UConn Researchers Study Mind-Healing Powers of Ketamine Derivatives for Severe Depression

Trials aim to treat the most intractable cases of depression

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UConn Health researchers are testing derivatives of the anesthetic drug ketamine in the treatment of the most severe, treatment-resistant depression (Adobe Stock).

UConn Health researchers are investigating in clinical trials the potential healing powers of derivatives of ketamine, a common anesthetic drug, to find a viable solution for those battling treatment-resistant severe depression.

But what exactly is treatment-resistant severe depression?

According to UConn Health’s Mood & Anxiety Disorders Program, it generally describes when someone with severe depression fails to respond to multiple medication trials of prescription anti-depressants.

“Many patients struggle for decades with treatment resistant depression,” says Dr. Jayesh Kamath, professor of psychiatry and immunology at UConn School of Medicine and research director of the Mood & Anxiety Disorders Program at UConn Health.

“When someone with depression fails to respond to medication – we have a problem,” stresses Kamath. “And the problem can keep growing, especially when they fail more and more medication trials of drugs known to treat and approved for depression care.”

‘What we are trying to treat with ketamine derivatives is far beyond severe depression’

Traditional antidepressants work by boosting levels of the neurotransmitters such as serotonin, norepipephrine, and dopamine in the brain, which are tasked with carrying signals between brain nerve cells to regulate our mood. But all standard of care antidepressants on the market can take four to six weeks to begin to take effect, says Kamath. That’s an especially long time for someone battling severe depression, who has failed multiple medications regimens, and may even be dealing with suicidal thoughts or ideation.

But Kamath, principal investigator for the ongoing ketamine concept clinical trials at UConn Health, is beginning to see a light at the end of the dark tunnel that his severe depression patients travel in daily.

“Already, thanks to our ongoing clinical trial research with esketamine nasal spray, one patient participating told me ‘For the first time in twenty years I finally feel better! I woke up as if it was a different morning.’

“When you are able to hear that from a patient with severe depression that makes you feel good as their doctor,” Kamath says. “It reminds me of the Hippocratic Oath I first took when I became a doctor.

Kamath adds that the trials may help offer treatment for the most intractable cases of depression.

“What we are trying to treat with ketamine derivatives is far beyond severe depression,” he says. “We are testing ketamine for treatment-refractory depression. This is the most severe depression disease threshold that hasn’t responded to therapies and no matter what medication is trialed the patient just doesn’t feel better.”

UConn Health’s two ongoing clinical trials are being conducted on both an outpatient and inpatient basis.

For example, UConn Health is testing in a randomized clinical trial the power of esketamine nasal spray in patients with treatment-refractory severe depression. Only those who qualify after passing an extensive screening process for the clinical trial receive either one month of the nasal spray weekly at either a low-dose (56 mg) or a high-dose (84 mg), or simply a placebo spray. Then for the next three months all enrolled study participants may choose to come in for open-label use of the esketamine spray. The trial is being sponsored by Janssen.

“Everyone enrolled in the trial gets the opportunity to eventually try the intranasal spray for their severe depression” at no cost to them, says Kamath, which is critically important since the medication is very expensive, usually costing around $2,000 a dose without insurance coverage – and right now, many insurers are not covering the drug’s cost.

Each patient in the clinical trial receives two hours of robust safety monitoring after taking the medication. Also, they are not permitted to drive a vehicle for 24 hours.

Currently, UConn Health is only testing ketamine derivatives in research clinical trials such as with esketamine nasal spray. Doctors at UConn Health are not prescribing these medications in the clinic.

Research continues as the need for treatment rises steadily, straining resources in the health care system

Another clinical trial currently underway is an inpatient-outpatient trial with the MIJ821 intravenous therapy, another ketamine-based investigational medication, as an adjunct to standard-of-care in the management of treatment-refractory depression with suicidal thoughts. This trial is sponsored by Novartis.

“Study after study has shown that esketamine works differently and faster than any other antidepressant medication on the market. It has an anti-depressant effect within hours and can reduce suicidal thoughts quickly,” says Kamath.

Ketamine is an anesthetic that has been used for decades via intravenous route. Ketamine-based medications can cause dissociation and can lead to euphoric feelings. Therefore, an important concern about ketamine-based medications is their potential for abuse and addiction. Ketamine and esketamine are both highly regulated.

Kamath and his team will be further investigating in clinical trial how long this relief from severe depression can last for patients with treatment-resistant depression, and what might be the best dose schedule each week.

Kamath also stresses that, given the mounting challenges and stressors of the COVID-19 pandemic and other societal issues, it’s hard for people who are struggling mentally to find a good therapist right now, even if they have insurance.

“Access to psychologists and psychiatrists right now is a big problem,” he says. Kamath wants patients to know that they can also turn to their primary care physicians with their anxiety and depression concerns for initial standard-of-care medication options.

According to Kamath, psychotherapy is usually recommended first to those struggling with mild or mild-to-moderate depression. But for those with moderate-to-severe depression, psychotherapy should be given a chance, but always in combination with an anti-depressant medication.

“Medication combined with psychotherapy works better than medicine alone for moderate to severe depression,” says Kamath. “Also, psychotherapy-learned skills can teach really important lifelong skills for those with depression, anxiety, or really anyone.” Plus, psychotherapy can often help minimize anti-depressants a depressed person is on. Since all medications come with potential side-effects, less medication is always best, says Kamath.

The ultimate hope of the clinical trials is to someday make an accessible pill instead of an intravenous medication based on ketamine, which would have beneficial mood-boosting effects while reducing any potential side effects, such as the dissociative and euphoric effects, and especially saving more lives from depression-induced suicide.


UConn Health is seeking volunteers for its ongoing depression clinical trial studies. If you are interested, in enrolling call: 860-679-7587.

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