Depression Rx Flashcards
What is ketamine and what is it classified as?
An uncompetitive N-Methyl-D-Aspartate (NMDA) receptor antagonist and dissociative anaesthetic.
It is a racemic mixture of equal amounts of Esketamine and Arketamine or (S)-ketamine and (R)-ketamine
Write about the discovery of ketamine as a Rx option for major depressive disorder
In 2000,Berman and colleagues, reported significant findings in a landmark RCT, administering a single dose of 0.5mg/kg ketamine over 40 mins to MDD pts
How quickly does ketamine produce a significant antidepressant effect after administration?
Within hours after the infusion, increasing progressively up to 3 days after administration
What are the two enantiomers of ketamine?
Esketamine and arketamine ie (S)-ketamine & (R)-ketamine
Which enantiomer of ketamine binds more potently to the NMDA receptor?
What form of use has been approved for use for TRD?
The nasal spray formulation of esketamine - Spravato has been approved for TRD in the US and Europe
Otherwise, ketamine remains an off-label rx for TRD
What is the primary mechanism proposed for the antidepressant effects of ketamine?
Wef 2018 the precise MoA of ketamine in TRD isn’t known but it is proposed that it is d/t Blockade of NMDA Rs on GABAergic interneurons.
These interneurons suppress glutamatergic neurons from releasing glutamate.
Thus the inhibition of this suppression leads to a glutamate surge in the cortex & activation of post-synaptic AMPA Rs thus leading to downstream effects on synaptogenesis & neuroplastic pathways.
What neurotransmitter surge is caused by the disinhibition from ketamine’s action?
The inhibition of the suppression of the interneurons ie the disinhibition causes a cortical glutamate surge
What receptors are activated downstream of the glutamate surge caused by ketamine?
Post-synaptic AMPA receptors
What is the gold standard for off-label ketamine administration?
IV ketamine (0.5 mg/kg over 40 minutes)
It is available as 50mg/ml
What are some alternative routes of administration for ketamine that have been proposed?
- Subcutaneous (SC)
- Intramuscular (IM)
- Oral
- Sublingual (SL)
- Intranasal esketamine ie Spravato
- Intranasal Ketamine as advised by Andrade et al
Why are routes other than iv not used?
Since further research is required to know the safety, efficacy & optimal dosing regimes of other routes.
Also these need more data
* Bioavailability
* Duration of effect
* Practicality
* Patient comfort
While no fixed dosing strategies have been developed Maudsley mentions dosing recommendations based on available evidence
True or False: There is a fixed dosing strategy established for ketamine across different administration routes.
False
What is the dosing strategy advised for Intranasal Ketamine by Andrade et al?
Intranasal ketamine with a 1mL dispenser using Ketamine (the same one that’s given iv).
Each puff =1mL = 5mg ketamine maybe administered in alternate nostril w/ a 2-3 mins gap b/w each puff
REMB : not the same as Spravato since that is Esketamine which is given as a bolus
What are the ADRs patients experience on ketamine ?
ADRs patients experience on ketamine at antidepressant doses are
A]. on slow infusion or slow intransal/oral admin: dizziness, nausea, elevation of BP, HR
B]. on fast infusion or rapid oral/ Intranasal admin (e.g.: Spravato or pt mistakenly drinks in a gulp instead of over 15-30mins): dizziness, nausea, dissociative effects, anxiety, transient elevation of BP, HR
CPApp: pt had synesthetic hallucinations- seeing music on gulping dose
edit acc to CP App vid around 1:20:40; at Anesthetic doses there are more S/Es reported as mentioned in the vid
What are the significant dissociative symptoms associated with ketamine when given at antidepressant doses?
Perceptual distortions and significant anxiety though rare if given at the advised regime & dose
These symptoms necessitate reassurance during and after administration.
Why is it necessary for patients administered ketamine to be observed by a trained clinician?
- To provide reassurance of the temporary & harmless nature of the dissociative symptoms
- potential complications like laryngospasm (as per Maudsley, CP App says cardio-resp Cx are unlikely
The observing clinician should be trained in intermediate or advanced life support.
What is the recommended observation period after ketamine administration?
One hour
as per Maudsley, none as per Andrade lec
How does the route of administration affect the likelihood of dissociative symptoms with ketamine?
Lower doses given orally or sublingually are less likely to induce strong dissociative symptoms
Hence, after a test dose under supervision, administration may occur in a non-clinical setting.
What activities should patients avoid after ketamine administration?
Driving, operating heavy machinery, or partaking in high-risk activities
for at least one hour after administration.
What should be considered by the prescribing clinician regarding ketamine?
The risks of diversion and illegal use
This consideration is crucial for patient safety and legal compliance.
What are the recommended physical examinations before administering ketamine?
Baseline BP, CBC, LFT
TFT, ECG
help assess the patient’s readiness for ketamine treatment.
Andrade : no baseline Ixs are necessary since the rise in the BP & HR thought maybe over 180 systolic and 90 diastolic, are always transient
What should be monitored during and after ketamine administration?
Blood pressure and heart rate
What is the initial dosing recommendation for IV ketamine administration?
0.5 mg/kg, increasing up to 1.0 mg/kg if no response
Titrate from 0.25 mg/kg in older people.
What is the frequency of IV ketamine dosing during the induction phase?
Once or twice a week
This phase is crucial for establishing the initial therapeutic effect.
What is the maintenance phase frequency for ketamine administration?
Weekly, then every 2 weeks, or even monthly
This frequency depends on the patient’s response and may include supplemental oral/sublingual doses.
What are the potential cognitive effects of ketamine administration?
Confusion and dissociation
These effects may occur occasionally during treatment.
What cardiovascular effects can ketamine be associated with?
Transient increase in blood pressure, tachycardia, and arrhythmias
Pre-treatment ECG is required to monitor these risks.
What is the dosing recommendation for subcutaneous (SC) ketamine administration?
0.5 mg/kg, increasing up to 1.0 mg/kg if no response
Titrate from 0.25 mg/kg in older people, similar to IV recommendations.
What is the administration method for SC ketamine?
Bolus injection to an appropriate SC site
This method is less invasive than IV infusion.
What is the comment regarding the tolerability of SC ketamine compared to other routes?
May be better tolerated than IV or IM routes
Patient response can vary, making individual assessments essential.
What is the pharmacological difference in the 2 ketamine enantiomers?
Esketamine binds more potently to the NMDA receptor
