Depression is a common mental disorder that affects more than 264 million people worldwide, irrespective of age (1). Clinically effective first-line treatments include pharmacotherapy and psychotherapy. However, ~30% of depression patients remain non-responsive to antidepressant medications and are suffering from treatment resistant depression (TRD) (2, 3). Conventionally, TRD is diagnosed when a patient is not experiencing any significant clinical improvement from at least two different methods of antidepressants (4). TRD patients are therefore in need of new (non)pharmacological treatment alternatives.

In recent years, there has been a considerable interest in the use of ketamine as an antidepressant in humans. Ketamine is a racemic mixture of two enantiomers, S-ketamine (esketamine) and R-ketamine and the antidepressant properties of N-methyl d-aspartate (NMDA) receptor antagonists have received much attention in experimental animal studies several years ago (5, 6). In patients suffering from TRD, the antidepressant effect of ketamine can be observed within a few hours following a single subanesthetic intravenous infusion (7). As reported by a two-site randomized controlled trial, a single infusion of ketamine was associated with greater improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, compared to an active placebo control condition (anesthetic midazolam), 24 h after treatment (7). The administration of ketamine was not only found to be effective for treating depression, but also in bipolar disorder, as well as in suicidal ideation (8, 9). Furthermore, repeated administration of ketamine may be associated with rapid, longer-term and sustained antidepressant effects (10, 11). According to a recent article by Kim and colleagues (10), methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) plays a crucial role in the sustained antidepressant effects of ketamine in mice. The authors also found that repeated ketamine administration induces processes of metaplasticity through post-synaptic functional changes. This may explain why repeated intake of ketamine doses produce sustained effects (10).

As a drug with brief euphoric effects that may last from 1 to 2 h, ketamine must be administrated under controlled settings (12). The most common adverse effects of ketamine administration are dizziness, drowsiness, poor coordination, blurring of vision, feeling strange, light-headedness, headache and nausea (13).

Ketamine is associated with a robust increase in glutamate and dopamine release in the prefrontal cortex as well as with improvement in neuroplasticity within the hippocampus. Both these brain regions play a crucial role in the pathophysiology of depression (14). The first randomized clinical trial (RCT) that aimed to assess the effectiveness of a single dose of an NMDA receptor antagonist in depressed patients showed a robust significant improvement in depressive symptoms within 3 days post ketamine (15). A recent review and meta-analysis highlighted the effectiveness of a single ketamine (0.5 mg/kg) infusion in reducing depression scores in TRD participants (5). The impact of ketamine was found to be rapid, as the antidepressant effect was observed 4 h post-infusion. However, a subsequent reduction of this antidepressant effect of ketamine appeared 7 days post-infusion, so its effectiveness seems to be short-term (5). In line with this, also other studies documented that the antidepressant effect of a single dose of ketamine typically vanishes after ca 7 days (7, 12).

Ketamine can be delivered in several manners such as via intravenous (IV), intranasal, oral, sublingual, subcutaneous and intramuscular (IM) routes (13). Only very few studies are available that investigated the potential use of IM ketamine delivery in the treatment of depression (16–18). A recent study aimed to compare the safety, tolerability, and efficacy of IM and IV ketamine delivery in treating major depression, showing that a small dose of IM ketamine (0.25 mg/kg) is as effective and safe as a larger dose (0.5 mg/kg). No statistically significant differences were found between IM and IV groups. Reduction of HAM-A scores have been reported 2 h post ketamine in all groups and sustained for the following 3 days. The adverse effects were mild and subsided within an hour post ketamine (19). Furthermore, 6 IV ketamine infusions over a 12-day period were associated with a large, sustained effect as the median time to relapse was 18 days (11).

The United States Food and Drug Administration (FDA) approved ketamine (ketalar) for human use for the first time in 1970 and more recently, in 2019, approved esketamine as an intranasal spray for the treatment of TRD in adults who have failed to receive sufficient improvements from other antidepressant medicines (20). However, the intranasal application of ketamine might not be the best treatment for TRD patients. According to a recent systematic review and meta-analysis, esketamine was found to be less effective, compared to racemic IV ketamine, in treating depression (21). IV and IM administrations of ketamine were also found to be 100 and 93% bioavailable, respectively, in contrast to other routes of administration such as intranasal, which is only 8–45% bioavailable (22). Medications with higher bioavailability could potentially be more effective. Furthermore, treatment using intranasal esketamine spray is more expensive compared to treatment using IV or IM ketamine. Ketamine can be safely given through the IM route and has an easier access of administration than then IV route. In the present study, we therefor applied IM ketamine.

Another, fundamentally different treatment alternative for TRD that has received much attention in the literature is transcranial magnetic stimulation (TMS). TMS is a non-invasive brain stimulation method using the repetitive administration of electromagnetic pulses to targeted regions in the brain to modulate neural activity (23). Repetitive TMS (rTMS) has been shown to lead to longer lasting neuroplastic changes with beneficial clinical effects across various neuropsychiatric disorders (24, 25). rTMS is by now a clinically proven effective, widely recognized, approved and well-tolerated depression therapy in TRD patients (26–28).

