Open label study with oral esketamine for treatment-resistent depression

Research

Major depressive disorder is one of the leading causes of burden of disease worldwide. Depression is highly prevalent and often shows a chronic or recurrent course. Approximately 20 - 30 % of patients do not achieve remission with regular treatment strategies such as antidepressants and psychotherapy.

In this open label study, we provide off-label treatment with oral esketamine to patients who have exhausted all conventional treatment steps according to the Dutch guideline for treatment of depression, including monoamine oxidase inhibitors and electroconvulsive therapy. Oral administration of esketamine might be less invasive, more patient friendly and potentially less costly than alternatives such as intravenous ketamine or intranasal esketamine.

The oral esketamine is administered twice weekly over the course of six weeks, in a liquid formulation. The treatment is provided in an inpatients or day clinic setting, with nurses providing (emotional) support and monitoring the acute effects of esketamine. After an elaborate evaluation after six weeks, optional maintenance treatment is based on shared decision making between the patient and clinician. Three specialized depression treatment centers offer this oral esketamine treatment protocol; the University Center of Psychiatry in Groningen, Pro Persona in Nijmegen and PsyQ / Parnassia Groep in the Hague. Together they collect data on effectiveness and side effects, to increase knowledge on this innovative treatment option.

Relevance

How our research benefits to society

This study offers patients who are desperately in need of new treatment options, the opportunity to try esketamine as an antidepressant. Through joint data collection in three treatment centers, the effectiveness, side effects and predictive value of different clinical characteristics can be investigated in a relatively large sample. Furthermore, the patients who enter the longer term maintenance phase are monitored until cessation of the esketamine treatment. This allows research regarding longer term side effects on cognition, live rand kidneys or the development of tolerance.

Timeline

Project finished and results published in Molecular Psychiatry (March 2024)

Posted ago
Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension
In this paper, we describe the results of our randomized, placebo-controlled trial with open-label extension. The study consisted of

a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day;

a four-week wash-out phase; and

an optional six-week open-label individually titrated treatment phase during which 72 participants received 0.5 to 3.0 mg/kg oral esketamine two times a week.

We found that:

Fixed low-dose oral esketamine when compared to placebo had no benefit on depressive symptoms.

In addition, except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we neither found a significant difference in safety and tolerability aspects.

During the open-label individually titrated treatment phase, depressive symptoms decreased significantly.

These results suggest that fixed low-dose esketamine is not effective in patients with highly severe treatment-resistant depression. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties, and may be a promising, patient-friendly, and affordable treatment for patients with depression.

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