It was in 1962 when Calvin Stevens, a chemist at the pharmaceutical company Parke-Davis, tried to synthesize an anesthetic that he wished had less negative side effects than the previously used compound phencycyclidine (PCP). Stevens was successful in doing so and called his product CI-581. Shortly after, it was a medical doctor called Edward Domino who applied this substance for the first time at sub-anesthetic doses to his study subjects, being inmates at the Michigan Jackson prison, seeking to describe its effect on human consciousness. Due to repeated out of body experiences, a state in which the mind seems to dissociate from the body, Domino’s wife suggested this substance to be classified as a dissociative anesthetic. As such, CI-581, later called ketamine, was added to the materia medica by the FDA in 1970.
The dose-dependent effects of ketamine to induce either anesthesia or dissociation do not share an equal amount of scientific interest in medicine and clinical research. On the one hand, the high safety profile on vital functions such as respiration and heart rate during anesthesia has boosted ketamine into the hall of fame within hospitals, being a WHO-declared “essential medicine” since 1985. On the other hand, the shared phenomenology of classical psychedelics and ketamine of a dose-dependent tendency towards a “loss of the ego” has attracted a lot off-label experimental use, with one of the most famous figures of the psychedelic scene, John Lilly, having been highly addicted to the substance for years. Partly for such reasons, the mind-body dissociation induced by lower-dose ketamine is recognized as a reminiscence of the “dirty drug” image that the substance has been carrying around since its psychedelic dawn. Ketamine has been recently identified as a possibly revolutionary novel antidepressant but it is by no means clear by which mechanisms this effect comes about. It is quite possible that the most unwanted dissociative “side-effect” is the key to this problem, opening a door behind which other psychedelics such as LSD or psilocybin await their call to the center stage of psychiatric medicine. Along with the dissociative effect of ketamine come phases of inward journey that can be both blissful or frightening, however both of these states are meant to be clinically helpful. For instance, a depressed patient might enter a stage of regaining meaning in life that is preluded with a stage of confronting the traumas that have led to the development of the disease in the first place. However, the vast majority of researchers follow a different path and are convinced that the actual antidepressive holy grail that ketamine might embody is separate and might even be separated in future pharmaceutical developments from the psychoactive experience that it induces and rather hidden deep in certain cellular pathways that are yet to be described.
To keep up with the pace of newly generated insights, this brief state-of-the-art-review brings about a description of the most important recent papers that have been published in 2018 about ketamine use in psychiatry so far and tries to integrate it into the larger mosaic of psychedelic medicine against depression.
What are we talking about?
Depression is more than just being sad. Depression (or major depressive disorder) is a devastating psychiatric illness, being the leading cause of disability worldwide. Today, more than 300 million people worldwide suffer from its health consequences. In the Western world, depression is diagnosed by psychiatrists based on one of two available manuals: The Diagnostic and Statistical Manual of Mental Disorders (DSM) as the US- American standard or the European International Classification of Disease (ICD). The DSM 5-based clinical parameters for diagnosing depression are depressed mood or a loss of interest or pleasure in daily activities for more than two weeks, mood representing a change from the person’s baseline, impaired social, occupational and educational function. The ICD 10-based clinical parameters for diagnosing depression are similar, split into the three main symptoms depressed mood, loss of interest and loss of energy of which at least two must be present for at least two weeks, and “other symptoms” (e.g. difficulty to concentrate, decreased self-estimation, feeling of guilt, retardation/agitation, self-mutilation, sleep disturbance, appetite disturbance). Depression can be treated pharmacologically and non-pharmacologically, with both approaches having the goal of having the patient regaining a stable sense of cognitive and emotional control. The wide range of non-pharmacological options that can be divided into psychotherapy such as cognitive behavioral therapy, interpersonal psychotherapy, cognitive analysis and social therapy such as enhancement of social skills and the work with relatives are valid and clinically effective. In the following, the focus will be on pharmacological treatment options as this method harbors many pitfalls that must be overcome for a successful psychiatric practice on depression in the 21st century.
What’s the problem?
Although the disease classification of depression by both DSM and ICD have been the gold standard for decades, accumulating criticism arises regarding the mere descriptive nature of gathering subjective symptoms into a complex pathological condition such as depression. Think about the scenario of a closely related person dying or less dramatic, an instant dismissal from your job. That might both lead to a mental state for at least two weeks that fulfill the criteria of a clinical depression, however you are likely to recover from that given sufficient time and without professional assistance or medication. Many voices are thus raised to articulate the demand that (neuro)biological mechanisms of depression should be added to complement these imprecise DSM and ICD-based parameters, framed into respective cultural/ sociological backgrounds. This would furthermore lead to a finer distinction between the already existing, but less clear-cut, sub-classes of a general major depressive disorder. These include mild, moderate and severe forms of depression as well as reactive depression, which results from environmental traumas as exemplified above.
