Major depressive disorder (MDD) is highly prevalent and affects more than 264 million individuals, globally. Remarkably, despite treatment, up to half of the patients with depression fail to reach remission and are at risk of experiencing treatment-resistant depression (TRD). The diagnosis and treatment of TRD can often be challenging due to co-existence of other mental disorder and increased treatment resistance. Traditionally, TRD patients non-responsive to pharmacotherapy had been treated with the electroconvulsive therapy (ECT). However, recent studies have highlighted a potential role of ketamine, and esketamine as a potential treatment for patients with TRD. Therefore, we have invited Dr. Marco Marchionni, from the NHS to discuss the change in TRD treatment paradigm. 

Depression: The New Invisible Plague
MDD is highly prevalent and associated with substantial burden and economic costs. Notably, more than 264 million adults live with depression, globally and nearly half of all cases are from the Asia-Pacific region¹. Interestingly, the World Health Organisation (WHO) has suggested MDD as the single largest contributor for loss of healthy life². Furthermore, despite available treatment, up to half of the patients with depression fail to reach remission, as a result their risk of experiencing TRD increase¹. What is TRD? Dr. Marchionni explained that TRD is defined as a lack of clinically meaningful improvement after treatment with at least 2 different antidepressants at adequate dosage and duration in the current depressive episode. Approximately, 30% of MDD patients suffers from TRD and even patients without TRD that initially responded to antidepressants may experience worsening of symptoms since the time required to reach the full effectiveness of an antidepressant is around 4-7 weeks³. 

Hence, patient suffering from TRD often have a higher healthcare utilisation and the need for a higher intensity treatment. In addition, the higher indirect costs reported in TRD patients is a consequence of relatively greater impairment in physiological, higher workplace disability and absenteeism. Dr. Marchionni emphasised that patients with TRD also have a disproportionately higher rates of suicide compared to the general population. In fact, studies have consistently found that patients with TRD have 29%-39% higher risk of all-cause mortality compared with those without TRD. These are further plagued by co-existence of other mental health problems in these patients since 45%-67% of patients with depression also have comorbid psychosis or anxiety disorder; thereby, predisposing them to lower remission rates. Thus, the unmet treatment needs persist in TRD patients and a novel therapeutic approach is urgently required to provide rapid symptomatic relief and support for these patients².  
 

Dampening the Siege of TRD

TRD is often difficult to diagnose due to pseudo-resistance. What is pseudo-resistance? Dr. Marchionni stressed that pseudo-resistance is when patients with depression are prescribed with suboptimal doses of an antidepressant or had early discontinuation of a medication due to intolerable side effects, patient non-adherence, or under-dosing. Furthermore, the clinical picture can be complicated further by co-existence of other mental health disorders⁴. Are there any diagnostic tools that may help when diagnosing patients with TRD? Yes, there are, as per Dr. Marchionni as he explained that prospectively using objective clinical scales such as the Hamilton Depression Rating Scale (HDRS) and the Inventory of Depressive Symptomatology is often helpful. Other tools such as the Antidepressant Treatment History Form-short form (ATHF-SF) can be useful in delineating the nature and course of treatment resistance⁴. Considering the complexity of the condition, how are TRD patients treated? Patients with TRD have traditionally been treated with augmentation or adjunctive therapies which includes the addition of a second medication not usually considered as an antidepressant on its own, to a first-line treatment⁴. 

If these are ineffective, then brain stimulation therapies such as ECT is used, according to Dr. Marchionni⁴. Recently, refinement in ECT has been made in this area to enable this procedure to be more commonly performed as an outpatient procedure⁵. What is ECT and how does it work? ECT deliver as series of high frequency electrical pulses to to the non-dominant right or left hemisphere. Thus, repetitive electrical stimulation over the cortex results in an entrainment of pyramidal cell firing with subsequent generalisation of cortical activity and production of a generalised tonic-clonic seizure, which is usually self-limiting within 30-60 seconds⁴. However, he argued that ECT remains underutilised due to its limited availability, social stigma, and concerns regarding the adverse effect on the cognitive function⁵. Other upcoming treatment modalities for TRD includes the use of repetitive transcranial magnetic stimulation (rTMS) which has shown to be effective in TRD patients since focused pulses of an electromagnetic coil are continuously discharged over the scalp to stimulate the cortical neurons and alter neural excitability without causing seizures^4,6. Regarding the efficacy of rTMS in patients with TRD, Dr. Marchionni shared a study by Holtzheimer et al., (2010) that evaluated the advantage of rTMS in TRD patients. 14 TRD patients with a median age of 51 years were included in the study. Among these, 1 was diagnosed with bipolar 2 disorder. The results highlighted the effectiveness of TMS since it significantly reduced the symptoms of deperssion and anxiety. More importantly, the improvement persisted for 3-6 weeks post-treatment; however, 1 patient experienced serious adverse event (increased suicidal ideation), and 2 patients failed to complete the full course of treatment⁷. Despite the positive findings reported by this study, a more recent meta-analysis by Yu et al., (2024) concluded that a higher doses of rTMS is not necessarily better in treating patients with TRD, compared to an intermediate or lower dose of rTMS. Here, Dr. Marchionni suggested that a precise dose-response relationship requires further evaluation to determine the effective dose of rTMS in patients with TRD⁸.  

