Psychedelics for the Treatment of PTSD

 

    Post-Traumatic Stress Disorder (PTSD) is a disorder that affects millions of people that have witnessed/experienced traumatic events, the effects of which alter the futures of those affected. There are no defining parameters that identify people who will experience PTSD symptoms, however, certain factors such as length, intensity, and reaction to the trauma all play a role, it is thought that 1 in 10 men and 2 in 10 women that experience traumatic events will experience PTSD symptoms.¹

   The behaviors that accompany PTSD are thought to be incurred from stress induced structural changes in the amygdala, hippocampus, and the prefrontal cortex, as well as neurochemical changes (cortisol and norepinephrine) altering the long term circuitry that is involved in the stress response (Figure 1 and 2.).³ Each of these areas can be seen to play a role in the symptoms that accompany PTSD. The amygdala becomes hyperactive and amplifies both the flight or fight response and feelings of anxiety/fear. The hippocampus becomes underactive/down regulated showing decreases in hippocampal volume along with deficits in memory. The prefrontal cortex acts on logical thinking and also becomes down regulated, impairing executive cognitive function.²

                                     Figure 1. Effects of stress on the cortisol/norepinephrine neurochemical response.

                                               Figure 2. Overview of regulation in the main areas affected by PTSD.

    To date, the current treatment plans are time intensive and geared more towards cognitive reframing and mitigation of symptoms.¹ Trauma-focused therapy is the most common approach used for treating PTSD and commonly lasts 3-4 months.¹  Antidepressants continue to be the first line of defense against PTSD. Both SSRI (selective serotonin reuptake inhibitor) and SNRI (serotonin-norepinephrine reuptake inhibitor) have shown to be effective in treating PTSD symptoms because of their ability to increase neurogenesis within the hippocampus. However, the common themes in literature suggests that this approach is modest at best and new therapies must be introduced. The unique world of psychedelics has shown promise in the area of treating not only PTSD but also anxiety, depression, even addiction disorders. The Multidisciplinary Association for Psychedelic Studies (MAPS) has entered into phase 3 clinical trials for the use of 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) in the treatment of PTSD.

     The usage of MDMA as a treatment differs from other psychedelics as it acts as an enactogen rather than a hallucinogen. This enhancement in feelings of openness highlights the difference between the psychoactivity between the two, and this is precisely the lens that allows the patient to process and eventually accept traumatic memories.⁴ The first controlled study was completed in 2010 and showed significant results in psychoactive assisted therapy using MDMA. The study used 20 patients with treatment-resistant PTSD, with patients either receiving a placebo or MDMA at the regular treatment intervals (Figure 3.) At follow up appointments of 2 and 12 months, 83% of participants in the experimental group no longer met the criteria to be diagnosed with PTSD.⁴

Figure 3. Treatment outline.

    MDMA exerts its effect as a release of serotonin, noradrenaline and even dopamine. As an activator of the 5-HT system that enhances activity at the 5-HT1a and 5-HT1b; MDMA reduces the fear response elicited by the amygdala.^4,5 In addition to dampening of the fear response, MDMA aids in the release of oxytocin, yielding a feeling of bonding and closeness which facilitates the effect of psychotherapy and causes a decrease in the overall stress response.⁴

     While the advent of this research still lies ahead of us, the initial breach has shown promising results. Even though we may feel like we are viewing an event horizon, there is a promise of better days ahead and in all cases it can’t come quite soon enough. Yet, as the light starts to edge its way over the horizon,quickly approaching we can forget how fast progress moves.  MDMA is currently in Phase 3 clinical trials and may potentially be approved by the FDA in 2021.

