CBD: an effective therapeutic for seizures?

During the past few years, cannabis has become increasingly accepted from a societal standpoint. Contrary to the overall acceptance of the public, very little funding was gathered to explore therapeutics derived from cannabinoids. The lack of funding may be attributed to psychoactive effects produced by some of the products harvested from the plant such as THC. This has limited the potential benefits that patients may be able to receive due to limited research involving of the isolation of compounds derived from cannabis. Recently, a new isolated compound from hemp, cannabidiol (CBD), looks to have potential benefits but more research still needs to be completed to understand its therapeutic applications.

Figure 1: Minimal energy conformations (A) and 2D structures of CBD and THC (B)(Burstein, 2015).

Cannabis is comprised of two main compounds, which are tetrahydrocannabinol (THC) and CBD. CBD is the main compound of cannabis that has sparked research interest due to its similar structure and nature to THC, without producing the psychoactive high that THC produces (Figure 1). CBD is a cannabinoid, so its chemical targets are the CB1 and CB2 receptors. The CB1 receptor is found on neurons and glial cells, while the CB2 receptor is primarily found throughout the immune system (Volkow, 2015). The difference in structural conformation between CBD and THC allows THC to tightly bind to the CB1 receptor while CBD binds to the CB1 receptor with low affinity. The difference in binding affinities allows CBD to act on other pathways in the brain without eliciting a psychoactive effect (Volkow, 2015). The broad range of CBD’s therapeutic effects include exerting antioxidant, neuroprotectant, anti-tumor, antipsychotic, and anti-anxiety activities. These therapeutic uses have been tested through cell culture and animal models, however, in recent years a new therapeutic benefit of CBD emerged. Emerging research has indicated that CBD may also be used to reduce seizures and act as a mild anti-convulsant and is now an FDA approved therapeutic for treating seizures within genetic diseases.

            Research completed by Patel et al. (2019) emphasized a possible clinical application of CBD. Using the TMEV-induced model of epilepsy, researchers were able to observe the role CBD plays in epileptic seizures. Here, researchers administered two different doses of TMEV to the mice; one group was administered 180 mg/kg and the other group was administered 150 mg/kg and each dose was administered twice a day. These mice were analyzed based on the number and intensity of seizures experienced daily (graded by the Racine scale). When observing the outcomes between the two populations, they observed that the population administered with the 180mg/kg dose of CBD experienced a significant decrease in the frequency and severity of seizures due to TMEV infection. While the population administered with 150 mg/kg of CBD experienced decreased frequency of seizures, they did not experience a significant decrease in the severity of seizures. These results from Patel et al. (2019) suggest that CBD displays promising characteristics as an anti-seizure therapeutic for intractable epilepsies. This evidence of therapeutic success within the TMEV model suggests that further studies should be completed to further investigate the pharmacological effects and mechanisms behind CBD.

            Following the research done by Patel et al., Anderson et al. (2019) explored the pharmacokinetics of CBD and clobazam as a therapeutic to treat Dravet’s syndrome. Dravet’s syndrome, similarly to TMEV, is an intractable childhood epilepsy. The evidence of CBD’s effects as an anti-seizure medication sparked Anderson et al.’s interest to test CBD’s pharmacokinetics as an adjunct with clobazam. Anderson et al. (2019) utilized Scn1a^+/- mice to model the effects of Dravet’s syndrome. Utilizing this mice population, they administered clobazam with various concentrations of CBD, including concentrations that were above and below the anticonvulsant dosage for CBD. Anderson et al. (2019) then subjected the Scn1a^+/- mice to hyperthermia-induced seizure experiments and measured the drug-drug interactions and overall therapeutic efficacy of the treatment. When an anticonvulsant dose of CBD was paired with clobazam, Anderson et al. observed an increased efficacy of clobazam treatment on the mice. CBD acted by extending the half-life, increasing exposure time, and increasing interactions of clobazam and its target, N-CLB. Anderson et al. also discovered a pharmacokinetic mechanism between CBD and clobazam that enhanced inhibitory GABA_A receptor activation, further contributing to its efficacy in treating intractable epilepsy.

