Novel rapidly acting drugs to treat depression and other psychiatric disorders: ketamine and esketamine

By J.E - Newcastle University

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KETAMINE

Ketamine was introduced in 1963 as a dissociative anaesthetic agent. It is a schedule three (III) compound (classified by the Drug Enforcement Administration in the United States) and a class B drug (under the Misuse of Drugs Act in the UK). Rapid and robust antidepressant effects have been seen with ketamine. In the 1990’s a pilot study in severely Difficult-to-Treat Depression (Link to article) patients showed a single sub-anaesthetic dose of ketamine had a robust antidepressant effect within 4 hours of intravenous (IV – injection directly into the vein) administration [1]. Difficult-to-Treat Depression (DTD) - is when a patient fails to respond to 2 or more adequate trials of treatment with antidepressants. An adequate trial is when a patient has been on an adequate dose of medication for a period of at least 4-6 weeks.

Early clinical trials used 0.5mg/kg of ketamine IV infused over 40 mins. Treatment is always carried out in a hospital environment - with a trained anaesthetist present. Antidepressant effects can occur within 2-4 hrs of treatment and are sustained for up to 3-7 days [2]. Repeated IV doses may prolong the treatment response [3]. Up to 6 infusions of repeated ketamine- administered once, twice or three times a week were found to be efficacious in maintaining treatment response [2]. Among responders, the median time to relapse following the last ketamine infusion was 18 days[3]. Murrough [3] studied 24 subjects with Difficult-to-Treat Depression (Link to article on TRDvsDTD). They had a washout of antidepressant medication then up to 6 IV (into a vein) infusions of ketamine at a dose of 0.5mg/kg over a period of 40 mins three times a week over 12 days. The response rate was 71%. Clinical response is defined as a 50% or greater reduction in depression scores on a depression rating scale. 4 of the responders were relapse free at the end of the study (83 days). This suggests there is a subset of patients able to sustain response for several weeks/months after the last ketamine dose.

In a study by Thase, 40-60% of patients showed an antidepressant effect with ketamine which lasted up to 7 days [4]. Most individuals who respond do so with the first 1-4 infusions. It is possible that some non-responders convert to responders if given repeated treatments 1-2 times per week [5]. Some ketamine responders require an indefinite course of maintenance infusions. The optimum dose may differ between individuals. Individual dose titration is best- although this is not routinely carried out in clinical practice [6]. There is no dosing interval that can be universally recommended [5].

The long-term use of ketamine treatment (>2weeks) is not well studied [6]. The limitation of ketamine trials that have so far been conducted and reported in the scientific literature include:

• Short term efficacy of a single infusion
• Short duration of follow up
• Lack of blinding to treatment (patients who take ketamine get acute adverse effects resulting in them being aware that they have had ketamine rather than the placebo treatment)

An additional finding with ketamine is that it may have an effect of reducing suicidality. When patients present to the emergency department in acute suicidal crises- the emergency room dosing of ketamine may help to shorten or avoid hospitalisation. The effects of ketamine infusions on suicidal ideations are as rapid and of comparable magnitude to the effects on mood and core depressive symptoms [7]. Rapid resolution of suicidal ideation was seen after a single infusion of ketamine in patients with Difficult- to -Treat Depression [8, 9] and does not seem to simply be due to an improvement in mood. Some patients have decreased suicidal ideas without significant changes in their mood [10].

Side effects

Mild-moderate transient side effects are seen within the first 2hrs of treatment. Adverse effects usually settle within a few minutes of stopping the infusion and generally are gone within 2hrs [2].

• Transient Euphoria
• Dissociative effects- a distortion of perception of sight and sounds
• Psychotomimetic effects-mimics symptoms of psychosis including delusions +/or delirium
• Cognitive impairment- this is a decline in cognitive abilities, including memory and thinking skills
• Sedation
• High Blood Pressure
• Increase in heart rate
• Lowered mood
• Overly elevated mood
• Drowsiness
• Anxiety
• Dizziness
• Feeling sick (nausea)

Patients can develop a tolerance to the antidepressant effects of ketamine over months of ketamine therapy (it fails to work as effectively). Individuals who abuse ketamine, develop tolerance fairly rapidly and typically escalate the dose taken over a period of sustained use. When misused, the doses taken are usually substantially higher than the doses given to treat depression. Risks of misuse include [4]:

• Persistent cognitive impairment in short and long-term memory
• Potential damage to the brain
• Aseptic/ulcerative cystitis – damage to the bladder.

These effects are hopefully avoided through the careful and controlled use of lower doses of ketamine under medical supervision. There is no evidence of these effects in longer term studies conducted to date.

The optimum route of administration of ketamine is unknown [6], though it is most commonly administered intravenously. The route of administration determines the peak blood levels and how much gets into the body. Ketamine gets into the body best when administered directly into a vein or inhaled through the nose. Much less gets into the body if the drug is swallowed (17-20%) [11].

ESKETAMINE

Esketamine is an isomer of ketamine that blocks N-methyl-D-aspartate (NMDA) receptors and interrupts the association pathways of the brain, resulting in dissociative anaesthesia and analgesia and in the restoration of neural pathways regulating mood and emotional behaviour (NICE). Most recently, the drug company Johnson and Johnson have been developing esketamine for inhalation through the nose.

In March 2019 the US Food and Drug Administration (US-FDA) approved esketamine the first member of a completely new class of antidepressant agents in the management of Difficult -to -Treat Depression [12] (when combined with oral antidepressants). Inhalation of esketamine is now licensed for use across Europe and in the UK. Its rapidity of action is one of its prime advantages, as current therapies have a delayed clinical response- esketamine may be used as a “bridging therapy” whilst oral antidepressants take their effect.

