Psychedelic Medicine: Excerpts from Field Trip Health’s Whitepaper

Major depressive disorder and treatment-resistant depression

Treatment-resistant depression (TRD)

Major Depressive Disorder (MDD), the complex mood disorder also known as clinical depression, is one of the most common psychiatric disorders seen in specialist and general medical practice. It is characterized by a sad, despairing mood that is present most of the day, nearly every day, for at least two weeks. MDD often impairs an individual’s ability to perform or function at work, at school and in social relationships. Additional symptoms might include trouble sleeping, loss of interest in activities or hobbies, changes in appetite and weight, feelings of hopelessness, trouble concentrating, physical discomfort (including chronic pain), and thoughts of suicide.

As a multi-factorial disorder, there is no single cause of depression. Risk factors and potential triggers include a genetic predisposition or family history of depression, biological factors such as brain chemistry or endocrinological imbalances, psychological stressors such as chronic stress or trauma, or the onset of physical illness such as cancer and heart disease.

While a standardized definition is not widely established, treatment-resistant depression (TRD) is generally classified as depression that has not responded to multiple antidepressant medications – usually two or more. Approximately 30% of depression cases qualify as treatment-resistant (Mazrec et al., 2014; Warden et al., 2007).

Burden of disease

The 12-month and lifetime prevalence of MDD in American adults has been estimated at 10.4% and 20.6%, respectively (Hasin et al., 2018). In Canadian adults, the 12-month and lifetime prevalence of MDD has been estimated at 4.7% and 11.2%, respectively (Knoll & MacLennan, 2017). With rising sociopolitical unrest and economic uncertainty, as well as the impact of the COVID-19 pandemic on daily living and human interaction, this number has been and is expected to continue rising.

Among people with MDD, up to 30% of cases have not responded to, or relapsed from, at least two antidepressant medications – considered treatment-resistant depression (Warden et al., 2007).

A lack of adequate treatment options in depression

Existing treatment options do not currently meet the needs of the millions of people suffering from TRD, nor the millions more with MDD who will eventually stop responding to their current medication regimen. Relapse rates when switching or progressing an additional medication step are high, at 65% and 71% for the third and fourth steps, respectively (Figure 3). Those who do respond to treatment must wait an average of six weeks before any response is observed. Further, once a patient has responded to their second antidepressant medication, before their depression is considered treatment-resistant, the average time to relapse is only four months. A trial and error, “wait and see approach” is not serving the best interests of these patient populations (Warden et al., 2007).

Figure 3. Depression relapse rates increase with each treatment step (switching or augmenting medication)

While the treatment of mental health conditions – like depression – should be holistic in order to be successful in the long term, a lack of access to holistic treatment (e.g. a combination of psychotherapy, medication and other socio-behavioural interventions) remains a problem (Phelps, 2017). Of the estimated 17.3 million US adults who experienced a major depressive episode in 2017, including the 64% of whom who experienced severe impairment due to the episode, only 44% received care by a health professional and medication treatment (NIMH, 2018).

Recently, Spravato (esketamine) was approved for use in TRD in Canada and the US. While the drug is a welcomed addition to the suite of treatment options, there lacks data comparing its efficacy to racemic ketamine, and its high list price may present access barriers for patients. Esketamine is a single enantiomer of ketamine, along with arketamine. Preclinical evidence suggests that arketamine may be largely responsible for the antidepressant effect of ketamine, rather than esketamine, alone (Hashimoto, 2019).

Beyond potential limitations in efficacy, chronic dosing at a high price point merits esketamine to be a less attractive option than ketamine for the treatment of mood disorders like MDD and TRD. In a cost effectiveness review of Spravato (esketamine), the US-based Institute for Clinical and Economic Review (ICER, 2019) deemed the drug to not be cost-effective in the treatment of TRD and estimated first-year direct medical costs at US$36,500, compared to US$3,600 for ketamine.

Trauma- and stressor-related disorders

Trauma, whether in the form of chronic stress exposure or a singular event, can lead to a number of psychiatric disorders, including depression, anxiety, acute stress disorder, and post-traumatic stress disorder (PTSD). The lifetime prevalence of PTSD, specifically, is estimated to be 9.2% and 7.8% in Canada and the United States, respectively. More acutely, past-month prevalence of PTSD is estimated to be 2.4% and 3.5% in Canada in the United States, respectively (Van Ameringen et al., 2008; Kessler et al., 2005). Lifetime prevalence is higher among certain professions, including military, police, firefighters and paramedics (Van Ameringen et al., 2008).

