In recent years, ketamine has emerged as one of the most promising treatments in psychiatry — especially for individuals struggling with treatment-resistant depression (TRD), suicidal ideation, PTSD, and certain chronic pain conditions. Unlike conventional antidepressants, which may take weeks to show effects, ketamine often produces relief within hours to days.

But how does this once-controversial anaesthetic work to relieve emotional pain so rapidly?

Let’s explore the fascinating neuroscience behind ketamine’s action on the brain and why it is revolutionizing modern mental health care.

💡 The Traditional Antidepressant Model

Most antidepressants — such as SSRIs (e.g., fluoxetine, sertraline) — work by increasing serotonin, norepinephrine, or dopamine in the brain. These monoamines modulate mood, sleep, and motivation. However:

• They take 2 to 6 weeks to produce meaningful results.

• About 30-40% of patients show partial or no response.

• They do not directly address structural and functional changes in the brain caused by chronic stress or trauma.

This is where ketamine brings something new to the table.

🚀 Ketamine: A Paradigm Shift in Psychiatry

Ketamine works via an entirely different pathway — one that targets glutamate, the brain’s most abundant excitatory neurotransmitter.

🧬 Core Mechanisms of Ketamine:

1. NMDA Receptor Blockade (Disinhibition of Glutamate Burst)

Ketamine is a non-competitive NMDA receptor antagonist. NMDA receptors are part of the glutamatergic system, which governs synaptic plasticity and learning.

By blocking NMDA receptors (specifically on GABAergic interneurons), ketamine disinhibits glutamate release — resulting in a glutamate surge.

This controlled glutamate burst stimulates AMPA receptors, another set of glutamate receptors, which in turn initiates a cascade of neuroplastic changes.

2. Activation of Brain-Derived Neurotrophic Factor (BDNF)

Glutamate–AMPA activation leads to increased production and release of BDNF — a protein critical for:

• Synaptogenesis (forming new synapses)

• Neuronal growth and repair

• Reversing stress-related atrophy in key brain regions

Chronic depression and trauma are associated with reduced BDNF. Ketamine’s rapid enhancement of BDNF may explain its fast-acting antidepressant effects.

3. Stimulation of the mTOR Pathway

Ketamine rapidly activates the mTOR (mechanistic Target of Rapamycin) pathway — a central cellular signaling system involved in:

• Building new synaptic proteins

• Forming new dendritic spines

• Enhancing connectivity in the prefrontal cortex and hippocampus

Animal studies show that within hours of ketamine exposure, there is visible formation of new neural connections in areas responsible for mood and cognition.

4. Anti-Inflammatory Effects

Emerging evidence suggests that ketamine also reduces the release of pro-inflammatory cytokines such as IL-6 and TNF-alpha, which are often elevated in depression.

This neuroimmune modulation may be especially relevant in cases of depression associated with medical illness, fatigue, or chronic stress.

5. Glutamate Rebalancing and Cortical Reset

In depression, glutamate signaling becomes dysregulated — either too excitatory or too deficient in key regions.
Ketamine seems to “reset” or normalize this signaling, particularly in the dorsolateral prefrontal cortex, anterior cingulate cortex, and default mode network (DMN).

This may explain improvements in:

• Emotional regulation

• Cognitive flexibility

• Self-perception and rumination

🧠 Where in the Brain Does Ketamine Act?

Functional imaging studies (e.g., fMRI, PET) show ketamine affects:

• Prefrontal cortex: Enhances decision-making and emotion regulation

• Hippocampus: Improves memory and contextual learning

• Amygdala: Reduces overactivity linked to fear and anxiety

• Subgenual anterior cingulate cortex: Normalizes mood circuitry

These effects begin within 1–4 hours after administration and often last days to weeks depending on dosage and individual neurobiology.

⚖️ Why Is the Relief So Fast?

Unlike SSRIs, which rely on long-term receptor adaptation, ketamine hacks into the synaptic communication network almost instantly, reshaping how neurons talk to each other.

This helps patients feel:

• More emotionally grounded

• Less hopeless or suicidal

• Better able to engage in therapy and daily functioning

🧪 Duration of Effect and Maintenance

A single ketamine session can bring relief for up to 1–2 weeks, though effects vary. Most protocols recommend:

• Induction phase: 2–3 sessions per week for 2–3 weeks

• Maintenance phase: Monthly or as needed

• Often combined with psychotherapy or lifestyle interventions

⚠️ Important Caveats

• Ketamine is not a first-line treatment and is used when conventional methods fail.

• It must be administered by qualified professionals in a clinical setting.

• Repeated or recreational use without supervision can lead to dependency, dissociation, or urinary tract issues.

• Long-term effects are still being researched, especially with frequent use.

🔬 Ongoing Research

Scientists are exploring:

• Esketamine (S-enantiomer) for nasal use

• Oral lozenges and sublingual microdosing

• Combining ketamine with CBT, EMDR, or neurofeedback

• Use in bipolar depression, OCD, and existential distress in terminal illness

🧘 Summary: How Ketamine Helps Heal the Depressed Brain

📘 Final Thoughts

Ketamine has opened a new chapter in the story of psychiatric care — offering hope, especially to those who felt beyond help. While it is not a cure-all, when used ethically and appropriately, it can reignite the brain’s ability to heal itself.

Written by:
Dr. Srinivas Rajkumar T, MBBS, MD (Psychiatry)
Consultant Psychiatrist
Apollo Clinic, Velachery, Chennai
📧 Email: srinivasaiims@gmail.com
📱 Phone: +91 85951 55808
🌐 www.srinivasaiims.com