What’s the solution?
The promises of the past…
A biologically-based assessment of depression would provide valuable information to the mostly unresolved question about the etiology of depression and subsequently its treatment. In their thoroughly researched publication1 “a brief history of antidepressant drug development: from tricyclics to beyond ketamine”, Vitor Pereira and Vinicius Hiroaki-Sato therefore argue for a rational, evidence based-driven search for pharmacological interventions against depression. This seems like a given in a science-driven field like clinical psychiatry. Nevertheless, it is exactly the historical application of antidepressants that has fallen victim to overemphasizing clinical observations and the failure to acknowledge new paths to be taken. Most antidepressants on today’s market increase the active concentration of the neurotransmitters serotonin (5-Hydroxytryptamine, 5-HT) and/or norepinephrine (NE) in the brain, molecules belonging to the chemical class of monoamines. The serendipitous discovery that led to the monoamine hypothesis of depression occured in patients who received reserpine, a substance used to treat high blood pressure, and simultaneously developed symptoms of depression as a side effect. It was found that reserpine lowered the amount of 5-HT and NE in the synapses by enhancing their degradation by an enzyme called monoamine oxidase (MAO). Conversely, tuberculosis patients that received iproniazid, a MAO-inhibitor, experienced elevation of their mood. Shortly after these discoveries, MAO-inhibitors (“MAOIs”) were the first pharmacological agents on the market against depression. A big problem arose with the observation that along with an unsatisfactory clinical efficacy, patients receiving MAOIs experienced serious side-effects such as changes in blood pressure, sweating, sleep disturbance, weight gain or hypertensive crisis (when combined with dietary tyramine). This has subsequently led to a declining prescription of MAOIs by physicians and psychiatrists over the years. After another unsuccessful trial with a class of antidepressants that due to their three-ring chemical structure were called tricyclics, today’s well known and prevalent selective serotonin reuptake inhibitors (“SSRIs”) were the first antidepressive agents that followed a rational drug design with fluoxetine being the first SSRI having reached the US-American market in 1988. However, also SSRI prescriptions fell and still fall short in providing a near complete restoration of the patient’s psychological homeostasis: Roughly one third of patients are not responding to this treatment at all and the time lag from first intake to clinical improvement can last up to several weeks, posing an additional psychological burden for the patient.
…and the hopes of the future
A possibly groundbreaking discovery was made at the beginning of this millennium. Robert Berman and colleagues reported that a single subanesthetic dose (0.5 mg/kg) of intravenous ketamine elicited an almost immediate antidepressive response in patients that lasted for several days. Many follow-up studies undermined this result and it was even extended with reports of ketamine treatments being especially promising for severely depressed patients with suicidal ideation and generally patients that had been treated unsuccessfully with two SSRI treatment schemes, so called “non-responders”.
How did the scientific community go about these results? It was known that the ketamine treatment scheme by Berman was accompanied by mildly dissociative effects. Also, ketamine was found not to alter 5-HT or NE but the glutamatergic neurotransmitter systems, pointing towards a paradigm shift in the way to think about depression’s etiology. Over the course of the following years, research has largely focused on the latter hallmark, dissecting the glutamatergic pathway and its alteration by ketamine, hoping to extract a biomarker candidate with which depression could be successfully treated on a large scale. The dissociative effect, on the other hand, has been again widely ignored or seen as unwanted side-effect that needed to be rationalized away. That is, just like with the development of SSRIs, which has turned out not to be a therapeutic success, ketamine research has begun as an investigation into its molecular underpinnings rather than investigating closer the holistic level, including the psychedelic experience. Let’s look at some of the discoveries of this developmental direction.