Figure 2: U.S. funding of the various cannabis research sectors (https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug)

The studies by Patel et al. and Anderson et al. displayed the therapeutic efficacy and the pharmacological interactions associated with the anti-seizure effects of CBD. Even with strong evidence supporting CBD’s therapeutic benefits, research is still slow to take off due in part, to cannabis being labeled as a Schedule I drug. This labelling has led to funding cannabis research that focuses on harm and abuse of cannabis, rather than the therapeutic benefits (O’Grady, 2021). This skewed distribution of funding has allowed for increased research on why cannabis is a dangerous and abusive substance, rather than the possible benefits of isolated compounds derived from cannabis. This has made introducing cannabis-derived therapeutics challenging, as it is illegal to produce so it is hard to obtain and further isolate its compounds. This negative stigma has been slowly chipped away by public opinion and cultural shifts, which can be observed by 36 states having legalized cannabis and their products for medicinal use. This rapid shifting of cultural norms and values has allowed further CBD and cannabinoid research to take place, allowing for further exploration of the therapeutic benefits that these compounds display. This increase in research has allowed the medical community to realize the therapeutic and clinical benefits of CBD use. The only question to be answered now is: when will society see CBD as a viable therapeutic, rather than simply another recreational substance?

           

By William Lathram, A Master's of Medical Science Student at the University of Kentucky            

References

Anderson, L. L., Absalom, N. L., Abelev, S. V., Low, I. K., Doohan, P. T., Martin, L. J., Chebib, M., McGregor, I. S., & Arnold, J. C. (2019). Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia, 60(11), 2224–2234. https://doi.org/10.1111/epi.16355

Bissell, L. J. L., Balneaves, L. G., Oliffe, J. L., Capler, N. R., & Buxton, J. (2013). Perceptions of cannabis as a stigmatized medicine: A qualitative descriptive study. Harm Reduction Journal, 10(1), 2. https://doi.org/10.1186/1477-7517-10-2

Burstein, S. (2015). Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic & Medicinal Chemistry, 23(7), 1377–1385. https://doi.org/10.1016/j.bmc.2015.01.059

Commissioner, O. of the. (2020, July 31). FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease. U.S. Food and Drug Administration. Retrieved October 27, 2021, from https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare.

O'Grady, C. (2020, August 27). Cannabis research database shows how U.S. funding focuses on harms of the drug. Science. Retrieved October 27, 2021, from https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug.

Patel, D. C., Wallis, G., Fujinami, R. S., Wilcox, K. S., & Smith, M. D. (2019). Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus. Epilepsia Open, 4(3), 431–442. https://doi.org/10.1002/epi4.12351

Volkow, N. D. (2015, June 24). The biology and potential therapeutic effects of cannabidiol. NIDA Archives. Retrieved October 17, 2021, from https://archives.drugabuse.gov/testimonies/2015/biology-potential-therapeutic-effects-cannabidiol.

  

Micro-dosing as a Potential New Therapy for Various Psychiatric Disorders?

 

Source: Vanity Fair

In our culture today we tend to learn about new information via media whether that is movies, Instagram, or YouTube. Recently, one tv-show that has spurred some commotion is, Nine Perfect Strangers, which can be found on Hulu. In the beginning we are introduced to nine different people who have each gone through different perils throughout their life and have had a hard time overcoming them. Each of them decides to attend a retreat where they are promised healing and transformation. Towards the end of the show, it is uncovered that Masha the women who has been hosting this retreat has been micro dosing each of the guest. Each morning she was making a tea with a miniscule amount of psychedelics, which would help them deal with deeply rooted issues such as anxiety, depression, anger management issues and addiction. Interestingly, throughout the show we see the benefits of this micro dosing but also the drawbacks. If you are someone like me, you may be wondering whether this would work? Would this be a new treatment for patients in the future? No worries, these will all be questions that I will answer as I discuss more about micro-dosing in the upcoming paragraphs.

