How Does Ketamine Work?
Ketamine is actually an anesthetic, but at low doses it becomes a fast-acting antidepressant that can substantially reduce depression symptoms in hours or days, rather than weeks.
According to the monoamine hypothesis, depressive symptoms are mainly related to a deficit in the availability of monoamine neurotransmitters, and most antidepressant drugs are believed to modulate these neurotransmitter systems (e.g., norepinephrine, dopamine, or serotonin). However, the therapeutic effects of these common antidepressant medications emerge only after 4-12 weeks of treatment. Ketamine, on the other hand, exerts rapid antidepressant effects.
When used to treat depression and anxiety, ketamine has a different mechanism of action from standard antidepressants. Ketamine acts by blocking N–methyl–d–aspartate (NMDA) receptors in the brain, which interact with the neurotransmitter glutamate. A 2018 article in the journal Nature concluded that depression is associated with increased burst activity in a part of the brain called the lateral habenula, which is essentially the “anti-reward center.” As a rapid antidepressant, ketamine works by blocking NMDA receptors in the lateral habenula. The resulting chemical changes in the brain are not yet fully understood, but likely involve ketamine-induced gene expression and signaling cascades that continue to act long after the drug has been eliminated from the body.
Across multiple studies, ketamine has been shown to have an immediate and marked antidepressant effect for the majority of patients. Ketamine can substantially reduce or eliminate the most acute and distressing symptoms of depression such as thoughts of suicide and self harm. In numerous research studies worldwide, the administration of six doses over several weeks has yielded a pronounced effect on severe depression, even in individuals for whom multiple prior treatments were ineffective. Although the duration of this effect varies substantially among individuals, the repeated administration of ketamine produces a more pronounced and longer-lasting effect.
Of note, ketamine has been shown to induce neurogenesis, or the creation of new nerve cells in the brain, beginning within two hours of administration. Additionally, exposure to ketamine has long-lasting effects on the activation of newly formed neurons in a part of the brain called the hippocampus, which regulates the formation of new memories.
At Cambridge Biotherapies, we remain vigilant about current research and work closely with other treatment providers to create individual ketamine treatment plans.
Ketamine and the Reduction of Suicide Risk
Based on three open-label studies, ketamine was found to be effective at reducing suicidality in treatment resistant depression (TRD) patients. Suicidal ideation in treatment resistant depression patients improved in numerous cases after only a few minutes of ketamine infusion and remained stable for up to 4 hours post–infusion.
These findings have been replicated in patients with treatment-resistant bipolar depression by Zarate et al. In this randomized double-blind placebo-controlled crossover study, 79% of subjects were reported to respond to ketamine at some point during the 2-week trial (although the effects of ketamine waned from days 7-10 and there was no significant difference compared to placebo at that point).
Ketamine isn’t like typical cutting-edge treatments, since it has been used for many years in other medical settings, and the safety and potential side effects are well known. Across multiple studies, adverse side effects are uncommon—however, some patients do report nausea during treatment, which can be quickly alleviated using an IV medication called ondansetron. Other additional adverse effects include drowsiness, dizziness, poor coordination, and feelings of strangeness or unreality during the infusion. Variation in blood pressure during treatment can also occur, but these variations are often not clinically significant.
For many years, ketamine has been used as an anesthetic in higher doses. As an anesthetic, ketamine is particularly favored for children and in mobile surgical units because it generally does not suppress breathing and has such minimal side effects. It is also on the World Health Organization’s List of Essential Medicines, which includes the safest and most effective medicines needed in most health systems.
The long-term side effects of ketamine are not fully known, but there have been no reports of significant medical concerns associated with the use of sub-anesthetic doses administered for a limited time, such as in the treatment of depression. Early research has confirmed that long-term of ketamine for depression - up to a year of weekly infusions - does not show evidence of adverse medical complications. Nevertheless, at Cambridge Biotherapies we take a cautious approach, and monitor patients carefully in an on-going manner if they choose to use ketamine as a maintenance treatment.
How is Ketamine Administered?
Ketamine is administered as an IV infusion over a period of 40 minutes, at doses substantially lower than doses used for anesthesia. This means there is no loss of consciousness and the patient remains awake throughout each treatment.
During the infusion, some patients experience odd perceptions, like seeing bright colors. Some report what is referred to as a "dissociative" or "out of body" experience. Most patients tolerate these experiences with no trouble, and many even find them pleasant. Once the infusion is complete, the dissociative effects of the drug rapidly dissipate.
The most thoroughly studied treatment schedule is six infusions over 2-4 weeks. The experience of the first infusion is typically the most intense, and after treatment patients tend to require variable amounts of time to feel fully comfortable resuming their normal activity. As the treatment schedule progresses, patients will generally leave the office within 30 minutes of an infusion and feel quite normal.
Some patients achieve full remission after a series of 6 infusions. However, some patients require ongoing weekly or monthly infusions to maintain the positive effects. Treatment plans, which include dose, frequency, and need for ongoing infusions after the initial series of 6, are developed with each patient on an individual basis.
Cambridge Biotherapies prescribes intranasal ketamine for patients on a case-by-case basis. While there is less empirically-validated evidence available to support the use of intranasal ketamine for depression and anxiety, we have found that in-office use of ketamine as a nasal spray can be of significant benefit to many patients, especially for those who have already experienced a decrease in their symptoms following a series of IV infusions. Intranasal ketamine is less than half the cost of IV ketamine treatment.
In some cases we may prescribe intranasal ketamine as a substitute for the standard series of six IV infusions. Again, this is on a case-by-case basis. For home use of ketamine in this manner, we require that patients have an initial evaluation with one of our psychiatrists followed by at least one IV infusion. We then monitor each patient at our clinic during 6 intranasal treatments to ensure that there are no adverse side effects. Patients are then seen on a monthly basis, and prescriptions for the intranasal formulation are continued as needed.
Interestingly, a family history of alcohol dependence seems to predict a rapid initial antidepressant response to an NMDA receptor antagonist. This may serve as a useful marker for the patient’s potential response to ketamine. It has been suggested that NMDA receptors are one of the targets linked to the action of ethanol, and genetic alterations of NMDA receptor subunits have been associated with the emergence of alcohol dependence.
Read More on Ketamine News
Use of an opioid to manage chronic pain is not a contraindication to receiving ketamine therapy for depression or anxiety. However, we evaluate the safety of ketamine for patients taking opioids on a case by case basis.
For anyone who has struggled with an opioid use disorder, we have a set of guidelines which, if met, can make ketamine therapy at Cambridge Biotherapies an option.
Guidelines for Receiving Ketamine Therapy at Cambridge Biotherapies if you have an opioid use disorder:
You must have a treatment team in place, which includes a clinician trained in issues related to addiction.
We must be able to work collaboratively with your treatment team.
You must be sober for 6 weeks prior to the first infusion.
You must be on some form of medication assisted therapy (MAT), such as suboxone, methadone, or vivitrol.
You must do a quick urine drug screen prior to each infusion.
Our goals in implementing these criteria are (1) to provide ketamine therapy in the safest possible manner, and (2) to provide structure and expectations around treatment and thereby support your efforts to stay sober.
If you do not have a treatment team in place, we can, under some circumstances, help you get connected to one.