Can’t see the wood for the trees
In March 2018, Panos Zanos and Ted Gould presented a detailed summary2,3 of proposed antidepressive mechanisms of ketamine. Believing that the dissociative properties of ketamine are distinct from its antidepressive effects, the two authors argue that it is neuroplasticity; the potentiation of pre-existing neuronal connections in addition with the establishment of de novo synapses that represents the key to understanding ketamine’s antidepressive properties. Ketamine’s most pronounced activity is probably the non-competitive antagonism of a glutamatergic ionotropic receptor called NMDA. In the “disinhibition hypothesis”, it is this mechanism of action in specific areas of the brain in which this receptor is highly expressed that leads to a higher production of proteins, ultimately giving rise to new synaptic connections. Apart from the disinhibition hypothesis, there are several other complementary proposed ideas of ketamine’s action that result in the same outcome. One revolves around a metabolite of ketamine that is not a NMDA antagonist but an AMPA (another ionotropic glutamate receptor) agonist. This metabolite has been found to have antidepressive but non-dissociative properties in mouse models of depression, further stimulating the authors’ conviction that ketamine’s psychoactive properties are unwanted for its medicinal properties. The general epistemological problem of translating results from animal studies to humans, especially when it comes to mental disorders, is however an important factor that seems to be underestimated here.
How does a caterpillar become a butterfly?
Now, assuming that neuroplasticity plays a crucial role in ketamine’s antidepressive properties, how could the establishment of new neuronal connections help depressed patients overcome their suffering? One speculation might be that more neuronal connections allow the brain to gain more cognitive flexibility. That idea might be hard to understand so let’s break it down to its basic principles: A very typical of the many existing symptoms in depressed patients is the inescapable loop of thoughts revolving around the patient’s inferiority, a mental state commonly known as rumination. If we would want to superficially describe rumination in a neuroanatomical way it would be the dominant non-dynamic behavior in a set of brain structures known as the default mode network (DMN). The DMN is active for example when we think about ourselves. A non-dynamic behavior means that the DMN is very rigid functionally within its defining brain structures. That is, because of the DMN’s rigidity in depressed patients, there is a tendency towards a negative thinking pattern about oneself. Let’s assume now that ketamine is given to a depressed patient with the result of an increase in synaptogenesis that results in a higher connectivity of the DMN with other brain areas. This increased neuronal dynamics means that the patient is no longer stuck in rumination but can think about other, non-depressing things.
Let’s go a step further. We just thought about transcending the molecular, single-cellular effect of ketamine onto the systems level, i.e. the overall brain connectome. A crucial point to think about is that the dissociation of the DMN via an increased synaptogenesis elicited by ketamine might be explanatory ground for the subjective mind-body dissociation of the patient. If this is true, then looking at optimizing the molecular pathway architecture by tedious laboratory work does not provide the whole picture behind ketamine’s use as antidepressant, it would rather be necessary to look at the resulting subjective quality, the mind-body dissociation, of ketamine for its antidepressive quality to see it as a whole.
In their manuscript4 “ketamine for the treatment against addiction: evidence and potential mechanisms”, Ezquerra-Romano et al. mention ketamine psychedelic therapy (KPT) as a model for this approach of utilizing psychedelic experiences as a way to treat depression. Mainly developed by the two Russian researchers Krupitsky and Grinenko, KPT makes use of an easier remodeling of emotional contents that are related to a specific behavior after ketamine has been applied in a psychoactive dose. The treatment scheme contains a focus on providing relieve of addictive behavior by providing verbal affirmations to create positing meaning and a purpose in life as well as enhancing negative emotional valence of thoughts related to the substance of abuse. In people suffering from heroin addiction – addiction is a disease with a high rate of depressive comorbidity – subjective ketamine experiences after intramuscular ketamine injection (2 mg/ kg) resulted in a better abstinence rate after two years compared to the control group that received the active placebo. Further studies have revealed that a lower dose of ketamine (0.2 mg/kg) showed a less effective result in creating abstinence in addicted patients, pointing towards an important role of ketamine’s psychoactive effect. Interestingly, it was not the mere dissociative effect that was responsible for the healing, but rather mystical-type experiences that mediated the motivation to quit. These experiences included to “undergo a cathartic process, improve relationships with the world and other people, maintain positive psychological changes and enhance self-awareness and personal growth”. The idea that inner journeys, i.e. states in which patients are given the opportunity to face their individual roots of their depression by self-reflection, contemplation and navigation through difficult emotions, mediate the antidepressive effect of ketamine is at least in part supported by another manuscript5 by Marc Niciu and his team. They investigated whether antidepressant efficacy is uniquely related to dissociative symptoms and concluded that both derealization and depersonalization were modest predictors of antidepressant response to subanesthetic dose ketamine infusion.
What are we heading for?