PTSD is highly comorbid with depression and substance use disorders (Table 1) and can cause stress mediated health conditions such as obesity, cardiovascular disease and type-2 diabetes (Ahmadi et al., 2011; Dedert et al., 2010; Van Ameringen et al., 2008). While common treatment options include medication and psychological support, analyses have found that most people suffering from PTSD experience symptoms for well over one year, despite ongoing treatment, and at least 50% remain resistant to treatment, facing recurrent or chronic symptoms (Steinert et al., 2015).

A lack of direct data has limited the estimates of the economic impact of PTSD. However, the traumagenic nature of other mood and substance use disorders undoubtedly renders the economic impact of PTSD as intertwined with that of said conditions.

Table 1. Lifetime PTSD and comorbid disorders (n=645, weighted analysis).

Ketamine-assisted psychotherapy

Ketamine as an antidepressant and anxiolytic agent

First approved by the US Food & Drug Administration (FDA) in 1970, ketamine was originally marketed as a safer alternative to existing anesthetics. At the start of the 21st century, ketamine was found to have potent and rapid antidepressant properties at sub-anesthetic doses (Zarate et al., 2006). The optimization of ketamine’s antidepressant potential is an increasingly active area of medical inquiry.

Efficacy

Ketamine is remarkably effective when compared with traditional antidepressant medications. Selective serotonin reuptake inhibitors (SSRIs) generally require weeks of continual exposure to achieve an antidepressant response, and approximately one third of patients will not respond to two or more antidepressant treatments. Moreover, the risk of violent and suicidal behavior increases in the acute period after starting a new medication. Thus, the need for safe, rapid-acting treatments for depressive conditions cannot be overstated (Earleywine & De Leo, 2020; Warden et al., 2007).

Ketamine can reduce depressive symptoms within two hours of administration, and these effects can be sustained for up to two weeks following a single dose. In the first studies of ketamine’s efficacy in TRD, Zarate et al. (2006) found a response rate of over 70%, 24 hours after only one ketamine infusion.

Additionally, a meta-analysis found that a single administration of ketamine reduced suicidal ideation in over 50% of patients immediately after dosing, compared to about 20% in the control group – effects held up to one week later. Singh et al. (2012) demonstrated the strong efficacy of a twice-weekly dosing regimen in treatment-resistant depression over three weeks, with nearly 70% of patients achieving a response by day 15 (Figure 4).

Figure 4. Change in Montgomery-Asberg Depression Rating Scale (MADRS) Score, by dose frequency, from baseline through Day 15 of the double-blind pahse in a study of intravenous ketamine in treatment-resistant depression

A. Twice-Weekly Dosing

Safety

Ketamine is generally considered safe when administered in a clinical environment by medical professionals. Ketamine is contraindicated for individuals with diagnosed or suspected psychiatrically unstable conditions. Increases in blood pressure and heart rate can occur but rarely require any medical intervention at sub-anesthetic doses. Also rare at subanesthetic doses are slowed breathing and hypercapnia (elevated carbon dioxide levels in the blood) (Tyler et al., 2017).

While dissociative, or “psychedelic”, properties may be present even at low doses, a number of studies point to these experiential components as positive mediators of the molecule’s antidepressant effects. Indeed, research on psychedelics such as ketamine and psilocybin suggests that the experiential components of the treatment may be integral to enhancing and sustaining clinical outcomes (Luckenbaugh et al., 2014).

Why is psychotherapy an integral component?

Ketamine alone can be used as a psychedelic molecule with antidepressant properties. When administered without psychotherapy, ketamine generally provides rapid relief from depressive symptoms for up to 1-2 weeks. Evidence supporting the combined use of ketamine and psychotherapy has a rich history and continues to emerge into mainstream psychiatry (Dore et al., 2019; Tyler et al., 2017). Studies with other psychedelics, such as psilocybin, suggest that the efficacy of the molecule may be amplified and extended substantially when psychotherapy is incorporated into the treatment protocol. For example, clinical research examining psilocybin-assisted psychotherapy has demonstrated a statistically significant antidepressant response after just two sessions. This benefit was maintained in numerous patients at a 6-month follow-up, without the use of traditional antidepressant medication (Figure 5; Carhart-Harris et al., 2017). These data were replicated in a randomized clinical trial by researchers at Johns Hopkins University in a study of patients with Major Depressive Disorder, with 71% of patient responding (>50% reduction in symptoms) and 58% of patients in remission at the 4-week follow-up (Figure 6; Davis et al., 2020).