         There are pharmacological mechanisms of action for micro-dosing; however, it is possible that individual differences in metabolism, psychopathological diseases, personality, interpretation of signals may affect how micro-dosing outcomes manifest (Anderson et al., 2019). The receptor involved in micro-dosing is the serotonin 5HT-2A receptor. A variety of mutations of this receptor which may affect how the 5HT-2A agonists such as LSD and psilocybin are processed may be present in different individuals. This may be exemplified with an example of a healthy person in comparison to an individual who may be suffering with depression. In addition, the effect of these substances on 5HT-2A receptors has enhanced neural plasticity and neurogenesis along with neuroprotective effects, which are relevant to neurodegenerative diseases (Ona & Bouso, 2019). As we can see, micro-dosing will not have the same effect on everyone and there really isn’t a one dose fits all since there are genetic components involved in micro dosing that result in differential responses.

Source:  www.slashgear.com

So, you may be wondering if I begin micro-dosing what type of benefits could I possibly expect? Many personal accounts of micro-dosing have been uploaded on to YouTube and qualitative study was completed looking at some of these personal accounts. Anderson and Kjelleren (2019), classified their findings from these YouTube videos into four categories. The first category included enhanced state and heightened senses (more focus and energy, experiencing the present moment, improved mood and reductions in sadness, anger, and stress). The second category included insights and transformations (augmented self-reflection, thoughtful insights which led to deeper connections and changes in habits). The third category included improved abilities and optimal performance (increased creativity, enhanced productivity and effectiveness, and extraversion in social settings). In the final category was relief and cure for health conditions (benefits regarding depression, anxiety, and ADHD etc). These qualitative studies are informative, but survey studies are a little more helpful when potential benefits are emphasized. One survey study recruited 278 participants who had already been micro-dosing either with LSD or psilocybin. Anderson et al. (2019a) reported the major benefits of micro-dosing to be an improved mood (26.6%), improved focus (14.8%), creativity (12.9%). Some users even reported a reduction in caffeine (44.2%), alcohol (42.3%), cannabis (30.3%), and tobacco (21%). They also found that micro-dosing resulted in lower scores for dysfunctional attitudes and negative emotions, but higher scores for wisdom, creativity, and open mindedness (Anderson et al., 2019). It is easy to get caught up on all these positive results especially in an age when people want a quick fix to issues such as mental illness. I believe micro-dosing has very positive benefits, but it is important to consider the harmful effects as well before participating.

         There were some negative side effects reported by some of the participants from these previous studies. Anderson and Kjelleran (2019), mentioned how some users experienced increased anxiety, panic attacks, gastrointestinal cramps, restlessness, jitters, insomnia, decreased problem solving skills and cognitive function. In some instances, patients experienced a worsening of symptoms including mental health, over stimulations, or a bad trip when LSD was combined with cannabis. Honestly, the side effects continue from there and contradict the positive effects experienced in the paragraph above. To me, this emphasizes how little we still know about micro-dosing, and how studies are difficult to compare due to the difference in methods and variables which may or may not be confounding variables. I believe this may be a promising therapy for the future, but studies still need to be completed to have a firmer understanding of these positive and negative benefits.

         In my view this is an exciting field, in which more research needs to be completed before more of the public jumps on the micro-dosing bandwagon. As we have seen from other therapies such as cannabidiol (CBD), that micro-dosing will not be an end all therapy where it will fix each issue that you have but will be helpful in mitigating issues you may be experiencing. This therapy is gaining momentum in the medical community, but research is still being completed before it will be offered as a legal therapy. We have a lot to look forward to as the scientific community continues to discover more about micro-dosing.

 By Ashely Wahlman, A Master’s of Medical Science Student at the University of Kentucky College of Medicine

 Sources:

Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., Hui, K., & Hapke, E. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal, 16(1), 43. https://doi.org/10.1186/s12954-019-0308-4

Anderson, M., and Kjellgren,A. (2019). Twenty Percent better with 20 micrograms?A qualitative study of psychedelic microdosing self-rapports and discussion on YouTube.Harm reduction Journal,16(1).

