By Dr Mathew Samuel, Psychiatrist Nedlands
Depression, specifically major depressive disorder (MDD), is a widespread mental health condition that affects hundreds of millions globally.
In Australia, over 1.3 million individuals – 5.9% of the population – are affected.
MDD is characterised by a persistent low mood and loss of interest or pleasure in most activities, accompanied by a range of somatic and cognitive symptoms.
These can include sleep disturbances (insomnia or hypersomnia), changes in appetite or weight, fatigue, poor concentration, psychomotor changes, feelings of worthlessness or excessive guilt, and recurrent thoughts of death or suicide. The impact of these symptoms often extends to daily functioning, relationships, and overall quality of life.
Treatment for MDD can be challenging with many not responding to initial therapies. Remission rates decrease with each successive treatment attempt (31% after a second treatment to 13% after a fourth).
Delays in finding effective treatment can prolong suffering and increase the risk of suicide – people with MDD have a suicide risk up to 20 times higher than the general population.
Early identification of inadequate treatment response and timely adjustments in therapy are crucial to improving outcomes.
Around one third of those with MDD develop treatment-resistant depression (TRD), defined as depression that does not improve after at least two adequate trials of antidepressants.
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It is associated with a longer duration of depressive episodes, greater functional impairment, higher rates of comorbid conditions, and a substantially increased risk of suicide attempts. This underscores the urgent need for more effective therapeutic strategies for TRD.
Esketamine for treatment-resistant depression
Esketamine nasal spray has emerged as a novel third-line treatment for adults with TRD. Esketamine acts as a glutamate receptor modulator, with evidence suggesting it may help restore synaptic connections in the brain affected by depression.
Multiple randomised clinical trials have demonstrated its efficacy and tolerability when used in conjunction with a newly initiated oral antidepressant. Esketamine has been approved by regulatory authorities in Australia and New Zealand for use in individuals with TRD, offering hope for those who have not benefited from traditional antidepressant therapies. It was made available on the PBS from 1 May.
Esketamine, the S-enantiomer of racemic ketamine, is an antidepressant with a novel mechanism of action. It is a non-selective, non-competitive, antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor.
Putative aetiological contributors of depression, including stress and other conditions, are known to cause structural and functional impairment of synapses in brain regions involved with the regulation of mood and emotional behaviour.
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Evidence within the literature suggests that through NMDA receptor antagonism, esketamine produces a transient increase in glutamate release leading to increases in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) stimulation and subsequently to increases in neurotrophic signalling that restore synaptic function in these brain regions.
Administering esketamine
Esketamine comes as a single-use device delivering a total of 28mg in two actuations – one actuation per nostril. To prevent loss of medication, the device should not be primed before use.
Administration is by the patient under the supervision of a psychiatrist, using one device for a 28mg dose, two devices for a 56mg dose, or three devices for a 84mg dose, with a five-minute rest between use of each device. This is followed by post administration observation under the supervision of a psychiatrist.
During and after administration at each treatment session, patients should be monitored until the patient is stable based on clinical judgment.
Before administration, patients’ blood pressure should be assessed and patients instructed not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery until the next day after a restful sleep.
After administration blood pressure should be reassessed at approximately 40 minutes and subsequently as clinically warranted. Due to the possibility of sedation, dissociation and elevated blood pressure, patients must be monitored by a healthcare professional until the patient is considered clinically stable and ready to leave the healthcare setting.
Since some patients may experience nausea and vomiting, advise not to eat for at least two hours before administration and not to drink liquids at least 30 minutes prior to administration.
Key messages
- MDD is a prevalent and disabling condition with a substantial proportion of patients experiencing inadequate response to standard treatments
- TRD represents a particularly severe and burdensome form of depression
- Innovative treatments such as esketamine nasal spray can improve patient outcomes and quality of life.
Author competing interests – the author was a member of the Janssen-Cilag Advisory panel.
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