The dorsolateral prefrontal cortex (DLPFC) is the most prominent and commonly used target area in rTMS treatment of depression (29–32). TMS over the left DLPFC for several weeks has been shown to be a safe and effective treatment for TRD (28), including often reported beneficial effects on psychomotor speed and cognitive control (33). Furthermore, TMS over the left DLPFC is associated with improvements of suicidal ideation in adolescents with depression (34). One of the largest studies testing the effectiveness of rTMS in depression, the THREE-D study, documented clinically meaningful improvements in patient-reported outcomes (PROs), including quality-of-life (QOL), and disability post rTMS treatment (35).

When targeting the DLPFC with TMS, different repetitive or patterned stimulation protocols can be applied. In addition to the standard high frequency 10 Hz rTMS protocol administering 3,000 pulses in one of the in total 20–30 treatment sessions each lasting for ca 38 min (36), theta-burst stimulation (TBS) has more recently gained in popularity due to its much shorter treatment session duration. TBS mimics endogenous theta rhythms and has the ability to induce long-lasting effects on cortical excitability (37, 38). Intermittent TBS (iTBS) is one of the main patterns of TBS that have been developed, which increases cortical excitability (39), similar to high frequency 10 Hz rTMS but in a much shorter time frame. According to a recent systematic review and meta-analysis, TBS over DLPFC is well-tolerated and has significant antidepressant effects (40). A double-blind sham-controlled study of Li and colleagues among 60 treatment-refractory patients showed that iTBS is a safe, well-tolerated, and effective treatment for TRD (38). A large non-inferiority trial further indicated that iTBS has the same level of clinical efficacy as standard high frequency 10 Hz rTMS, thus offering a potentially much shorter and therefore cost-effective rTMS protocol alternative for TRD (41). In 2018, based on this study, FDA cleared the iTBS protocol for the treatment of MDD, in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication.

A few case reports and a long-term retrospective review reported that the combination of ketamine and rTMS may be an effective long-term therapy for patients with depression (42–44). To the best of our knowledge, there is no study comparing the effectiveness of ketamine and rTMS in patients with depression in a naturalistic setting. Only a limited number of alternative non-pharmacological treatments for TRD are available today and more research is needed to directly compare a non-pharmacological treatment with a pharmacological treatment in terms of their efficacy and tolerability. In this study, we exploratively describe and compare the acute antidepressive efficacy of both, 8 sessions of intramuscular ketamine administered twice weekly for 4 weeks, as well as 30 sessions of left DLPFC-iTBS (over a period of 6 weeks) in depression patients seeking help in a naturalistic clinical mental health setting. While the iTBS protocol is FDA approved and by now a widely used method for the treatment of TRD in clinical practice, the potential use of IM ketamine in TRD has not been extensively researched and therefore is not widely used. This comparative study is important in order to point out that more research need to be done in this area and in order IM ketamine to be considered for FDA approval for TRD. Thus, the present study aimed to indicate for first time the potential of IM ketamine to reach similar effects in TRD as rTMS in shorter duration (less visits).

To our knowledge, this is the first study describing the effectiveness of both, ketamine treatment and rTMS treatment, in depressive and anxiety symptoms of MDD patients in a naturalistic real-life setting. Patients in the rTMS treatment group received 30 iTBS sessions over a period of 6 weeks, whereas patients in the Ketamine treatment group received 8 IM injections over a period of 4 weeks. Using three clinical assessments (HDRS, HAM-A, BDI-II), our data reveals that both therapies led to significant improvement in symptoms from pre- to post- treatment. Based on the HDRS, in the Ketamine group, 33.3% were responders and 66.7% were remitters and in rTMS group, 25% were responders and 66.7% were remitters. Based on HAM-A, in both experimental groups, 25% were responders and 75% were remitters. Finally, based on BDI-II, in Ketamine group, 25% were responders and 58.3% were remitters and in rTMS group 8.3% were responders and 75% were remitters. An explorative post-hoc direct statistical comparison indicated that ketamine therapy did not differ significantly from rTMS therapy with respect to pre- to post- depressive and anxiety symptoms, indicating that the effect of both experimental groups in our sample was equally effective. In line with this notion, statistical χ² tests showed that there were no statistical differences between the patients of ketamine group and rTMS group in remission and response rates. These results indicated that IM ketamine therapy has the potential to reach similar effects in patients with TRD as rTMS therapy in a shorter treatment period as less visits are needed to complete the treatment. No significant side effects were reported from either the rTMS group or the ketamine group.