Joseph Devine, Master’s Medical Sciences Student, University of Kentucky 

 References

 1.  Https://www.ptsd.va.gov/publications/print/understandingptsd_booklet.pdf. (n.d.). Retrieved November 17, 2020, from https://www.ptsd.va.gov/

2.  Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2012). A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology, 27(1), 40-52. doi:10.1177/0269881112464827

3.  Bremner, J. D., MD. (2006). Traumatic stress: Effects on the brain. Dialogues Clinical Neuroscience, 8(4), 445-461.

4.  Sessa, B., Higbed, L., & Nutt, D. (2019). A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Frontiers in Psychiatry, 10. doi:10.3389/fpsyt.2019.00138

5.  Sessa, B. (2011). Could MDMA be useful in the treatment of post-traumatic stress disorder? Progress in Neurology and Psychology, 15(6).

6.  Devine, W. (2019). Crowd’s at 23rd. New York, NY: www.billydevine.com..

Postpartum Depression: Brexanolone the next best thing?

 Illustration by Erin McPhee (Tansey, 2016)

“I refused to take prescribed medication because I believed the best cure for depression was hard work, faithful prayer, and persistence. Not taking antidepressants turned out to be a really good bad decision. My search for natural healing led me to a huge Ah-ha revelation that my own toxic thoughts were making me sick. Learning how to retrain my brain has changed my life!

 

Today I faithfully pray, work hard, AND take [MEDICATION]. Every day. I wouldn’t trade my journey through postpartum depression because it taught me awesome life tools like practicing gratitude, yoga, nutrition, and prioritizing self-care and relationships. I’ve learned to let go of perfectionism and enjoy the richness of ordinary life.

                                                                                                                                                                 —Maleah W.”

 *Adaption from Danielle Radden’s Real Stories of Postpartum Mood Disorders: Motherhood beyond the smiling images.

             Just like Maleah’s story, many women are suffering from postpartum depression but are reluctant to share their symptoms with their physician or want to take medications to help with their depression. Postpartum depression affects up to 15% of women and can have long lasting effects on mother-infant interactions (Perfetti et al., 2004). Yet in the media, the portrayal of motherhood is one of perfect health, glowing skin, happiness and lacking mental illness. In reality, society's picture of motherhood is not always the true picture for every case, oftentimes leaving women suffering in a silent battle against this vicious illness. Postpartum mood disorders range from postpartum blues, postpartum depression, and postpartum psychosis (Perfetti et. al, 2004). The symptoms typically include anxiety, fatigue, anger, sadness, irritability, with more extreme cases presenting with suicidal ideation, hallucinations, paranoia, infanticide (Perfetti et. al, 2004). Postpartum depression can start as early as 1 day postpartum and last up to 1 year, with most mothers experiencing symptoms within the first three months postpartum. Without treatment, 30-70% of women will experience depression for a year or longer (Perfetti et. al, 2004).

            Treatment remains an imperative part of fighting this illness because of the impact chronic depression of the mother has on the infant. Children born to women with chronic depression typically have greater developmental delays in language, cognition, and emotion (Yonkers et. al 2009; Perfetti et al, 2004). Often children of depressive women have behavioral difficulties in school as well. This raises two questions. First, what are treatment options? Secondly, which are the best options for combating PPD?

            Fortunately, there are therapies that can be used for treatment of postpartum depression that have proven to be successful at combating and preventing severe depressive moods.  Currently, the most common tools are psychotropic medications (Perfetti et. al, 2014). Recently, the FDA approved the drug in this class, called Brexanolone, specifically to be used for treatment of postpartum depression (NIH, 2019). Brexanolone is an analog of the endogenous human hormone allopregnanolone, specifically developed and designed through a series of basic and translational neuroscience studies (NIH, 2019).

Figure 1. Comparison of Normal brain signaling compared to patients with PPD and treatment with Brexanolone.

The journey to Brexanolone began in 1980’s when NIMH Intramural Research Program (IRP) researchers discovered that metabolites of the hormones progesterone and deoxycorticosterone bound to and acted upon receptors for gamma-aminobutyric acid (GABA) (NIH, 2019). When these steroids act on GABA, they amplify GABA-activated chloride ion currents and impact the excitability of neurons (Figure 1). Researchers funded by NIMH and researchers of NIMH IRP continued their research by clarifying how the metabolites fluctuate during times of stress in rats, the estrous cycle in rats and the menstrual cycle in humans.  Concentrations of allopregnanolone, a metabolite from steroid hormones, was shown to increase during pregnancy then drops after birth (NIH, 2019). This shift in hormone changes is believed to lead to the development of depression and anxiety. This information resulted in a biopharmaceutical company developing the injectable drug brexanolone.

