If you are reading this, you may be asking yourself: is Ketamine therapy actually effective against treatment resistant depression? Let’s start by better understanding what causes depression and why Ketamine infusions are such an innovative and promising option. Depression is a common mood disorder that is sometimes improperly characterized as “being sad all the time.” Feelings of sadness and the inability to get motivated are symptoms of depression, but additional criteria are required. A major depressive episode is ‘at least two weeks when a person experienced a depressed mood or loss of interest or pleasure in daily activities and had a majority of specified symptoms, such as problems with sleep, eating, energy, concentration, or self-worth.'(DSM 5) According to 2017 statistics from the National Institute of Mental Health, 4.5% of US adults have had at least one episode of major depression. That is approximately one person out of 22—a large number. In fact, with clinical depression so widespread, most people have a family member or friend battling it.
Depression’s causes are likely multifactorial, with numerous possibilities probably working in concert to produce its symptoms. For instance, neurotransmitter deficits, genetic predisposition, diet, stressful life circumstances, hormonal imbalances, and as a secondary response to other illnesses like chronic pain or substance abuse, and many more are all “on the table.”
According to the ‘Monoamine Theory,’ a deficiency of neurotransmitters causes depression. Neurotransmitters regulate signaling through the brain, including that involving mood regulation. They facilitate the movement of activity from one neuron to another via the junctions between two neurons, known as ‘synapses.’ These signaling processes regulate many essential functions such as mood, sleep, and appetite. More specifically, according to the monoamine theory, serotonin, norepinephrine, and dopamine are the three significant neurotransmitters affecting depression, and all three of them are monoamines, i.e., they have one amine group in their chemical structure.
These neurotransmitters are released by the presynaptic neuron (the first neuron) when a nervous impulse reaches it. They then travel through the synapse to bind to the postsynaptic neuron (the second neuron) transmitting it. Once the signaling process is complete, these monoamines are removed from the synaptic cleft, at which point either the presynaptic membrane reabsorbs these monoamines or the enzyme monoamine oxidase breaks them down. When neurotransmitter levels are insufficient, depression and other mental health symptoms can manifest as a result.
In addition, there are other theories attempting to explain the cause of depression:
- negative affective bias – an unrealistic or obsessional concentration on painful emotions non-reflective of a more balanced reality
- neuroendocrine mechanisms – for example: CRF stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary. ACTH, in turn, increases cortisol, enhancing stress, including mood manipulation.
- trophic effects flowing from nutrition
- neuroplasticity – Well-worn paths of thought and behavior create and reinforce pathways through the brain. This process can be “used for good” in the case of positive rebuilding. However, negative moods and thoughts can also be built and solidified through this plastic process.
Mainstream Antidepressant Drugs
Standard pharmacological treatment for depression begins with targeting monoaminergic transmission. However, these medications have several drawbacks, such as the delayed onset of action (when they work at all) and disturbing side effects. Additionally, their effects wear off upon the discontinuation of treatment.
Frequently prescribed drugs for depression are “antidepressants,” such as:
- Inhibitors of monoamine reuptake
- Selective Serotonin Reuptake Inhibitors (SSRIs)
- Tricyclic antidepressants (TCAs)
- Noradrenaline Reuptake Inhibitors
- Serotonin-Noradrenaline Reuptake Inhibitors
- Monoamine Oxidase Inhibitors (MAOIs)
- Monoamine Receptor Antagonists
These drugs restore or maintain the levels of monoamines, enhance the availability and release of monoamines, and facilitate the normalization of signaling between neurons. For some, managing these processes does reduce the symptoms of depression. Unfortunately, they can cause numerous adverse effects such as diarrhea, nausea, dry mouth, dizziness, sleep disturbances, weight gain, and disruption of sexual function. Sometimes the side effects arrive before the therapeutic. People also often wonder about the safety of antidepressants which should be a balanced evaluation of the clinical effects on one hand and the impact of not taking medications on the other.
Ketamine came into being in the 1960s as an anesthetic. It is a commonly used intravenous anesthetic and analgesic agent. Ketamine is less risky than other agents, but it can cause hemodynamic changes like heightened blood pressure and the possibility of apnea or other airway obstruction. For this reason, vital signs are monitored during ketamine administration. Ketamine is also employed as a ‘dissociative anesthetic,’ which means the patient stays at a psychological distance from the procedure, protecting them from traumatic reaction or memory.
