Ketamine Treatment and the Emergence of a New Era in Psychopharmacology

By Tracey A. Reger


A Picture of Depression

        “Depression affects an estimated 8% of persons in the United States and accounts for more than $210 billion in health care costs annually.” (Maurer, et al. 2018). Developed in 2005, psychologists created the PHQ-9 - a nine-item Patient Health Questionnaire. This is a commonly used measurement tool to assess the presence and severity of depression in individuals. It consists of 9 simple, Likert scale questions in which the patient responds in levels of agreement between “0” (not at all) to “3” (nearly every day). For example, one question states, “Feeling down, depressed, or hopeless.” When a respondent answers highly affirmative to this statement, then this may indicate they are experiencing a symptom of depression at that time. The PHQ-9 is both a valid and reliable measurement of the presence of depression (Bo, et al., 2020). While this measurement tool accurately captures the experience of depression, it does not provide any further insight beyond presence and severity. The diagnosis of depression is based upon a cluster of co-occurring symptoms over time in which the underlying pathophysiology is not known (Das, et al., 2018). For example, the commonality of “change in appetite” in the diagnosis of depression exists, but over-eating and under-eating are still vastly different behaviors, and may reflect different underlying mechanisms. Based upon SPECT scans, it is theorized there may be 7 different categories (with differing underlying mechanisms) of depression (Amen & Routh, 2003).

“Treatment Resistant Depression”

        And within the population of people who suffer from major depressive disorder, about 1/3 of people have what is termed “Treatment Resistant Depression,” or TRD (Baker, et al., 2020). TRD is defined by the lack of a positive response to two or more adequate trials of antidepressant medications (Baker, et al., 2020). Considering the modern treatment of depression began only in the 1950’s with MAOI’s (Lieberman, 2003), it is bold to call an illness as treatment resistant when its mechanism is hardly understood. In addition, when 1 out of 3 people are not responding to a treatment method (Blumberger, et al., 2020), perhaps the methods of treatment should be questioned rather than the illness being described as somehow particularly difficult. This term subtly speaks to the stigma of the mental illness by putting an additional burden upon the people who suffer from it. The underlying pathological mechanisms of depression are still poorly understood (Baker, et al., 2020). The concept of TRD is simply the result of the failure of a pharmacological treatment which was only very recently developed. “The current definition of treatment resistance determined by treatment failure is tautological, and ignores the many reasons why a patient may not respond to a particular intervention.” (Das, et al., 2018).

“Traditional Treatment”

        Typically, the first medical treatment for depression is an SSRI, or a serotonin reuptake-inhibitor. This is often called a traditional treatment. While the wonder drug Prozac (fluoxetine hydrochloride), the first SSRI to be marketed in the United States, was a clear breakthrough in our understanding of the neurochemical pathology of depression, it was approved by the FDA for the treatment of depression very recently – 1987- a mere 35 years ago. This “traditional treatment,” has a short history. With the discovery of SSRIS came SNRIs or serotonin-norepinephrine reuptake inhibitors, which are also now considered a part of the first-line treatment for depression (Blumberger, et al., 2020). Even when these medications prove to be successful, conventional treatment typically requires 2-6 weeks for a positive response to take place, and often accompanied by unsavory side effects. This time delay is problematic when the person suffering from depression is also experiencing suicidal ideation. Furthermore, several studies indicate that these conventional treatment methods are ineffective in treating suicidal ideation (Chang, et al., 2020). Consequently, “Given this large population of patients with TRD, there is a significant need for development of novel and more efficacious antidepressant treatment.” (Baker, et al., 2020)

Ketamine Infusion Therapy

        In 1965, ketamine (C1-581) was confirmed to be an effective analgesic and anesthetic, and by 1970 it was approved for anesthetic use by the US Food Drug Administration (FDA), and since then has been used for many years as an intravenous anesthetic. Studies on Ketamine Infusion Therapy to treat depression emerged in the early 2000’s by specialists at Yale University, and it is becoming a common off-label treatment for depression. Typically, a sub-anesthetic does is administered intravenously (over approximately 40 minutes) by a healthcare professional in a clinic providing close monitoring. Common side effects can include elevation in blood pressure and heart rate, nausea, feeling of disassociation, drowsiness, dizziness, and blurred vision, but usually dissipate quickly with the conclusion of treatment (The Journal for Nurse Practitioners, 2020.)

        Ketamine treatment has several attributes that sets it apart from traditional treatment methods as the response rate for patients is both rapid and robust. Researchers discovered that a single dose of ketamine produced rapid results in ameliorating depression within only 1-2 hours of its administration (Abdallah, et al., 2019), with 50-70% of patients with TRD feeling relief from that single dose (Abdallah, et al., 2019). While most medication’s therapeutic effect remains only while it is in the body, this is not necessarily the case with Ketamine as it proves to be effective up to 2 weeks after intravenous administration (Mandal, et al., 2019). In addition, the fundamental depressive symptom anhedonia (defined as diminished pleasure from, or interest in, previously rewarding activities) seems to be uniquely treated by ketamine while standard treatments not only do not appear to treat this symptom but may in fact cause a blunted neural response to rewards (Ameli, et al., 2014). Further, Ketamine has shown to be a promising treatment method when suicidal ideation in a patient requires immediate attention (Bartoli et al, 2019).

