 36, 40, 41].

In this overview, no systematic review assessed how their results varied in relation to the inclusion or exclusion of individual studies with a high risk of bias (item 12). A justification of the authors of the reviews was the small number of RCTs included in the combined effect estimates that made this analysis unfeasible. Non-adherence to this item was less frequent in the literature on systematic reviews of treatments for mental disorders [35, 36, 41].

The development of a research protocol prior to conducting a review is considered a critical item by the AMSTAR-2 (item 2). Nevertheless, only a few reviews have fully adhered to this item, which is like the findings of other overviews on treatments for mental disorders [35, 36, 40, 41]. Adherence to a well-developed protocol promotes transparency of the review process and can help avoid the biased post hoc decisions, for example selective outcome reporting [42].

Opportunities for future research

This overview revealed that there is room for improvement in the future studies. Though the number of RCT evaluating ketamine and its esketamine isomer in depression has grown in recent years, the evidence summarized is from 20 RCTs including ketamine (Appendix 4) and four RCTs including esketamine (Appendix 5). From that, it was noted that more evidence is needed on the effects of these drugs on a treatment period longer than 2–4 weeks (i.e., able to elucidate long-term efficacy and safety), head-to-head trials (directly comparing ketamine and esketamine or using active-control with antidepressant drugs), and also on the use of different doses and routes of administration of both drugs (ketamine was frequently administered by intravenous route and esketamine by intranasal route).

In addition, future systematic reviews with meta-analyses on this theme should be appropriately designed and conducted, primarily in reporting an explicit statement that the methods were established prior to conducting the review and justifying any significant deviations from the protocol, reporting on the sources of funding for the RCT included in the systematic review, assessing the potential impact of risk of bias in RCT on the results of the meta-analysis; accounting for risk of bias in RCT when interpreting/discussing the results of the review, and conducting an adequate investigation of publication bias and discuss its likely impact on the results of the review.

Strengths and limitations of the overview

To our knowledge, this is the first overview to summarize evidence on the use of ketamine and esketamine in adult patients with depression. In addition, the study assessed the methodological quality of systematic reviews using the validated AMSTAR-2 tool. However, this study also presents some limitations. Only systematic reviews with meta-analysis were included in this overview. Reviews including simultaneous use of ECT and ketamine or esketamine were excluded, and this may have excluded important reviews on the theme and decreased the number of reviews to compose the new evidence generated from this overview. We did not conduct searches for unpublished reviews from thesis repositories and conference proceedings, or ongoing reviews. In addition, the quality of evidence for the outcomes was extracted based on the assessment of this parameter by the review authors, and not all reviews performed this analysis. Finally, we do not provide the prediction interval, which would be helpful to assess whether the between-study variation was clinically significant.

Conclusion

The findings of this overview showed a significant superiority of ketamine and esketamine in most results for clinical response, clinical remission, depression scales scores, and suicidal ideation compared to control. No systematic review performed a meta-analysis for adverse events of ketamine (except for oral ketamine and esketamine). It is very important to note that the data came from the first 2 weeks of treatment with ketamine and 4 weeks for esketamine, and the long-term efficacy and safety are lacking. In addition, most reviews showed a critically low methodological quality, which limits the reliability of the evidence. Thus, it is necessary to carry out more primary studies, and future systematic reviews should follow the quality assessment tools so that best evidence can be used in the decision-making for the use of ketamine and its isomer in adult patients with depression.