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Ketamine is very effective in treating severe depression

Major Depressive Disorder (MDD) is a leading cause of disability all over the world, affecting 21 million adults in the United States alone. For patients who do not respond to conventional psychiatric treatment, electroconvulsive therapy (ECT), in which seizures are induced via electrical stimulation of the brain, has been an alternative method for nearly a century. 

However, since this technique often has adverse undesirable side effects – such as memory loss and musculoskeletal problems – scientists have struggled for a long time to find alternatives. 

Now, a team of researchers from Mass General Brigham has found that the administration of low doses of subanesthetic intravenous ketamine – a low-cost dissociative drug approved by the Food and Drug Administration (FDA) as a sedative/analgesic and general anesthetic – can alleviate depressive symptoms in non-psychotic, treatment-resistant patients without major side effects.

“ECT has been the gold standard for treating severe depression for over 80 years,” said study lead author Amit Anand, the director of the Psychiatry Translational Clinical Trials at Mass General Brigham and Professor of Psychiatry at Harvard Medical School. “But it is also a controversial treatment because it can cause memory loss, requires anesthesia, and is associated with social stigma. This is the largest study comparing ketamine and ECT treatments for depression that has ever been done, and the only one that also measured impacts to memory.”

The experts conducted a clinical trial from March 2017 to September 2022, involving 403 patients randomized to either receive ECT three times per week or ketamine twice per week for three weeks.

The participants were followed for six months after treatment and had to respond to a depressive symptom self-assessment questionnaire that included memory tests and questions regarding their quality of life. 

The investigation revealed that 55 percent of the patients receiving ketamine and 41 percent of those receiving ECT reported at least a 50 percent improvement in their symptoms and quality of life.

However, while ECT treatment was associated with memory loss and musculoskeletal adverse effects, the ketamine one was not linked to any side effects besides the experience of transient dissociation at the time of treatment.

“For the ever-growing number of patients who do not respond to conventional psychiatric treatments and need a higher level of care, ECT continues to be the most effective treatment in treatment-resistant depression,” said co-author Murat Altinay, a psychiatrist and lead of the trial site at the Cleveland Clinic.

“This study shows us that intravenous ketamine was non-inferior to ECT for treatment of non-psychotic treatment resistant depression and could be considered as a suitable alternative treatment for the condition.”

Although the study is based on self-reported outcomes and the trial’s real-world design may have influenced response rates – which could be interpreted as limitations – these features could also allow the findings to be more easily translated into clinical practice.

In future research, the scientists plan to compare ECT and ketamine treatments for patients with acute suicidal depression to assess whether similarly promising results could be seen in that population.

“People with treatment-resistant depression suffer a great deal, so it is exciting that studies like this are adding new options for them. With this real-world trial, the results are immediately transferable to the clinical setting,” Anand concluded.

The study is published in the New England Journal of Medicine.

More about ketamine and depression

Ketamine is an anesthetic drug that has been used in medicine for many years. More recently, it has gained attention for its potential use in treating severe and treatment-resistant depression. Ketamine and its isomer, esketamine, have been used in clinical settings for this purpose, often when other treatments for depression have failed.

Ketamine appears to work differently than other antidepressants. Traditional antidepressants, like SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors), increase the levels of neurotransmitters, which are chemicals that transmit signals in the brain. It typically takes a few weeks for these medications to take full effect.

Ketamine, on the other hand, appears to work by acting on the glutamate system, the most common neurotransmitter in the brain. It is thought to promote the growth of new connections between nerve cells, potentially improving mood and relieving depressive symptoms relatively quickly. Some studies suggest that ketamine can provide relief from symptoms of depression within hours, though the effects may not be long-lasting.

Ketamine is usually administered under medical supervision, often as an intravenous infusion or a nasal spray (esketamine). There are potential side effects, including hallucinations or other serious changes in perception, increases in blood pressure and heart rate, and potential for abuse and dependence. Because of these risks, ketamine is usually used only when other treatments have been unsuccessful.

It’s also important to note that while the use of ketamine for depression is promising, it’s not a cure for depression. It’s a tool that can potentially provide rapid relief from symptoms, but it needs to be part of a comprehensive treatment plan that may include other medications, psychotherapy, and lifestyle changes.

By Andrei Ionescu, Staff Writer

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