Ona,G., and Bouso, J.C.(2020).Psychedlic drugs as a long-needed innovation in psychiatry. Qeios, https://doi.org/10.32388/T3EM5E.2

 

Sleep and No-Sickness? The Preventative Impact of Melatonin on Covid-19 Patients

 

http://toonclips.com/600/cartoon-sleep-deprived-businessman-sleeping-standing-up-by-toonaday-66847.jpg

Being the hardworking students that we are, we tend to allow our sleep schedules to fall out of “circadian-rhythm” (haha get it?). We tend to give into the marketing of pretty Starbucks coffee drinks to keep us awake and the idea of studying for hours prioritizing good grades over getting a good night’s sleep. This contributes to the 50 to 70 million Americans who suffer from sleep disorders or sleep deprivation and more than 60 million Americans who take sleep medications every year. It is estimated that Americans spend more than $41 billion on sleep aids and remedies (Penn Medicine). But sleeping issues have been around since our earliest existence, so what did we do before?

 

When we think of sleep remedies, we can look back as early as early Egyptian and ancient Roman times. One of the most well-known ancient remedies is chamomile. Not only was it great for sleeping issues but has many other positive effects including its ability to act as a cold remedy (Wise Ape, 2021). Today we often use it as a common nighttime staple to help us sleep and relax. However, for some people it does not work, or they need something stronger to aid their sleep. This is where the understanding and pharmacological production of melatonin became a game changer to the sleep-deprived people of the world and now possibly Covid-19 patients? First, let’s understand where melatonin comes from.

 

Melatonin is a natural hormone that is produced by our pineal gland. It is a derivative of tryptophan, an important amino acid necessary for maintaining of many of bodily functions. It was first isolated by Aaron B Lerner in 1958 of Yale University School of Medicine when he was conducting vitiligo research on frogs. He isolated a hormone melatonin thinking it would lighten the skin of frogs, only it didn’t. Instead, he found that it was responsible for maintaining cycles of wakefulness and rest. With respect to its target, melatonin binds to two type of G-protein receptors, MT1 and MT2, in the suprachiasmatic nucleus, a tiny region of the hypothalamus in the brain. High levels of melatonin can induce sleep. When our sleep schedule is normal, darkness prompts our pineal gland to secrete melatonin. The lack of melatonin production during the day will elicit wakefulness. This is why if your sleep schedule is off because you are doing things like staring at your phone until 2am, you are exposing yourself to blue light which will not let you produce melatonin. Now you are a walking zombie at your 8am class because you got no sleep. However, as important as melatonin is to sleep, it has been found to have other amazing benefits, including helping in learning and memory, fertility and reproduction, and most-recently immune activity (Srinivasan et al., 2005). This finding has been used to explore its benefits to Covid-19 patients.

 

SARS-CoV-2 can cause severe inflammatory responses and oxidative stress; two biological events alleviated by melatonin. One way melatonin can act is by reducing oxidative stress through its ability to increase an antioxidant known as glutathione. Glutathione is an important antioxidant that combats damage within cells, such as free radicals. With respect to COVID-19, a common symptom resulting from viral infection is oxidative stress caused by an increase in free radicals. Thus, melatonin can increase glutathione levels and reduce conditions of oxidative stress in COVID-19 patients. In addition, melatonin has anti-inflammatory abilities which arise from its affinity to G-protein-coupled receptors which control the secondary signaling pathways that impact the immune response. With respect to COVID-19, the infecting SARS-CoV-2 virus binds with high affinity to angiotensin-converting enzyme 2 (ACE2) receptors on the epithelial lining of the lungs. This binding triggers a proinflammatory response. However, calmodulin, an important messenger protein in the G-protein-coupled secondary pathway, controls the amount of ACE2 receptors on the plasma membrane. Melatonin can inhibit the coupling of ACE2 receptors and SAR-COV2 during viral particle fusion through its inhibition of calmodulin as it is regulated by the secondary messenger pathway (Cross et al., 2021). But if you don’t believe me, just look at how complex melatonin’s target pathway is (Cecon et al., 2017).

Fig. 1. Melatonin receptor pathway. Graph from E Cecon et al., Melatonin receptors: molecular pharmacology and signaling in the context of system bias. British Journal of Pharmacology. (5 July 2017).