The results support the preliminary effectiveness of the treatments and adds to the existing literature regarding the efficacy of both treatment options in depression. Regarding TMS, a prior study by O'Reardon et al. (36), found that TMS was effective in treating MDD with minimal side effects. Furthermore, iTBS protocol, has proven to be an effective, safe and well-tolerated treatment for depression (38, 40, 41). Although there are many studies regarding the efficacy of ketamine in depression (5, 7, 11), the research in IM ketamine remains limited. There are only a few case reports that demonstrated the potential effectiveness of IM ketamine in depression, therefore the optimal use of IM ketamine warrants further investigation. A report on two cases with acute depression has shown that IM ketamine injection bring rapid relief from depressive symptoms and especially in the suicidal ideation (17). Another case report demonstrated that IM ketamine is a potential treatment for treatment-resistant bipolar depression (16). IM ketamine injection was also used in a female patient with metastatic ovarian cancer. The treatment was well-tolerated and after 6 sessions the patient achieved remission of her depressive symptoms (18).

Previous studies investigated the potential efficacy of combining ketamine and rTMS therapy in depression and bipolar disorder. However, to our knowledge, only a few case reports and a long-term retrospective review were reported so far. It is important to note that, a case report by Best and Grifflin, indicated that the combination therapy of ketamine and rTMS may be a more effective treatment for refractory depression, than either ketamine or rTMS alone (43). Furthermore, a recent long-term retrospective review demonstrated statistically significant reduction of depressive symptoms, after the combination therapy showing clear indication of the effectiveness of the treatment for refractory depression (44). Their review also found that this reduction in depressive symptoms could be sustained for a period of 2 years (44). Finally, according to some case reports, the combination therapy can be effective in treating severe depression in bipolar I disorder (42) and in bipolar II disorder (53).

Whereas previous research suggests that a combined treatment by ketamine and rTMS is an effective and long-term treatment for depression, the present comparative study represents a first attempt to describe and exploratively compare both treatment options as standalone therapies in a naturalistic setting. It is important to consider the limitations of our conclusions here. The current study is a retrospective comparative study with no a priori randomization and a very limited number of patients. Small sample sizes usually undermine the internal and external validity of a study and affect the generalizability of the results (54, 55). Especially for statistically comparing the effectiveness of two treatment options (clinical inferiority trial), a much larger same size would be needed. Another main limitation is the retrospective design of the study. Specifically, this study was based on data of patients with MDD, who were referred to the Cyprus rTMS Center in the past and received either intramuscular ketamine or rTMS as treatment for depression. Therefore, the patients were not randomly divided into these two experimental groups and no sham control groups were used. Finally, this study suffers from sample selection bias. A larger number of patients was treated with either IM ketamine or rTMS in the Cyprus rTMS center during that period, but we chose to include only patients who completed the total number of sessions required (rTMS: 30 sessions; Ketamine: 8 sessions) and patients with completed clinical evaluations prior and post treatment in our analysis. Unfortunately, we did not collect information about the number of patients with incomplete clinical evaluations prior or post treatment and the number of patients who terminated treatment prematurely. Thus, we selected only completers from a larger sample of patients of unknown size. Despite these limitations, this study could serve as a starting point for identifying and comparing the efficacy of these two depression treatments in a real life clinical setting.

Future research should further develop and confirm these initial findings by comparing the efficacy of ketamine treatment, rTMS treatment and the combination treatment in depression using a randomized, double-blind, sham-controlled clinical trial sufficiently powered to also reveal potential non-inferiority. Furthermore, clinical assessments should be collected weekly in order to investigate whether there are differences in response time between the treatment groups. In a future study, a follow up measurement is needed to examine and compare the long-term efficacy of these treatments. To the best of our knowledge, this comparative study was the first that directly compare the efficacy of rTMS and IM ketamine, a non-pharmacological treatment, and a pharmacological treatment for TRD. Finally, our results showed that the iTBS protocol, which has received FDA approval for MDD, and IM ketamine, which is not an FDA approved treatment for MDD, are equally effective treatments. This is an important finding as IM ketamine treatment is not widely used in clinical practice and can be administrated in a shorter duration compared to rTMS. Further research with more focus on the use of IM ketamine treatment in depression is therefore suggested, which may allow this treatment to gain a formal approval and a wider acceptance in daily practice.

This retrospective study compared the efficiency of IM ketamine administered twice weekly for 8 sessions and 30 sessions of iTBS applied to the left DLPFC in MDD patients. Our results indicated significant pre- to post-treatment reduction in depressive and anxiety symptoms, with no significant differences between the two experimental groups, indicating that the effect of both therapies was equally effective in our limited sample. In line with this notion, response and remission rates were not statistically different between the two treatment groups. This study can be seen as a first step toward enhancing our knowledge regarding the therapeutic efficacy of two alternative depression treatment options such as ketamine therapy and rTMS therapy in a naturalistic real-life setting.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Cyprus National Bioethics Committee. The patients/participants provided their written informed consent to participate in this study.

GM, PM, and LP analyzed data and wrote the manuscript. TS and AS critically reviewed the manuscript and supervised the project. All authors agree with the contents of the manuscript and were fully involved in the study, preparation of the manuscript, have read the final version of the manuscript, and approved the submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.