Ketamine: A New Horizon in the Battle Against Depression

Depression and anxiety are the two most common emotional disorders. They might affect just anyone during their lifetime. US data suggests that, on average, about 18.5% of adults are living with depression. (1) Yes, those numbers are massive. Hence, researchers think that it is perhaps the most common mental health issue in the US. Moreover, compared to anxiety, it is a more severe disorder, and hence a need to find its effective treatment.

It is difficult to understand why depression has become so common in the last few decades. Just by the middle of the last century, depression was described as a rare disorder. When first anti-depressants were introduced, there were worries that there were not enough patients who needed such medications. (2)

There are many reasons for the rise of depression. Lifestyle changes have resulted in an increase in stress-related ailments. Further, researchers now understand that anxiety and depression might be related, but they are distinct ailments. Hence, improved diagnosis of the condition has also resulted in its rise.

Although anxiety and depression frequently coexist, they are very different. It is vital to understand the difference between the two.

Anxiety is more about excessive worry and phobias. However, depression is about a loss of interest in life. Unlike anxiety, depression might not have many readily visible physical signs. However, depression is more dangerous. Since it may progress to major depressive disorder (MDD). In MDD, people lose so much interest in life that they start thinking about ending it. Depression is among the leading causes of suicide. So, it can kill if not treated. This only underlines the importance of finding effective treatment for the condition.

Signs and Symptoms of Depression

Depression or clinical depression is about feeling persistently low. A person with depression feels sad and hopeless all over them. Quite often, a person loses interest in activities that were interesting to the person earlier. It is about a feeling of guilt and worthlessness.

There are some physical signs of the condition, like loss of energy, fatigue, and difficulty remembering things. Generally, those living with depression tend to oversleep. Depression may cause weight changes and digestive problems, too.

However, in more severe cases, a person may experience delusions like false beliefs and experience hallucinations. This is dangerous, as this is the phase when a person is more likely to have suicidal thoughts.

Medical Depression Treatment

Needless to say, in all mood disorders, a person would benefit from non-pharmacological means like exercise and psychotherapy. Thus, in mild instances, any treatment must begin with such approaches.

As depression has become a common ailment, tens of new medications have been created to manage depression. These massive numbers of drugs work by altering levels of various chemicals in the brain. Anti-depressants particularly focus on increasing brain serotonin levels.

Hence, some of the commonly used anti-depressants are Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline. Noradrenaline and specific serotonergic antidepressants (NASSAs) like mirtazapine. Older tricyclic anti-depressants (TCAs) like amitriptyline and many others. (3)

Overall, there are tens, if not hundreds, of drugs to manage depression. However, there is none that works in all the cases. In fact, the availability of so many anti-depressants just shows that most of them do not help much. Hence, in most instances, doctors keep prescribing different medications to those diagnosed with depression in the hope that something will work. This only underlines the importance of finding more effective treatment options.

Issues with Traditional Pharmacological Approach

Depression must be treated in all cases. However, there are multiple issues with depression treatment. First and foremost, science has still not fully understood its pathogenesis. Science has no idea what causes depression and what brain changes lead to depression.

Even worse, although science understands that anti-depressants can change certain brain chemicals, but they do not know how these medications work. (4)

Another significant concern is the side effects. Although newer anti-depressants are much safer than old-generation medications, they are still quite toxic. It means that anti-depressants, when used regularly, still cause many side effects. Studies show that about 86% of patients using newer anti-depressants like SSRIs still experience some side effects. In fact, 55% experience bothersome side effects. Issues like dry mouth, blurred vision, diarrhea, weight loss, headaches, insomnia, and rashes are all pretty common with these medications. (5)

However, there is an even bigger concern, which is regarding the effectiveness of anti-depressants. It might be difficult to believe, but one of the best-kept secrets of the healthcare industry is that anti-depressants are not proven to work. In fact, clinical studies show that most of these highly toxic drugs are just slightly superior to placebo. Since, in most cases, they barely produce any noticeable benefits, some experts have even challenged the concept of using anti-depressants. (6)

In fact, 2010, one of the groundbreaking studies was published in the journal JAMA. This study analyzed data from all the studies published between 1980 and 2009, and it found that anti-depressants do not seem to help with mild to moderate depression. However, they appear to help those living with severe depression. (7)

All the above issues show that there is a need to explore other treatment options for this severe health condition. One such option could be ketamine.

Ketamine and Depression Treatment

Ketamine is quite an old drug, first discovered in the 1950s. It is an anesthetic and analgesic that is often used in various surgical treatments. It is US FDA-approved and thus safe for human use. However, it also has strong mind-altering properties, and it is also used as a substance of abuse. Hence, ketamine is a DEA schedule III controlled substance, something clinicians must know.

Although it is unclear how ketamine works precisely, it is known to be an N-methyl-D-aspartate (NMDA) receptor antagonist. It also influences various other brain chemicals and receptors. It is known to affect brain plasticity and increase brain-derived neurotrophic factor (BDNF) levels. (8)

There is a reason for an increase in interest in ketamine. Studies show that it is quite effective at managing depression. There are a few things that make this drug unique. First, it acts much more quickly than traditional medications used to treat depression. Hence, it can benefit in hours, unlike traditional anti-depressants that take weeks and even months to start acting.