Complex, I know! There are so many other ways melatonin has proven to be a great drug for other disease use other than just sleep. But from those short explanations on how melatonin can work, you get the idea. This is an incredible new form of exploration that can truly help so many people fighting COVID-19. As incredible as these findings do sound, we are still exploring the full accuracy and positive effectiveness of this drug on COVID-19 patients. More importantly, it is imperative to stay on top of new research and findings as we are constantly at risk of COVID-19 as the world begins opening up again. So now we ask the big question, do we bring this idea further to light that COVID-19 is a potential drug market for COVID-19? Researchers have already explored melatonin’s benefits in viral disease similar to COVID-19 so why not to treat COVID-19 patients? One problem is that we could be risking another “Ivermectin” fiasco, with multiple people storming our local CVS and buying all of the over-the counter melatonin thinking it can completely fight COVID-19 (only this being a much safer and beneficial option if you are a struggling college student who never sleeps). What do you think?

By Sarah Mandviwala, A Master's of Medical Science Student at the University of Kentucky

 

Works Cited

Ape, T. W. (2018, April 17). The history of chamomile tea. Wise Ape. Retrieved October 12, 2021, from https://www.wiseapetea.com/blogs/knowledge/the-history-of-chamomile-tea.

Cecon, E., Oishi, A., & Jockers, R. (2017, August 17). BPS Publications. British Pharmacological Society | Journals. Retrieved October 12, 2021, from https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13950#:~:text=Melatonin%20receptor%20signalling%20pathways.,and%20increase%20in%20intracellular%20Ca2%2B.

Cross, K. M., Landis, D. M., Sehgal, L., & Payne, J. D. (2021, August). Melatonin for the early treatment of covid-19: A narrative review of current evidence and possible efficacy. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Retrieved October 12, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190272/#bib38.

Melatonin and zolpidem: Do sleeping aids actually work? Penn Medicine. (n.d.). Retrieved October 12, 2021, from https://www.pennmedicine.org/updates/blogs/health-and-wellness/2018/july/sleeping-aids.

Srinivasan, V., Maestroni, G. J. M., Cardinali, D. P., Esquifino, A. I., Perumal, S. R. P., & Miller, S. C. (2005, November 29). Melatonin, Immune Function and aging. Immunity & ageing : I & A. Retrieved October 12, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1325257/.

 

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.

Tuberculosis - A disease old as ancient civilizations still wreaking havoc

 

TB granuloma.
https://www.merckmanuals.com/professional/infectious-diseases/mycobacteria/tuberculosis-tb

    Usually, when you are about to join new job or enroll in a school/university, you are told go through a mandatory health check-up to make sure you have been vaccinated. You may even get a Tuberculosis (TB) skin test. If you were born in the United States, the TB skin test will most likely not result in any reaction. For me, however, I develop a giant, itchy red bump within two days where the nurse had inserted a small fluid known as tuberculin underneath my skin. Looking at my medical history, I have had the BCG vaccine and had been treated for latent TB. The next step for me is to get a chest x-ray which have been normal so far. Although tuberculosis cases in the United States are low, about 2.7 cases per 100,000 persons, nearly 80% of the active TB cases are due to reactivation of latent TB¹. These cases can become incredibly serious, if the person with reactivated TB had already been treated with TB previously¹. Screening for drug resistance becomes an immediate priority. 

    To understand the growing concern of drug-resistant Mycobacterium tuberculosis bacteria, we must understand TB history and how it infects people. Tuberculosis has been around since antiquity. Mycobacterial DNA has been found in ancient Egyptian mummied remains dating back to the Middle Kingdom, 2050 B.C².  During the 17^th and 18^th century, many scientists have documented various pathological signs of tuberculosis. It was not until 1882 when Robert Koch figured out that the cause of tuberculosis was a mycobacterium³. M. tuberculosis spreads when an infected person coughs, sneezes, spits or speaks. Most people infected with TB do not have any signs or symptoms of the disease until the disease is activated. These people have latent TB and about 10% of persons with latent TB later have active TB if untreated⁴. Interestingly, persons who have latent TB are not contagious; only persons with active TB are⁴. When the bacteria is activated and grows in the lungs, it’s known as pulmonary TB⁴. Extrapulmonary TB affects tissues such as the lymphatics (tuberculosis lymphadenitis), bones (skeletal tuberculosis), various tuberculosis of the abdomen, or CNS tuberculosis which causes meningitis⁵. However, let us just focus on pulmonary tuberculosis, which is the most common.