So how successful is brexanolone? In Kanes et al. (2017) a small proof of concept study on brexanolone, the drug was well tolerated in all patients with severe PPD. The study participants were assessed for depression using the Hamilton Rating Scale for Depression (HAMD and Edinburgh Postnatal Depression Scale (EPDS) and for anxiety using the Generalized Anxiety Disorder 7-item scale (GAD-7). Overall, the mean HAMD, EPDS, GAD-7 and Patient Health Questionnaire (PHQ-9) scores were decreased after infusion initiation and remained low through the end of infusion (60 hours post infusion) and at the last time point assessed (84 hours post infusion) (see Figure 2.).

Figure 2. Changes in mean total scores of assessments: HAMD, EPDS, GAD-7, PHQ-9 from baseline to last time point assessed ( Kanes et al.,2017).

Following the results reported by Kanes et al. (2017), larger studies were performed as phase III clinical trials which reported very promising results (Dacarette-Galeano & Diao, 2019). In March 2019, Brexanolone was approved through a risk evaluation and mitigation strategy known as the (REMS) program and is now available only to patients at certain certified health facilities with active monitoring by health care providers (Dacarette-Galeano & Diao, 2019). So dear reader, I’m sure you are asking why is such a huge requirement and precaution undertaken with a drug that has been proven to be successful? Brexanlone, though very effective, produced adverse events in a couple of the women in the larger studies, which included suicidal ideation, intentional overdose attempt and altered states of consciousness (Dacarette-Galeano & Diao, 2019). Therefore despite the enthusiasm surrounding the novel drug, there are still concerns about Brexanolone’s accessibility, contingent approval only with a REMS program, and cost-- which comes to around $34,000 for patients not including hospitalization cost (Dacarette Galeano & Diao, 2019).

 

By Toacca Taylor, Master of Medical Science candidate, University of Kentucky

 References

Tansey, Claire (2017). Recognizing the signs of postpartum depression. Retrieved November, 2020, from https://www.todaysparent.com/family/womens-health/recognizing-the-signs-of-postpartum-depression/

 

Radden, D. (2020). Real Stories of Postpartum that Mamas should know about - Mindful Mamas: Self-Care and Mindfulness for Moms. Retrieved November, 2020, from https://www.mindfulmamasclub.com/bloghub/real-stories-of-postpartum-mood-disorders danielle-radden

 

Perfetti, J., Clark, R., & Fillmore, C. M. (2004). Postpartum depression: identification, screening, and treatment. WMJ-MADISON-, 103, 56-63.

 

NIH, NIMH. (2019). Bench-to-bedside: NIMH research leads to brexanolone, first-ever drug specifically for postpartum depression [Press release]. Retrieved November, 2020, from

https://www.nih.gov/news-events/news-releases/bench-bedside-nimh-research-leads-br exanolone-first-ever-drug-specifically-postpartum-depression

 

Yonkers, K. A., Wisner, K. L., Stewart, D. E., Oberlander, T. F., Dell, D. L., Stotland, N.,

& Lockwood, C. (2009). The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General hospital psychiatry, 31(5), 403-413.

 

Kanes, S. J., Colquhoun, H., Doherty, J., Raines, S., Hoffmann, E., Rubinow, D. R., & Meltzer-Brody, S. (2017). Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression. Human Psychopharmacology: Clinical and Experimental, 32(2), e2576.

 

Dacarett-Galeano, D. J., & Diao, X. Y. (2019). Brexanolone: A Novel Therapeutic in the Treatment of Postpartum Depression. American Journal of Psychiatry Residents' Journal, 15(2), 2-4.