Novel Treatments for Depression: TMS & Esketamine/Ketamine

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Depression is a common illness that can cause substantial suffering, disability, and death. Depressive disorders are complex syndromes that take different forms and have a multitude of underlying factors. In fact, we still don’t fully understand what causes depression, apart from the recognition that it arises from an interaction of genetic and environmental factors. There are many kinds of depression (unipolar, bipolar, postpartum, substance induced, etc.), as well as significant variations in individual responses to treatments.

To be clear, the primary challenge in tackling the toll of depression is inadequate access to affordable effective mental health care, including treatments such as psychotherapy (talk therapy) and medications. 

While depression is a treatable illness, and treatment saves lives, we need more tools for the subset of people who do not recover from the initial modalities tried. 

Until recently, even the newer antidepressant medications were largely based on mechanisms of action similar to drugs developed decades ago (involving neurotransmitters such as serotonin, norepinephrine, and dopamine). Even with these medications, 1/3 to ½ of people have an inadequate response or are unable to tolerate the side-effects. Also, medication effectiveness can take weeks to kick in.

Note: Electroconvulsive Therapy (ECT), which is highly effective for depression and other serious conditions, has also been used for many decades (with many advancements in how it is administered). Significant improvement can occur in a short timeframe.

Now, novel treatment modalities are being developed, with different mechanisms of action. Compared to traditional antidepressant medications, these therapies promise quicker onset of response, fewer side-effects, and possibly better effectiveness for what is referred to as “treatment resistant depression” (TRD). TRD refers to depression that as not responded well to at least two prior treatments.

This column will discuss two newer FDA- approved treatment options for TRD, repetitive Transcranial Magnetic Stimulation (r-TMS) and Esketamine. We will also touch on Ketamine, which does not have FDA approval for depression and carries more risks and concerning side-effects.

Repetitive Transcranial Magnetic Stimulation (r-TMS or TMS)

TMS is a “neuromodulation” therapy, a category of therapies that target specific areas of the brain. TMS is a non-invasive treatment, FDA approved for Major Depressive Disorder (including TRD). It is a useful alternative for people unable to take or tolerate medications. It is an outpatient procedure, administered in a clinic or doctor’s office, requiring daily treatment sessions, usually over a period of 4-6 weeks. Anesthesia is not used, and you remain awake throughout the procedure. 

A coil is fitted over the scalp, which delivers brief repeated magnetic pulses from the TMS machine. The resulting magnetic field generates electric current. The theory is that TMS works by stimulating certain areas of the brain, activating regions which are believed to be underactive in depression.

Traditional TMS is administered during 30–40-minute sessions, five days a week for 4-6 weeks. There are now some newer variations such rapid “theta burst” stimulation, with multiple shorter, high dose treatments administered in one day, given over a course of five days (vs. several weeks).

TMS for depression leads to clinically meaningful improvement in about 60% of people, a substantial response rate. 

TMS is generally well tolerated. The most common side-effects include scalp discomfort, headache (usually mild), and dizziness/lightheadedness. Some people have trouble tolerating the loud “clicking” or “tapping” noises emitted by the device during the treatment session; ear plugs are worn to mitigate this sound. Rare but more serious side-effects include seizure and hearing loss.

People are not candidates for TMS if they have implanted metal hardware or are at increased risk for having a seizure.

Good candidates for TMS include people who want to avoid taking medications; for example, it is a safe and effective treatment for women who are pregnant or breastfeeding. 

In addition to treatment resistant depression, TMS is FDA approved for OCD, migraines, and quitting smoking. Many insurance companies now cover TMS if you haven’t responded to a couple of prior trials of antidepressant medications.

TMS is being investigated as treatment for many other mental health conditions, including bipolar disorder, PTSD and substance use disorders.

Esketamine (Spravato)

Esketamine, a derivative of Ketamine, was approved by the FDA in 2019 for treatment-resistant depression. 

Esketamine and Ketamine act at the glutamate receptors in the brain, and are thought to increase the connectivity between brain cells (neurons). Ketamine gained recognition for its extremely rapid anti-depressant and anti-suicidal effects (see below).

Esketamine is administered as a nasal spray in the doctor’s office and requires monitoring for two hours afterwards due to risks of elevated blood pressure and other side-effects.

These side-effects can include: drowsiness, nausea/vomiting, dissociation/perceptual distortions, a sense of “floating,” confusion, headache, and increased blood pressure and heart rate. Rare but more serious side-effects can occur, such as serious elevations in blood pressure or suicidal thoughts. 

Esketamine is only modestly effective. However, one main benefit of Esketamine (like Ketamine) is its rapid onset of action (within 24 hours). This is in stark contrast to traditional antidepressant medications, which take weeks to kick in. Esketamine is usually taken along with another antidepressant, for ongoing effectiveness. 

The treatments usually start twice a week for a number of weeks, then space out to weekly, then twice a month, and then monthly for maintaining the effect. The duration of the antidepressant effect is unclear. Long term risks and side-effects are unknown.

Ketamine is a dissociative anesthetic agent which is not FDA approved for treatment of depression. It is categorized by the FDA as a “scheduled” substance, meaning it is associated with risk of misuse/abuse. Ketamine is used as a recreational drug, largely for its dissociative and psychedelic effects: a floating feeling, euphoria, hallucinations, sensory detachment etc. It is also sometimes used as a “date rape” drug, because it can cause amnesia. Ketamine can be dangerous if used recreationally, as it can lead to sedation, coma, respiratory depression (dangerously slowed breathing), elevations in heart rate and blood pressure, and changes in heart rhythm. Side-effects can also include bladder and kidney problems. Ketamine can also have potentially dangerous interactions with other drugs and medications, as well as alcohol.

Ketamine, as an intravenous (IV) infusion, is sometimes used at lower doses as an “off-label” treatment for depression because of its ultra rapid onset of action (hours instead of weeks). This can include quick reductions in suicidal thinking, possibly avoiding the need for hospitalization in some instances. 

For safe administration, it should be given in a medical facility with close monitoring during the infusion period, including EKG, oxygenation status, and blood pressure. And people need to arrange for a ride home after the treatment. A general treatment schedule might be 40-minute infusions administered 2-3 times a week for two to four weeks, then decreasing in frequency for maintenance treatment. Currently there are no clear guidelines on frequency or duration of treatment. Initial response rates are high (up to 2/3’s of people respond). But there are also high rates of relapse (the depression returning): up to 90% at 4 weeks after ending treatment.

Ketamine clinics are popping up all over the country, some without the recommended medical and psychological monitoring, raising concerns about safety. 

Bottom line: Esketamine is not thought to be as effective as intravenous Ketamine for depression, but Ketamine is not FDA-approved for this use and carries more risk. 

On the horizon: This is an exciting time in neuroscience and mental health treatment research, with extensive ongoing exploration into modalities with truly different mechanisms of action. Examples include: anti-inflammatory agents, psychedelics, therapies targeting different neurotransmitter receptors, neuroactive steroids (as discussed in a previous column about postpartum depression), other neuromodulation therapies and more. 

And, as always, we also need to prioritize and advocate for access to affordable treatment for those who need it (including psychotherapy).

If you or someone you know is struggling or in crisis, help is available. Call or text 988 or chat 988lifeline.org. 

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