Robert Koch
.https://www.thefamouspeople.com/profiles/robert-koch-6563.php

    When tuberculosis bacterium is inhaled, the bacteria migrates to the alveolar sacs. Here pulmonary macrophages endocytose the bacterium. The bacteria reside in the phagosome and replicate and evade macrophage digestion⁶. The infected macrophage attracts other cells of the immune system such as more macrophages, T cells and B cells⁶. Macrophages fuse around the infected macrophage and T cells form a barrier around the macrophages⁶. Fibroblasts and collagen that surround the T cells and form a granuloma⁶. The on-going infection is a constant battle between tissue destruction and healing causing an increasing amounts of scar tissue⁶. In the chest x-ray, granulomas are the primary characteristic of a TB infection⁶. TB can become dormant during the granuloma stage and can be reactivated if the immune system is weakened when challenged by other events such as an infection by another pathogen like HIV ⁶. Therefore, it is essential that persons with latent TB are treated to reduce any chance of activating the infection⁷. Persons wIsoniazid is a pro-drug that is activated by the catalase-peroxidase enzyme found in M. tuberculosis⁸. Once activated, isoniazid becomes isonicotinic acyl-NADH which inhibits the synthesis of mycolic acids in the mycobacterial cell wall⁸. Rifampin, also known as rifampicin, inhibits bacterial RNA polymerase ⁹. Isoniazid and rifampin are two of the most potent drugs used to treat active and latent TB. From 2018 to 2019, there have been a 10% increase of multi-drug resistant (MDR) TB, where both rifampin and isoniazid no longer have an effect⁴. Only 57% of MDR TB patients have been successfully treated globally⁴. MDR TB is diagnosed by detecting growth rate of the bacteria in a sputum sample treated with the rifampin or isoniazid¹⁰. This is then followed by a series of PCR tests to check for drug resistant genotypic markers¹⁰. Persons with MDR TB are treated with a second line of TB medications which are much more toxic.  Other agents used are expensive injectable agents such as amikacin/kanamycin, fluoroquinolone as well as other compounds that might have some activity against the infection like cycloserine¹⁰. The side effects vary from nephrotoxicity to drug induced hepatitis depending on the treatment plan¹⁰. Although rare, extensively drug resistant (XDR) TB exists as well where the person is not only resistant to the first line of drugs but also resistant to at least one of the second line of drugs¹⁰. Scientists are now focusing on generating better antibiotic drugs that better target mycobacteria for patients with MDR TB¹⁰.

https://www.who.int/news/item/30-10-2017-who-report-signals-urgent-need-for-greater-political-commitment-to-end-tuberculosis

     For the first time in few decades, two new TB drugs have shown to have positive outcomes for persons with MDR-TB as compared to those treated with the usual regime¹⁰. Delamanid belongs to a class of nitroimidazoles and was developed by Otsuka Pharmaceutical Development and Commercialization, in Osaka, Japan¹¹. The mechanism of action is similar to isoniazid. It inhibits mycolic acid synthesis¹¹. The side effects are dizziness and QT prolongation, which means the heart takes a longer time to repolarize¹¹. Bedaquiline belongs to the diarylquinoline group and was developed by Janssen Pharmaceuticals in Titusville, NJ¹¹. The drug inhibits mycobacterial ATP synthase and has a long half-life¹¹. More studies need to be conducted regarding bedaquiline’s side effects and toxicity as well as possible resistance¹¹. With two new drugs on the market, there is potential that MDR-TB can be treated and hopefully eradicated in countries where TB is endemic.

By Bhavani Gudlavalleti, A Master’s of Medical Sciences Student at the University of Kentucky

Literature Cited

1.       Schwartz, N. G., Price, S. F., Pratt, R. H., & Langer, A. J. (2020, March 19). Tuberculosis - United States, 2019. Retrieved October 23, 2020, from https://www.cdc.gov/mmwr/volumes/69/wr/mm6911a3.htm

2.     Zink, A. R., Sola, C., Reischl, U., Grabner, W., Rastogi, N., Wolf, H., & Nerlich, A. G. (2003). Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. Journal of clinical microbiology, 41(1), 359–367. https://doi.org/10.1128/jcm.41.1.359-367.2003

3.     Iseman, M. (2013, February 01). Tuberculosis: History. Retrieved October 23, 2020, from https://www.nationaljewish.org/conditions/tuberculosis-tb/history

4.     WHO. (2020, October 14). Tuberculosis (TB). Retrieved October 23, 2020, from https://www.who.int/news-room/fact-sheets/detail/tuberculosis

5.     Golden, M. P., & Vikram, H. R. (2005). Extrapulmonary tuberculosis: an overview. American family physician, 72(9), 1761–1768.