Ketamine Saves the Day!
Over the last two decades, ketamine has emerged as a promising treatment for TRD⁹ since ketamine affects multiple neurotransmitters and their receptors, particularly the N-methyl-D-aspartate (NMDA) receptors. Nonetheless, the precise mechanism of ketamine’s antidepressant activity remains elusive¹⁰, but the antidepressant activity of ketamine may possibly be related to several of its metabolites (norketamine and hydronorketamines)¹¹. So what does this means? Dr. Marchionni shared his view on this and explained that ketamine seems to be an attractive alternative for patients with depression because it is generally easier to administer compared to ECT and is not associated with significant retrograde amnesia. However, he reminded us that ketamine is a schedule III medication with a potential for abuse, this may limit its applicability in clinical practice5. But how effective is ketamine when compared to ECT for TRD? An open-label, randomised noninferiority trial by Anand et al., (2023) compared the effectiveness of the ketamine with that of ECT in patients with TRD. 

365 patients were randomised to receive either ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week (n=195) or ECT three times per week (n=170). The primary outcome was a response to treatment (decrease of ≥50% from baseline score on the 16-item Quick Inventory of Depressive Symptomatology-self-report). The secondary outcome included scores on memory test and patient-reported quality of life5. Remarkably, the results revealed a total of 55.4% of patients in the ketamine group and only 41.2% in the ECT group had a treatment response (difference of 14.2 percentage points; 95% confidence interval [CI], 3.0 to 24.2; p<0.001 for the noninferiority of ketamine to ECT) (Figure 1).

Figure 1. Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16) between ketamine and ECT groups⁵. 

Even more importantly, ECT was reported to be associated with a decrease in memory recall after 3 weeks of treatment with gradual recovery during follow-up. The study concluded that ketamine was noninferior to ECT as therapy for TRD without psychosis⁵. Dr. Marchionni reiterated that even though these findings are promising, questions still remains whether ketamine is effective in different population group (older adults vs adolescents), effective administration routes (intravenous vs tablet), and the precise dosage required (high vs low) for therapeutic effects.
 

From Chaos to Calm with Esketamine
TRD is a challenging since individuals with TRD often experience prolonged depressive episodes, which can lead to treatment discontinuation prior to reaching recovery, according to Dr. Marchionni. As a result, they may find it difficult to socialise and seek employment¹²; therefore, effective and specific treatments for TRD is urgently required. Esketamine (ESK), which is a non-competitive NMDA receptor antagonist may help fulfil the unmet treatment needs in TRD since several real-world studies have demonstrated the benefit of ESK treatment in adult patients with TRD¹². Dr. Marchionni shared the findings from a phase 2, double-blind, doubly randomised, delayed-start, placebo-controlled study that  evaluated the efficacy, safety, and dose-response of intranasal ESK in patients with TRD. Notably, the study consisted of 4 phases (screening, double-blind treatment [days 1-15], optional open-label treatment [days 15-74], and post-treatment follow-up [8 weeks]. Moreover, during period 1, participants were randomised (3:1:1:1) to placebo (n=33), ESK 28 mg (n=11), 56 mg (n=11), or 84 mg (n=12) twice weekly¹³. 

Subsequently in period 2, 28 placebo-treated participants with moderate-to-severe symptoms were re-randomised (1:1:1:1) to 1 of the 4 treatment arms and those with mild symptoms continued to receive placebo. Interestingly, all participants continued their antidepressant throughout the study period. The primary efficacy endpoint was the change from baseline to day 8 (each period) in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Among 67 participants, the change in MARDS total score (both periods combined) in all 3 ESK groups was superior to placebo (p<0.001), with a significant ascending dose-response relationship (p<0.001) (Figure 2).