        Ketamine is a non-competitive antagonist at glutamate N-methyl-D-aspartate (NMDA) (Baker, et al., 2020), and clinical research has found evidence of glutamatergic dysfunction in individuals suffering from depression (Hillhouse & Porter, 2015). Glutamate is an excitatory neurotransmitter that makes significant contributions to the functioning of more than half of all synapses in the brain. The effect of Ketamine is complex: “It involves a multistep and complex cascade of events relying on different molecular targets.” (Pereira & Hiroaki-Sato, 2018, pg.313). Furthermore, ketamine may promote neuroplasticity (Aleksandrova, & Phillips, 2021). Neuroplasticity is the brain’s ability to grow and reorganize synaptic connections. For example, it was noted that ketamine treatment may have the ability to reverse the effects of chronic stress on the brain in the prefrontal cortex (Lacerda, 2020). According to Yale psychiatrist Dr. Krysta, the positive effect of ketamine is due to how the brain responds to the presence of ketamine, and it is that response that constitutes its therapeutic benefits (Chen, 2022).

A New Era

        The efficacy of ketamine has spurred new avenues of research in the underlying mechanisms of depression. “The discovery of ketamine's antidepressant effects is among the most important discoveries of the last half century.” (Chang, et al., 2020). It has also encouraged the development for more viable methods of treatment. While it is highly effective, the method of administration for ketamine infusion is labor intensive. Nevertheless, ketamine may serve as a prototype for an entirely new class of antidepressant medications (Abdallah, et al., 2019). Indeed, on March 5, 2019, the US Food and Drug Administration approved an (S)-ketamine nasal spray, Esketamine, for use in TRD (although its use is still limited to certified medical offices or clinics). While consensus seems to indicate that Ketamine Infusion is still the superior treatment, it is clear a new era in the psychopharmacological treatment of depression is now upon us.


    Abdallah, C.G., Krystal, J.H., Sanacora, G., Charney, D.S., Duman, R.S., (2019) Ketamine: A Paradigm Shift for Depression Research and Treatment, Neuron, (101)5,774-778.

    Aleksandrova, L.R., & Phillips, A.G., (2021) Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics, Trends in Pharmacological Science, 42(11):929-942.

    Ameli, R., Lally, N., Nugent, A.C., Luckenbaugh, D.A., Roiser, J.P., Zarate, C.A., (2014) Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Translational Psychiatry, (14)4.

    Amen, D.G., & Routh L.C., (2003). Healing Anxiety and Depression (1st ed.). Berkley.

    Baker, G., Matveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M. A., Baker, G. B., & Dursun, S. M. (2020). Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Therapeutic advances in psychopharmacology, 10.

    Bartoli, F., Crocamo, C., & Carrà, G. (2019). Ketamine for suicidal ideation treatment: available evidence remains convincing. Neuroscience and Biobehavioral Reviews, 99, 1–2.

    Bo, Q., Sun, Y., Fu, Z., Mao, Z., Ma, X., Wang, C., (2020) The reliability and validity of PHQ-9 in patients with major depressive disorder in psychiatric hospital, BMC Psychiatry, (20)1,474.

    Blumberger, D. M., Voineskos, D., Daskalakis, Z. J., (2020). Management of Treatment-Resistant Depression: Challenges and Strategies, Neuropsychiatric disease and treatment, (16), 221–234.

    Chang, L., Wei, Y., Hashimoto, K. (2020) A historical review of antidepressant effects of ketamine and its enantiomers. Pharmacology, Biochemistry, Behavior, (3)190.

    Chen, J. (2022, March 9). How Ketamine Drug Helps with Depression.

    Das, P., Malhi, G.S., Mannie, Z., Irwin, L. (2019) Treatment-resistant depression: problematic illness or a problem in our approach? The British Journal of Psychiatry: the journal of mental science, (214)(1),1-3.

    Hillhouse, T.M., Porter, J.H. (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Experimental and Clinical Psychopharmacology, 23(1), 1–21.

    Ketamine in the Treatment of Major Depressive Disorder. (2020). The Journal for Nurse Practitioners, 16(3), 228-231.

    Lacerda, A. L. T. (2020). Esketamine/ketamine for treatment-resistant depression. Brazilian Journal of Psychiatry, 42(6), 579–580.

    Lieberman, J.A., (2003) History of the Use of Antidepressants in Primary Care, The Primary Care Companion to The Journal of Clinical Psychiatry, (5)7.

    Mandal S, Sinha VK, Goyal, N. (2019) Efficacy of ketamine therapy in the treatment of depression. Indian J Psychiatry. 61(5), 480-485.

    Maurer, D. M., Raymond, T.J., Davis, B.N. (2018) Depression: Screening and Diagnosis, American Family Physician, 508-515.

    Mion, G. (2017) History of anaesthesia: The ketamine story - past, present and future, European Journal of Anaesthesioly, (34)9, 571-575.

    Pereira V.S., Hiroaki-Sato, V.A. (2018) A brief history of antidepressant drug development: from tricyclics to beyond ketamine, Neuropsychiatry, (6)307-322.


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