Intranasal esketamine is administered intranasally twice a week for the initial few weeks, followed by once a week or bi-weekly depending on the patient’s response. Kaur [12] Canuso [13]and Daly [14] demonstrated that intranasal esketamine had a clinically meaningful effect compared to a dummy (placebo) treatment. There was a rapid reduction in symptoms of depression and suicidality in patients with Major Depressive Disorder at risk of suicide. Canuso [15] looked at 68 patients randomly assigned to receive intranasal esketamine or a placebo twice a week for 4 weeks. These patients also received oral antidepressants in a comprehensive standard of care treatment plan. Esketamine use resulted in a rapid improvement of depressive symptoms- including some measure of suicidal ideation among depressed patients at imminent risk of suicide. Changes were seen on depression rating scales at 4 hrs and 24 hrs following administration of the intranasal esketamine. A significant reduction in suicidal thoughts were observed in the esketamine group compared to the placebo at 4 hours [15]. Daly (2017)[14] studied patients with Difficult-to-Treat Depression receiving intranasal esketamine twice a week for a period of time. After 1 week there was a significant improvement in depressive symptoms. This improvement appeared to be sustained with a reduced dosing frequency for up to 9 weeks. Patients continued with their existing antidepressant treatment during this study. One study identified a clear improvement in general functioning in adults aged 18-64yrs with Difficult-to-Treat Depression after just 4 weeks of intranasal esketamine[16]. Intranasal esketamine has benefits for comfort, cost, safety, and efficacy compared with intravenous ketamine. The long-term safety evaluation of intranasal esketamine was studied by Wajs[17]. Responders to the drug completed various cognitive assessments over a period of 48 weeks and no impairments were observed.

Intranasal esketamine can cause:

• Dizziness
• Vertigo
• Headache
• Increased Blood Pressure

Hence it must be administered in a healthcare setting and under healthcare supervision for at least 2 hours from administration. Patients should also be advised not to drive for 24hrs.

Like other treatments for Difficult-to-Treat Depression, future importance includes optimising its efficacy, by looking at predictors of response. The potential of esketamine to produce a physical dependence needs to be carefully investigated, using long term withdrawal studies. Long term benefit/risk assessment with monitoring of cognition and behaviour are also required.

Unanswered questions

• What is the optimal dose?
• Frequency of administration to maintain treatment response?
• Effects on cognitive function- positive or negative effects?
• How sustainable are the anti-suicidal properties?

Ketamine and Esketamine: Mechanisms of action [18]

The exact mechanism of action of ketamine and esketamine, or how they treat depression, is not known. However, they have effects on the neurotransmitter glutamate within the brain.

Glutamate has been directly or indirectly implicated to play a role in mood and anxiety disorders. Glutamate receptor systems are complex. One type of glutamate receptor is called N-Methyl-D-Aspartate (NMDA). Ketamine and esketamine block NMDA receptors - it is an “NMDA antagonist”.

NMDA receptors may play a fundamental role in depression, particularly in patients who have not responded to conventional antidepressants [19]. Through its effect on NMDA receptors, ketamine can have multiple effects including:

• Restores decreases in connections between different parts of the brain
• Increases the number of connections between nerve cells
• Increases the chemical messenger dopamine which may help decrease symptoms such as tiredness and increase the ability to experience pleasure
• Increases chemicals that promote brain growth and repair

Predictors of response to ketamine [20]

While still very preliminary and requiring confirmation in further larger studies, a number of factors may predict a good response to ketamine:

• Greater probability of response if there is a family history of alcohol use disorder
• A higher Body Mass Index (BMI) predicts a greater improvement in depressive symptoms
• Improved response if there is no history of suicide attempts
• Greater response in individuals with a family history of childhood trauma [21]

Ketamine and Esketamine: Ethical Issues

There are a number of potential ethical issues around using ketamine clinically to treat depression. Not least of these are concerns regarding drug misuse. This is in part addressed by the use of ketamine in carefully controlled situations. However, the enthusiasm for the use of ketamine as an antidepressant has clearly travelled far ahead of the evidence. There is a genuine need for the treatment of patients with Difficult -to -Treat Depression. However - to date, there is insufficient safety and efficacy data to guide the use of ketamine. The use and dosing is largely based on small scale clinical experience and case studies rather than large clinical trials. Long term use of ketamine for Difficult -to -Treat Depression needs evidence from randomised control trials- to critically evaluate its efficacy and tolerability. These issues may be in part resolved with the large-scale studies being conducted by Johnson and Johnson with intranasal esketamine.

Ketamine should currently be considered as an augmentation therapy to be used alongside other antidepressants. In patients in whom ketamine is required for continuation and maintenance therapy, sessions are best scheduled at an individualised frequency (typically once in 3-5 days) where each dose is administered a little before the effect of the previous dose wears off [5]. Careful and consistent monitoring is necessary. Rapid relapse needs careful management clinically.

The excitement that accompanies the antidepressant action of ketamine and esketamine must be tempered by the need to systematically evaluate the potential benefits and limitations of these treatments. The challenge remains to find the best way to sustained antidepressant response, taking into account the possible development of tolerance (even in its antidepressant response) and dependence. Novel NMDA receptor modulators are being tested to mimic the rapid antidepressant effects of ketamine while minimising adverse effects [19]. It seems likely that additional effective therapies may soon be available for patients with the more advanced stages of Difficult-to-Treat Depression.

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