Figure 2. Mean Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score Over Time in Double-Blind Phase. Changes shown in periods 1 (A) and 2 (B). Period 2 consisted only of participants who had received placebo in period 1 and had moderate to severe symptoms (n = 28). Period 1 (days 1-8) and period 2 (days 8-15) are discussed in the Design section of the Methods and shown in the vertical axis of Figure 1. BL indicates baseline; 2H, 2 hours post dose. Error bars indicate standard error (SE)¹³.

The findings from this study suggests that intranasal ESK provides a rapid onset symptomatic relief, and the response persists for more than 2 months with a lower dosing frequency¹³. Similarly, findings from the phase 3, open-label study (SUSTAIN-2), demonstrated ESK nasal spray added to oral antidepressant therapy improved the depression in TRD patients¹⁴. Considering guideline-supported antipsychotic augmentation agents are often used in TRD patients, is ESK suitable for augmentation compared to these agents? An open-label, single-blinded, multicenter, phase 3b, randomised, active controlled trial evaluated the efficacy and safety of ESK nasal spray with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) in patients with TRD¹⁵.  
 

The primary endpoint was remission, defined as a score of 10 or less on the MADRS, at week 8 (scores ranging from 0-60, with higher scores indicative of more severe depression)¹⁵. The key secondary endpoint was no relapse through week 32 after remission at week 8. Analysis of the primary and secondary endpoints were adjusted for age and number of treatment failure. 336 patients were randomised to ESK and 340 to quetiapine. Astonishingly, more patients on ESK had remission as early as week 8 (27.1%) compared to those on quetiapine (17.6%), (p=0.003) (Figure 3).

Figure 3. Primary and Key Secondary End Points. Panel A shows the percentage of patients with remission (primary endpoint) in the two trial groups; the esketamine group and the quetiapine group. Remission was defined as a score of 10 of less on the Montgomery–Åsberg Depression Rating Scale (MADRS; scores range from 0 to 60, with higher scores indicating more severe depression) and no treatment or study discontinuation before week 8. Panel B shows the comparison of the two trial groups with respect to freedom from relapse through week 32 after having remission at week 8, without treatment or study discontinuation (key secondary endpoint),, as well as the number of patients who had a relapse and the number of patients who remained free from relapse through week 32 after having remission at week 8 but who discontinued treatment. CI = confidence interval¹⁵.

More importantly, these patients had no relapse through week 32 after remission at week 8 (21.7% ESK group vs 14.1% quetiapine group). These findings suggest that patients with TRD treated with ESK intranasal spray plus an SSRI or SNRI have better remission rate (as early as 8 weeks) compared to extended-release quetiapine plus an SSRI or SNRI¹⁵. In conclusion, Dr. Marchionni suggested that ESK is a stepping stone toward controlling symptoms of TRD, however, clinicians are strongly encouraged to identify MDD patients at risk of developing TRD early so they can be referred to specialist for further evaluation. 

References
1. Chan VKY, et al. The Lancet Regional Health - Western Pacific 2022; 22: 100426.  2. McIntyre RS, et al. World Psychiatry 2023; 22(3): 394-412.  3. Chen X, et al. Neuropsychiatr Dis Treat 2023; 19: 693-707.  4. Voineskos D, et al. Neuropsychiatr Dis Treat 2020; 16: 221-34.  5. Anand A, et al. N Engl J Med 2023; 388(25): 2315-25.  6. Adu MK, et al. Behav Sci (Basel) 2022; 12(6).  7. Holtzheimer PE, et al. Depress Anxiety 2010; 27(10): 960-3.  8. Yu CL, et al. Asian J Psychiatr 2024; 92: 103891.  9. Vestring S, et al. Journal of Affective Disorders 2024; 350: 895-9.  10. Yavi M, et al. Discov Ment Health 2022; 2(1): 9.  11. Glue P, et al. Nature Medicine 2024.  12. Castro M, et al. CNS Drugs 2023; 37(8): 715-23.  13. Daly EJ, et al. JAMA Psychiatry 2018; 75(2): 139-48.  14. Wajs E, et al. J Clin Psychiatry 2020; 81(3).  15. Reif A, et al. N Engl J Med 2023; 389(14): 1298-309.

Answers for CME quiz of Focus of Issue 24: 1.A, 2.C, 3.C, 4.B, 5.A