Another incredible benefit of this drug is its long-lasting impact, even after a single dosage or treatment session. Doctors generally give ketamine as a slow IV infusion in a clinic. One needs to stay in a clinic for a few hours, as the drug may cause euphoria and specific unpleasant effects that generally do not last for more than a couple of hours. However, after that, the patient can return home and expect to continue experiencing its benefits for several weeks.

Researchers have not been fully able to explain why even a single ketamine infusion is so good for those living with depression. However, they think these long-lasting effects are due to some brain changes. It appears that ketamine promotes brain rewiring; hence, it may alter the course of the disease, resulting in long-lasting benefits.

Further, if we compare it to prolonged anti-depressant therapy, ketamine is relatively safe. After all, ketamine therapy sessions may result in benefits that last pretty long. Ketamine may cause some side effects, like unpleasant feelings and blurry vision. Still, these adverse effects are temporary and do not last long.

On the other hand, if one uses oral anti-depressants, they do not help much. They cause many side effects. Moreover, withdrawing anti-depressants is quite challenging, as they might make things worse. Ketamine, on the other hand, does not cause depression exacerbation or withdrawal.

Of course, people can also abuse ketamine, and doctors must be careful using it in patients who are more likely to abuse drugs.

Ketamine Therapy in Depression: Benefits, Efficacy & Scientific Evidence

Ketamine has been tested extensively for managing depression patients. Thus, there is a sound reason to recommend this therapy with great confidence. For example, one of the studies in 25 treatment naïve patients with severe depression found that subanesthetic doses of ketamine, that is, 0.5 mg/kg intravenous injection given six times over two weeks, could result in a significant improvement. The study found that, unlike anti-depressants that take several weeks to start working, ketamine could help quite quickly. (9)

Encouraged by the findings, researchers are now increasingly comparing ketamine with more aggressive depression treatments. They are now comparing it with other treatments for severe or major depression. Hence, in one of the studies published in the New England Journal of Medicine (NEJM), researchers compared ketamine treatment to electroconvulsive therapy (ECT). ECT helps reset the brain quickly and is quite good for those living with severe depression and experiencing delusions. The study was done on 403 patients, with 200 given ketamine and 203 ECT. The study concluded that ketamine was not inferior to ECT. Needless to say, it was safer and better tolerated. (10)

For a long, doctors have used ketamine as an off-label drug to manage depression. However, it is worth knowing that ketamine is now a US FDA-approved depression treatment. US FDA has already approved one of the drugs called Esketamine, which essentially contains ketamine to manage depression. The drug is especially good when quick relief is required. (11)

Ketamine approval by the US FDA says a lot. It finally confirms that this therapeutic approach works and is safe for clinical use. It shows that the treatment is supported by numerous high-quality clinical studies. Moreover, another systemic review found that IV ketamine can be more effective than US FDA-approved Esketamine nasal spray. The study found that IV allows for providing higher dosages, and this results in more significant benefits among those living with depression. (12)

Of course, these are still early days, and many studies are happening. Doctors use anti-depressants in combination with other treatments. Hence, it also makes sense to combine ketamine treatment with other medications and treatments. Ketamine will likely work better in combination with other depression treatments.

One of the effective treatments for depression is cognitive behavior therapy (CBT). It is a non-pharmacological treatment or psychotherapy that helps people alter their thinking patterns and emotional responses to stress. Studies show that ketamine makes people more receptive to suggestions and thus can boost the efficacy of psychotherapy like CBT. Further, combining CBT with ketamine may result in prolonged benefits. (13)

Here, one more thing is worth noticing: ketamine has mostly been tested in severe patients and those who were resistant to other anti-depressants. This means that treatment naïve patients or those living with mild or moderate depression might show even greater benefits. Further, there is also a need to explore various ketamine regimes in combination with other treatments for managing depression.

For example, apart from IV ketamine, researchers are also exploring slow-releasing ketamine tablets for managing depression. Such a kind of ketamine therapy may have many distinct benefits, and it can be used more easily than IV therapy. However, such a therapy is more likely to work as a maintenance therapy. (14)

These are definitely exciting times as, for the first time, we are seeing the emergence of therapy that appears to work fast and have a long-lasting effect. Unlike traditional anti-depressants, ketamine can help rewire the brain and thus alter stress responses. It is pretty likely that ketamine might even cure depression in some individuals.

Finally, there is a need for more extensive studies using ketamine with other treatment methods. Doctors need to test ketamine therapy along with other drug therapies.

Nonetheless, ketamine IV therapy offers much hope. It is the first therapy in which patients can expect to experience a better mood in a few hours. Thus, those experiencing severe depression might consider IV ketamine therapy, and many can expect significant benefits within hours. It means that many would feel better almost instantly after going out of the clinic after having ketamine treatment for their condition.

Ketamine Safety

Since ketamine is a controlled substance and substance of abuse, many are worried about its side effects. However, it is worth understanding that ketamine is quite safe when used in clinics. It mainly causes side effects when mixed with other drugs of abuse or some other substances. For example, it is very dangerous to mix ketamine with alcohol.