It is an N-methyl-D-aspartate (NMDA) receptor antagonist, slowing down the glutamatergic system’s activity. Intravenous Ketamine is a racemic mixture of (R)-Ketamine and (S)-Ketamine (esketamine). Its benefits and effects are well-understood from over 60 years of use. More recently (2019), the FDA approved the use of esketamine (Spravato) intranasal spray as a version of ketamine therapy for treatment-resistant depression specifically. TRD sufferers are those who have not responded to at least two conventional medications.
According to recent evidence, dysregulation of the glutamatergic system is a primary cause of psychiatric disease. This revelation makes that system a promising target for antidepressant action. More specifically, it appears that increased stress upregulates the secretion of glucocorticoids (e.g., cortisol), driving the production of excessive glutamate, causing structural and functional changes with deleterious effects.
The development of NMDA receptor antagonists like Ketamine has opened new avenues of research for more effective antidepressants acting on this system directly.
Ketamine’s antidepressant mechanisms are dividable into two broad categories based on whether they involve NMDA receptors or not. NMDA receptor-dependent mechanisms include inhibition of NMDA receptors on GABA interneurons, spontaneous NMDAR-mediated transmission, extra-synaptic NMDARs, lateral habenula neurons, and GABAB receptor expression/function. On the other hand, NMDA receptor-independent mechanisms are hydroxynorketamine, stabilization of glutamate release/excitatory transmission, regulation of the dopaminergic system, and reconfiguration of brain homeostasis.
Inhibition of NMDA Receptors on GABA interneurons
GABA (gamma-aminobutyric acid), which is an inhibitory neurotransmitter in the brain, reduces glutamate release. When Ketamine blocks GABA interneurons’ discharge, the excitatory activity of the brain caused by glutamate increases via mTOR signaling.
Inhibition of spontaneous NMDAR-mediated transmission
Via a slightly different mechanism, Ketamine increases the synthesis of BDNF rapidly, which enhances glutamatergic transmission in the brain. As discussed above, some theories propose that BDNF levels are reduced in patients with depression. BDNF is a protein produced in the brain which promotes the growth, maturation, and maintenance of neurons. Ketamine increases the expression of the gene which codes for BDNF and restores BDNF levels. Both of these mechanisms are interconnected as BDNF also enhances mTOR activity.
Inhibition of extra-synaptic NMDARs
Ketamine action on extra-synaptic NMDARs enhances antidepressant activity by suppressing mTOR signaling and limiting protein synthesis in principal cortical neurons. This theory receives confirmation from rodent, primate, and human studies.
Inhibition of lateral habenula neurons
The lateral habenula is a critical region that mediates communication between monoaminergic systems in the midbrain and the hindbrain with the forebrain. The studies that looked into this mechanism have shown that Ketamine might quickly elevate the mood by blocking the NMDAR-dependent burst activity of LHb neurons, which removes the inhibition on monoaminergic reward centers.
GABAB receptor expression/function
GABAB receptors are a type of inhibitory G-protein coupled receptor present in most neuronal and glial cell pre and postsynaptic membranes. Although the activation of GABAB R is required to stimulate mTOR kinase activity, a significant outcome of ketamine actions, there is no evidence in the literature indicating Ketamine’s direct involvement in this.
Animal models show that HNK, a potent metabolite of Ketamine, can produce antidepressant activity on its own without affecting the NMDA receptors. Scientists suggest that even though the drug’s initial effects are due to unmetabolized Ketamine, HNK might be what prolongs its effect after 24 hours. However, this finding has not been confirmed in humans.
Stabilization of glutamate release/excitatory transmission
Ketamine stabilizes both excitatory and inhibitory transmission pathways in areas involved in major depressive disorder. However, the net effect of stabilizing effect is more towards the excitatory side. It maintains a sustained activation stage in the prefrontal cortex, positively affecting stress reactivity and mood.
Regulation of the dopaminergic system
Dysregulation of dopaminergic pathways causes people to lose their ability to feel pleasure – a condition known as ‘anhedonia’ – one of the two core symptoms of major depression. Ketamine can reactivate dopaminergic neurons, reducing depressive symptoms.
Reconfiguration of brain homeostasis
Ketamine also helps restore the disrupted brain function by reconfiguring brain network connections, helping restore metabolic homeostasis, and synchronizing gamma oscillatory activity. This global enhancement action of brain connectivity can be a massive benefit in terms of treating depressed patients.
What is in the future of Ketamine therapy?
Although this list of mechanisms will be amended over time, it is already clear that Ketamine’s methods of action are multi-dimensional, not unlike the complex causality of the conditions it treats.
Two lines of inquiry are of current interest going forward: 1) how to isolate and tune the elements of these processes to make Ketamine applications more robust, long-lasting, safe, and affordable and 2) how to determine which patients are most likely to benefit before treatment and how to personalize their protocols.