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Is Ketamine the Future Clozapine for Depression? A Case Series and Literature Review on Maintenance Ketamine in Treatment-resistant Depression With Suicidal Behavior

Chan LF, Eu CL, Soh SY, Maniam T, Shahidii Kadir Z, Chong BTW, et al.

J Psychiatr Pract, 2018 07;24(4):279-291.
PMID: 30427812 DOI: 10.1097/PRA.0000000000000316

Ketamine has shown effectiveness as a rapid-acting antidepressant with antisuicidal effects in terms of reduction of suicidal ideation in the short term. However, the evidence for long-term maintenance ketamine therapy for treatment-resistant depression (TRD) and suicidal behavior is limited. This case series (N=13) highlights the role of adjunctive serial maintenance ketamine infusions in restoring functionality in treatment-resistant unipolar and bipolar (mixed) depression with significant suicide risk and multiple comorbidities, including alcohol dependence. Two cases of TRD achieved functional remission with long-term maintenance ketamine treatment. The first case illustrates the potential synergistic interaction between ketamine and lamotrigine to achieve a sustained antidepressant response in the patient for 7 months. The second case may possibly be the longest reported case of maintenance ketamine therapy, with treatment continuing for 5 years to date. Ketamine treatment showed acute effectiveness in another 7 cases, especially in terms of reduction of suicidal ideation, albeit without significant long-term antidepressant effect. Factors that may contribute to lack of effectiveness of serial ketamine include inadequate mood stabilization in TRD in bipolar spectrum diagnoses, concomitant benzodiazepine use, complex comorbidities, and adverse effects such as significant hypertension and severe dissociation. Future systematic controlled studies are warranted to establish the efficacy and safety profile of long-term ketamine as maintenance therapy for TRD with suicidal behavior.

Matched MeSH terms: Depressive Disorder, Treatment-Resistant/drug therapy*
Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication

Ramli FF, Singh N, Emir UE, Villa LM, Waters S, Harmer CJ, et al.

Transl Psychiatry, 2024 May 07;14(1):200.
PMID: 38714646 DOI: 10.1038/s41398-024-02899-8

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Matched MeSH terms: Depressive Disorder, Treatment-Resistant/drug therapy
Fulltext Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2)

Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al.

J Clin Psychiatry, 2020 04 28;81(3).
PMID: 32316080 DOI: 10.4088/JCP.19m12891

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD).
METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase.
RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).
CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

Matched MeSH terms: Depressive Disorder, Treatment-Resistant/drug therapy*

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