However, it is entirely safe therapy when carried out under medical supervision. After all, the drug has been in extensive clinical use since the 1950s, making it one of the oldest and most extensively tested medications.

Of course, it does cause some minor issues like confusion, drowsiness, blurring of vision, nausea, and vomiting. Ketamine is known to increase blood pressure, and hence, it must be used with caution by hypertensive. (8)

Ketamine must not be used in those living with mental health issues. It must be avoided by those living with neurological disorders.

The Bottom Line

Depression is a severe ailment. It is also among the leading causes of suicides. Hence, it is vital to understand that, unlike other emotional disorders, it can kill people. What is worrisome is that despite years of research, little progress has been made in finding its effective treatment. That is why depression is quite prevalent in prosperous nations, where despite the best of the treatment, many continue to live with the condition. This only highlights the need to find effective treatment for the condition.

Further, one should keep in mind that anti-depressant drugs do not work much in mild to moderate cases, and they are barely superior to placebo. These medications work by altering brain chemicals; however, such a strategy has not been shown to work.

Even if anti-depressants work, they have many issues, like they work very slowly over the period of several weeks. One has to continually take these medications, as discontinuing these drugs causes quick reemergence of the symptoms. Not only that, these medications are quite toxic, causing many side effects.

Ketamine has emerged as a beacon of hope. It is very different from traditional anti-depressants, offering many benefits. Although its mechanism of action is not fully understood, it is known to start working quickly. What is notable is that in many cases, people may experience benefits from the first therapy session. Another good thing is its long-lasting action.

Researchers are also exploring other ways to enhance ketamine therapy efficacy. For example, some of the new studies suggest that using CBT or psychotherapy post-ketamine treatment may help retain benefits for longer.

Finally, it is worth understanding that although IV ketamine therapy is still not fully FDA-approved. However, ketamine use for managing depression is a US FDA-approved approach. The US FDA has already approved an intranasal spray of ketamine for fast depression management. However, studies show that IV therapy is better as it allows using higher ketamine dosages, whereas slow-releasing tablets and nasal sprays might be a better fit as maintenance therapies.

So, it would be correct to say that ketamine is a new horizon in the battle against depression.

References

1. Lee B. National, State-Level, and County-Level Prevalence Estimates of Adults Aged ≥18 Years Self-Reporting a Lifetime Diagnosis of Depression — United States, 2020. MMWR Morb Mortal Wkly Rep [Internet]. 2023 [cited 2024 Feb 16];72. Available from: https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm
2. Horwitz AV. How an Age of Anxiety Became an Age of Depression. Milbank Q. 2010 Mar;88(1):112–38.
3. Depression – National Institute of Mental Health (NIMH) [Internet]. [cited 2024 Feb 16]. Available from: https://www.nimh.nih.gov/health/topics/depression
4. nhs.uk [Internet]. 2021 [cited 2024 Feb 16]. Overview – Anti-depressants. Available from: https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/antidepressants/overview/
5. Kelly K, Posternak M, Jonathan EA. Toward achieving optimal response: understanding and managing anti-depressant side effects. Dialogues Clin Neurosci. 2008 Dec;10(4):409–18.
6. Moncrieff J. Against the stream: Anti-depressants are not anti-depressants – an alternative approach to drug action and implications for the use of anti-depressants. BJPsych Bulletin. 2018 Feb;42(1):42.
7. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Anti-depressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis. JAMA. 2010 Jan 6;303(1):47–53.
8. Rosenbaum SB, Gupta V, Patel P, Palacios JL. Ketamine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Feb 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470357/
9. Mandal S, Sinha VK, Goyal N. Efficacy of ketamine therapy in the treatment of depression. Indian Journal of Psychiatry. 2019 Oct;61(5):480.
10. Anand A, Mathew SJ, Sanacora G, Murrough JW, Goes FS, Altinay M, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine. 2023 Jun 22;388(25):2315–25.
11. Gastaldon C, Papola D, Ostuzzi G, Barbui C. Esketamine for treatment resistant depression: a trick of smoke and mirrors? Epidemiology and Psychiatric Sciences [Internet]. 2020 [cited 2024 Feb 16];29. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061126/
12. Nikolin S, Rodgers A, Schwaab A, Bahji A, Zarate C, Vazquez G, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. eClinicalMedicine [Internet]. 2023 Aug 1 [cited 2024 Feb 16];62. Available from: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00304-8/fulltext
13. St W, D W, Mk F, L F, M G, Rb O, et al. Cognitive Behavior Therapy May Sustain Anti-depressant Effects of Intravenous Ketamine in Treatment-Resistant Depression. Psychotherapy and psychosomatics [Internet]. 2017 [cited 2024 Feb 16];86(3). Available from: https://pubmed.ncbi.nlm.nih.gov/28490030/
14. Newsroom | University of Adelaide [Internet]. [cited 2024 Feb 16]. World-first trial uses slow-release ketamine to treat depression. Available from: https://www.adelaide.edu.au/newsroom/news/list/2023/12/11/world-first-trial-uses-slow-release-ketamine-to-treat-depression