Introduction

For a long time, and sometimes still today, anxiety and depressive disorders have been presented as irremediable conditions. Rooted in brain chemistry or, more recently, genetics.

For decades, patients were told that they were suffering from chemical imbalances, in particular a lack of serotonin, which would explain their symptoms.

The classic remedy? “Selective" serotonin reuptake inhibitor antidepressants would correct this supposed imbalance. The reality is very different: several weeks of waiting (or even worsening of symptoms) for uncertain results, sometimes minimal and accompanied by side-effects.

More recently, a "new" molecule has burst onto the scene as an alternative to SSRIs in the treatment of anxiety and depressive disorders: ketamine. Initially used as an anaesthetic, it has proved capable of relieving, sometimes in just a few hours, deep depression resistant to standard treatment, including in suicidal patients.

Where SSRIs take several weeks or even over a month to provide a therapeutic effect, a single injection of ketamine can bring about a spectacular improvement overnight.

This speed defies conventional theory. How can such a complex psychological condition be reversed almost instantaneously?

If depression was simply a question of missing serotonin, why is it that blocking another receptor, NMDA, linked to glutamate, is enough to achieve such a result?

Behind these symptoms lies a more fundamental mechanism, linked to the way the brain produces and uses energy.

Ketamine: a radically different approach

Whereas SSRIs target serotonin and seek to increase its availability at the synapse, ketamine acts on an entirely different system: that of glutamate, the brain's main excitatory neurotransmitter. Glutamate is essential to neuronal life, and is involved in learning, memory and motivation, as well as regulating day-to-day brain activity.

Under normal conditions, there is a balance (ratio) between the excitation provided by glutamate and the inhibition provided by GABA, its complementary neurotransmitter.

When this balance is upset, the brain becomes unstable.

• Too much glutamate → agitation, anxiety, ruminations, intrusive thoughts,
• Too little → apathy, cognitive slowness, lack of motivation.

NMDA receptors

Glutamate acts through various receptors. Among them, the NMDA receptor plays a special role. It controls the entry of calcium into the neuron; this calcium is essential for neuronal plasticity, i.e. the brain's capacity to learn and adapt.

In situations of stress or imbalance, this receptor can become hyperactive. This leads to excessive calcium entry, inflammation and progressive degradation of neuronal connections, a phenomenon known as excitotoxicity.

Once inside the neuron, calcium travels to the mitochondria, the cell's energy centers. In small quantities, it stimulates energy production, but in excess, it saturates them and paralyzes them, blocking cellular respiration. This is where the problem becomes systemic: oxygen is present, but it is no longer used efficiently, a state that can be described as functional hypoxia.

It is observed not only in severe depression, but also in chronic anxiety, PTSD and certain neurodegenerative diseases(Demartini et al., 2023).

As an NMDA antagonist, ketamine binds to the receptor and prevents glutamate from activating it, thus immediately halting the massive influx of calcium and putting an end to the vicious circle of excitotoxicity. By blocking this flow, ketamine reduces the neuron's toxic overstimulation and re-establishes a balance between excitation and inhibition. This is why, unlike SSRIs, its effects can be felt in just a few hours.

Brain plasticity and BDNF

Activation of AMPA receptors, another type of glutamate receptor, acts like a switch, triggering the rapid release of BDNF (Brain-Derived Neurotrophic Factor), a key molecule for neuronal health and growth. BDNF acts as a veritable fertilizer for the brain, stimulating neuronal plasticity - the brain's ability to create new connections and strengthen existing ones. By restoring BDNF, ketamine restores the brain's ability to rebuild itself. This process results in a rapid return of motivation, mental clarity and emotional resilience.

When the brain suffocates: functional hypoxia

The brain is the most energy-intensive organ in the human body. Despite its low weight, barely 2% of body mass, it consumes around 20% to 25% of the body's available oxygen. This energy is produced by the mitochondria, intracellular structures often described as the power plants of neurons. Every thought, emotion and movement relies on this constant flow of energy, transforming oxygen and glucose into ATP, the molecule that powers the brain's vital functions.

But when stress becomes chronic or the body is subjected to repeated aggression, this system gradually becomes dysregulated. It's not a lack of oxygen in the blood, as in the case of drowning or a respiratory crisis. Here, oxygen is present, but the cells can no longer use it properly. This phenomenon is known as functional hypoxia. The mitochondria stop converting oxygen into energy efficiently. Neurons continue to receive the usual chemical signals, but no longer have the resources to respond to them.

In depression, this state manifests itself in a cascade of disturbances: ATP production declines, calcium accumulates in the cells and glutamate, the main excitatory neurotransmitter, is no longer regulated. The system then enters a phase of profound disorganization. Initially, this results in agitation, anxiety and hypervigilance. Then, as the energy deficit worsens, there's a feeling of overall slowing down, cognitive and emotional exhaustion, culminating in the inner emptiness characteristic of severe depression. This state is not limited to depression. It can also be found in chronic anxiety, post-traumatic stress disorder, and even certain neurodegenerative diseases such as Alzheimer's or Parkinson's(Demartini et al., 2023). These conditions share a common signature: neurons unable to produce sufficient energy, trapped in a state of functional hypoxia that makes them vulnerable to excitotoxicity and degeneration.

This model offers a radically different perspective on depression. Rather than seeing it as a simple chemical imbalance, it describes it as an energetic crisis in the brain. This helps explain why some treatments fail, and why others, such as ketamine, can have such a rapid effect: by temporarily restoring cellular respiration, they lift the blockage and restore the brain's ability to function normally, at least for a while.

Limits and dangers of ketamine

While the effect of ketamine may seem miraculous, it's essential to remember that it remains transitory and does not correct the underlying causes of depression. The molecule acts like a switch, cutting off the excitatory crisis and momentarily restoring energy to the brain. But as soon as its action disappears, the metabolic terrain that led to depression remains unchanged. This is why symptoms often return after a few days or weeks, sometimes more intensely than before (which is also the case with SSRIs).

What's more, ketamine carries considerable risks, especially with repeated or long-term use. Psychologically, it can provoke episodes of dissociation, confusion and even depersonalization. Some patients experience profound emotional relief, but also a feeling of strangeness or detachment that can be disturbing.

With regular administration, there is also progressive tolerance, requiring higher doses to achieve the same effect, as well as psychological dependence, with the patient fearing the sudden return of symptoms.

On the physical side, urinary and bladder damage have been widely documented in chronic recreational ketamine users (Mason et al., 2010).

Finally, some research suggests that long-term, high-dose ketamine may also affect memory and cognitive function.

These side effects show that ketamine cannot be a single or permanent solution. It needs to be seen as a punctual tool, integrated into a comprehensive treatment program aimed at restoring cellular respiration, reducing oxidative stress, correcting nutritional deficiencies and re-establishing hormonal balance. Without this in-depth approach, it runs the risk of becoming a mere chemical crutch, without ever offering a lasting cure.

Conclusion

Ketamine turns our understanding of depression on its head. By acting quickly and powerfully, it demonstrates that depressive states are not fixed and can be reversed in a matter of hours. But it only lifts the veil temporarily: as soon as its action wears off, the brain slips back into the same energy blockage that plunged it into suffering in the first place.

Rather than seeing depression as a chemical imbalance to be corrected by a molecule, it becomes essential to see it as an energetic crisis of the brain. True healing will come not from a punctual blockage of receptors, but from a lasting restoration of mitochondria, cellular respiration and energy production mechanisms.

The challenge now is to transform this temporary respite into lasting change, by tackling the root causes that stifle the mind long before symptoms appear.