Figure 5. Psilocybin-assisted psychotherapy for treatment-resistant depression demonstrates rapid, long-lasting improvements in depression severity (n=16).

Depression severity determined by the primary outcome measure, self-rated QIDS-SR16. Data are shown for the QIDS scores of 16-20 considered to reflect severe depression. All post-treatment assessments were obtained after the high-dose session, i.e. 1-week post-treatment refers to 1 week after the 25-mg psilocybin dose. All contrasts vs baseline yielded p values of < 0.001 with the exception of the 6 month contrast which was p = 0.0035.

Figure 6. Psilocybin-assisted psychotherapy for Major Depressive Disorder demonstrates rapid, long-lasting improvements in depression severity (n = 24)

The mean (SD) GRID-HAMD score was 22.8 (3.9) at baseline, 8.7 (7.6) at week 1, and 8.9 (7.4) at week 4. Effect sizes (Cohen d with 95% CI) and P values reflect the results of a paired sample t test that compared scores between baseline and week 1 (Cohen d = 3.6; 95% CI, 2.2-5.0; P < .001) and week 4 postsession-2 follow-up (Cohen d = 3.6; 95% CI, 2.2-4.9; P < .001)

The prevailing hypothesis, put forth by leading researchers in the field, states that ketamine and other psychedelics induce a neuroplastic state that can then be used to facilitate insight and the formation of new patterns of thought and behavior in patients suffering from depression (Vollenweider & Preller, 2020). A skilled psychotherapist can help the patient in this creative endeavor, ensuring that the newly induced neuroplasticity and insights gained from their psychedelic experience(s) are sustained and integrated into their lives, ideally prolonging and preventing relapse (Phelps, 2017)

Psychedelic Medicine

While psychedelics have been used for millennia via traditional medicine and some indigenous spiritual-cultural practices, their incorporation into modern medical practices has been met with legislative and social hurdles (Vollenweider & Preller, 2020). The unmet and increasing need for treatments for neuropsychiatric disorders such as depression, coupled with the growing body of evidence supporting the efficacy of psychedelics, has renewed public and medical interest in psychedelic medicine. Scientists widely agree that psychedelics present promising health benefits and favorable safety profiles compared to most consumed substances (Figure 7; Nutt et al., 2010).

Psychedelics have shown the great promise in treating psychiatric and substance use disorders when used in a controlled environment with one or more skilled facilitators (Phelps, 2017). The various nuances of psychedelic medicine, from preparation for and integration of the experiences to the consideration of aesthetic features of the surrounding environment, are being studied at many world renowned institutions such as Johns Hopkins University, Harvard, Imperial College London, Yale University, and the University of Toronto.

Evidence is mounting such that governments are beginning to acknowledge the benefits of these substances and permitting their use in a medical context. In 2020, Health Canada has approved the use of psilocybin-containing mushrooms to relieve depression and anxiety in patients facing terminal illnesses, and one patient without a terminal diagnosis.

Commercially, various companies are developing psychedelic molecules through the traditional clinical drug development pathway. Psilocybin and MDMA are in late-stage clinical trials for the treatment of treatment-resistant depression and post-traumatic stress disorder, respectively. Both molecules have been granted Breakthrough Therapy Designation by the US Food & Drug Administration (FDA) – a designation saved for drugs that treat serious conditions and demonstrate a substantial improvement over available therapies.

Notably, the Multidisciplinary Association for Psychedelic Studies (MAPS), has demonstrated substantial cost effectiveness of MDMA-assisted psychotherapy (MAP) in a population with PTSD. The peer-reviewed study estimated that, when used instead of traditional care, costs for MAP break even at 3.1 years post-treatment. Over a 30-year time horizon, a population of 1,000 individuals receiving the treatment would lead to a discounted net savings of $103.2 million, the avoidance of 43 premature deaths, and an additional 5.5 quality-adjusted life years (QALYs) gained per patient, on average (Table 2; Marseille et al., 2020).

Table 2. Net present costs, health benefits and cost-effectiveness results for 30, 10, 3.1 and 1-year analytic time horizons for 1,000 patients undergoing MDMA-assisted psychotherapy (USD; Marseille et al., 2020).

Excerpts were published by permission of Field Trip Health.

psilocybin mdma ketamine psychiatry psychedelic therapy major depressive disorder breakthrough therapy psychotherapy depressive disorder depression antidepressant anxiolytic anxiety ptsd serotonin psychedelics field trip health field trip breakthrough therapy designation health canada fda research

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