In the “park scene” of the Oscar-winning movie good Will Hunting, the good-hearted psychotherapist played by Robin Williams gives a thoughtful lecture on the difference between knowledge and experience to the young genius Will Hunting:
“If I’ll ask you about art, you’ll probably give me a skinny on every art book ever written… Michelangelo? you know a lot about him. Life’s work, political aspiration, him and the pope, sexual orientation, the whole story, right? But I bet you can’t tell me what it smells like in the Sistine chapel. You never stood there and looked up to that beautiful ceiling. If I ask you about women you probably give me a syllabus of your personal favorites, you may have even been laid a couple of times. But you can’t tell me what it feels like to wake up next to a woman and feel truly happy. If I ask you about war you probably throw Shakespeare at me: Once more into the breach, dear friends! … But you’ve never been near one. You never held your best friend’s head in your lap and watch him gasp his last breath. If I ask you about love, you probably quote me a sonnet. But you never looked at a woman and felt totally vulnerable.”
This quote encapsulates the status quo that we are in with regards to research into ketamine as a novel antidepressant. We have a lot of literature knowledge about ketamine but we lack the practical and professional wisdom of experience that it can bring about. In today’s pharmacological interventions against depression treating the cause is mistaken for treating the symptoms. SSRIs are suited to have depressed patients regain a certain degree of control over their life. The value of this treatment is however questionable if the very root of why the individual patient’s life got out of control remains untouched. This is a fundamental problem. Many experiments worldwide are performed to establish a most detailed map of brain structures involved and cellular pathways affected in depression to find biomarker candidates and develop personalized medicine. At the same time, the possibilities of treating the causes through addressing mechanisms that come from within the patient are mostly disregarded. Just like you cannot still your hunger by looking a food pictures on Instagram, depressed patients cannot be completely cured by a pill that neglects the aforementioned fundamental problem.
As stated above, psychotherapy has always been a very valid approach to treating depression on an individual patient basis. Psychotherapeutic sessions are targeted towards an emotional opening of the patient, such that a deeply buried combination of trauma-fear-anxiety-sorrow-regret-pressure can be released and processed. A typical session is conducted with a therapist that assists the patient, and with ketamine and other psychedelics, this effect can be potentiated dramatically.
So, what can we expect from future research into antidepressive medication? A seemingly hard-to-solve dichotomy has been outlined between a reductionist’ view of depression and that of a psychotherapist. The former focuses on unraveling the cellular mechanisms behind depression and its pharmacological antidotes. The latter, if it is connected to a therapeutic phenomenology induced by psychedelic compounds, wants to bring cure from the inside. If looked into closer, however, those two approaches do not exclude but complement each other. It is of utmost importance to push the boundaries of knowledge in any field that human curiosity can get a hold on. This is equally important to prevent and fight false beliefs and convictions as it is to understand our very self. Clinical Neuroscience and its methodology can help us understand the very basics of a disease and how to cure or prevent it. However, we must be aware that our ability to understand is limited by our Euclidian-based three-dimensional thinking. In cases like psychedelic-associated psychotherapy against depression, this boundary can be dissolved and bring about new hope to severely ill people. It is time to step out of the exclusive thinking between black and white and embrace the shades of grey that exist in psychiatric research. It is time to not only preach interdisciplinarity but to fully put it into practice.
In a real world-scenario, Robin Williams who committed suicide due to his depression in 2014 would have probably loved to extend his advice to Will Hunting by the words: “If I ask you about depression, you can tell me all about the cellular mechanisms behind classical antidepressants and the new developments with regards to ketamine. You know all about how ketamine induces neurogenesis by increasing the expression of important genes. But you can’t tell me how it feels like to be relieved from excruciating mental pain and be given a new hope in life by that one psychedelic experience.”
1 Pereira, V., Hiraoki-Sato, V. (2018). A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatrica; doi: 10.1017/neu.2017.39.
2 Zanos, P., Gould, TD. (2018). Intracellular Signaling Pathways Involved in (S)- and (R)-Ketamine Antidepressant Actions. Biological Psychaitry. 83(1): 2-4; doi: 10.1016/j.biopsych.2017.10.026.
3 Zanos, P., Gould, TD. (2018). Mechanisms of ketamine action as an antidepressant. Biological Psychiatry. 23: 801–811; doi: 10.1038/mp.2017.255.
4 Ezquerra-Romano, I. I., Lawn, W., Krupitsky, E., & Morgan, C. J. A. (2018). Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology; doi: 10.1016/j.neuropharm.2018.01.017.
5 Niciu, M., Shovestul, BJ., Jaso, AJ., Farmer, C., Luckenbaugh, DA., Brutsche, NE., Park, LT., Ballard, ED. and Zarate, CA. (2018). Features of Dissociation Differentially Predict Antidepressant Response to Ketamine in Treatment-Resistant Depression. Journal of Affective Disorders; doi: 10.1016/j.jad.2018.02.049.