Discussion: Ketamine & SSRIs

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Ketamine & SSRIs
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Ketamine's primary action is as an antagonist of the NMDA receptor, a type of glutamate receptor. Glutamate is the main excitatory neurotransmitter in the brain, and NMDA receptors play a crucial role in synaptic plasticity, memory function, and learning. By blocking these receptors, ketamine decreases glutamate transmission, leading to several effects:

• Dissociation: The blocking of NMDA receptors results in a dissociative state, characterized by a sense of detachment from reality, body, and environment. This dissociation can range from mild to intense, depending on the dose.
• Analgesia: Ketamine's ability to reduce pain perception is partly due to its action on the NMDA receptors, which are involved in the transmission and perception of pain signals.

While ketamine’s primary action is on NMDA receptors, it also affects other neurotransmitter systems, contributing to its wide range of effects:

• Opioid Receptors: Ketamine can interact with mu and kappa opioid receptors, contributing to its analgesic properties.
• Monoaminergic System: Ketamine influences the release of monoamines (serotonin, norepinephrine, and dopamine), which can affect mood and cognition. This is particularly relevant in its use for depression, where increased synaptic levels of these neurotransmitters are beneficial.
• Cholinergic System: Ketamine inhibits the reuptake of acetylcholine, which might contribute to its cognitive and memory effects.

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs commonly used to treat depression, anxiety disorders, and several other mental health conditions.

Serotonin is a neurotransmitter that plays a key role in regulating mood, emotion, and anxiety. It is also involved in various other physiological processes, such as sleep, appetite, and pain perception. In the context of mood regulation, serotonin’s effect is primarily modulated through its action on specific receptors in the brain.

Under normal circumstances, serotonin is released from the presynaptic neuron into the synaptic cleft (the space between neurons). It then binds to serotonin receptors on the postsynaptic neuron, exerting its effects. After serotonin has carried out its function, it is typically reabsorbed into the presynaptic neuron by a protein called the serotonin transporter (SERT). SSRIs inhibit the reuptake of serotonin by blocking SERT. This inhibition prevents serotonin from being reabsorbed back into the presynaptic neuron, leading to an increased concentration of serotonin in the synaptic cleft.

Effects of Increased Serotonin Levels:

• Enhanced Serotonergic Transmission: The increased availability of serotonin in the synaptic cleft enhances serotonergic neurotransmission. This heightened activity at serotonin receptors is believed to contribute to the alleviation of depressive and anxious symptoms.
• Mood Improvement: Over time, the increased serotonergic activity can lead to improvements in mood and emotional stability. This is because serotonin has a stabilizing effect on mood, reducing symptoms of depression and anxiety.

Examples of SSRIs:

• Fluoxetine (Prozac)
• Sertraline (Zoloft)
• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Paroxetine (Paxil)
• Fluvoxamine (Luvox)

Combining ketamine with SSRIs presents a complex interaction that can have potentially adverse effects:

1. Serotonin Syndrome: Combining ketamine with SSRIs raises the risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin activity. Symptoms include agitation, confusion, rapid heart rate, and high blood pressure.
2. Increased Cardiovascular Strain: Both ketamine and SSRIs can influence cardiovascular parameters. Ketamine can increase heart rate and blood pressure, and when combined with SSRIs, the cardiovascular effects might be amplified, necessitating careful monitoring.
3. Psychotomimetic Effects: Ketamine’s dissociative properties can cause hallucinations, confusion, and perceptual disturbances. The interaction with SSRIs might exacerbate these effects in some individuals, particularly those with a predisposition to psychiatric conditions such as schizophrenia or bipolar disorder.

Recently, there have been reports of potential application points and ketamine properties that can be used to treat mood disorders. Perhaps in the future we will see combinations of it and SSRIs, but so far all potential benefits remain only theorizing and speculation. Current state does not support the safe or effective use of this combination outside of controlled clinical settings.

We have not come across confirmed data on acute and fatal conditions associated with this combination. At the same time, there are no signs of worthwhile positive recreational effects that could cover the risks of this combination.

It's also important to highlight that SSRIs re commonly prescribed for managing psychological and psychiatric conditions. Introducing psychoactive substances during treatment with such medications generally diminishes the efficacy of the therapy, further destabilizes compromised neural systems, and elevates the likelihood of exacerbations and negative side effects.

Considering the above, we recommend treating this combination with great caution.