6.     Desai, Rishi. [Medscape]. (2018, Jan. 9). Tuberculosis | Clinical Presentation. [Video]. YouTube. https://www.youtube.com/watch?v=0qFiflLL21U

7.     CDC. (2020, February 13). Treatment Regimens for Latent TB Infection. Retrieved October 23, 2020, from https://www.cdc.gov/tb/topic/treatment/ltbi.htm

8.     Timmins, G. S., & Deretic, V. (2006). Mechanisms of action of isoniazid. Molecular microbiology, 62(5), 1220–1227. https://doi.org/10.1111/j.1365-2958.2006.05467.x

9.     Wehrli W. (1983). Rifampin: mechanisms of action and resistance. Reviews of infectious diseases, 5 Suppl 3, S407–S411. https://doi.org/10.1093/clinids/5.supplement_3.s407

10.  Millard, James, Ugarte-Gil, Cesar, and Moore, David A J. "Multidrug Resistant Tuberculosis." BMJ : British Medical Journal 350.Feb26 10 (2015): H882. Web.

11.  Migliori, G. B., Pontali, E., Sotgiu, G., Centis, R., D'Ambrosio, L., Tiberi, S., Tadolini, M., & Esposito, S. (2017). Combined Use of Delamanid and Bedaquiline to Treat Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis: A Systematic Review. International journal of molecular sciences, 18(2), 341. https://doi.org/10.3390/ijms18020341ith latent TB are treated with either rifampin for three to four months or isoniazid for six to nine months⁷. The dosage and drug concentrations vary based on age and body mass. These same drugs are used for persons with active TB⁷.

Parkinson’s Disease: A New Avenue for Drug Development

     Neurodegenerative Diseases affect millions of people worldwide and your chances only go up as you age. Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease behind Alzheimer’s affecting ~10 million worldwide. PD is mainly a movement disorder causing tremors in the extremities. As the disease progresses tremors worsen along with the development of a stooped posture, shuffling gait, gastrointestinal issues, and many cases progress into dementia¹. Simply put, these effects are caused by the accumulation of Lewy bodies (aggregates mainly composing of the protein α-synuclein) in dopamine producing neurons (dopaminergic neurons). These Lewy bodies affect the neuron’s ability to produce dopamine along with negatively affecting other cellular functions. There are no current cures for PD, but there are a host of treatments to offset symptoms. One of the most successful of these treatments is dopamine injections which help compensate for the dysfunction of the affected neurons².

https://www.labiotech.eu/medical/axovant-parkinsons-disease-gene/

    Research and drug development for PD has focused mainly on the main culprit of the disease, dopaminergic neurons.  However, there are many other cell types in the brain which all interact with each other. Astrocytes have recently become of interest as drug targets for neurodegenerative disease. Astrocytes perform many roles in the brain and work directly with neurons to keep them healthy and functional. They provide metabolic and structural support, are involved in the blood brain barrier, contribute to neuroinflammation, and take up and degrade extracellular debris including α-synuclein. In fact, reactive astrocytes are a key factor in PD development³. To study the interaction of astrocytes and dopaminergic neurons Domenico et al. employed a co-culture system using induced pluripotent stem cells (iPSC). These stem cells are made by taking an adult cell and transfecting them with four specific genes. These genes help the cells revert to a stem cell state wherein they can become any type of cell, a state similar to that of early embryos. The resultant stem cells were then induced to become either dopaminergic neurons or astrocytes. The use of iPSC allows us to create cells which will have the disease of any patient. 

(Domenico et al. 2019)

    This co-culture system allows us to study the interactions between astrocytes and dopaminergic neurons with and without PD. Using this system, we have been able to detect astrocyte involvement in the progression of PD. Most notably is their role in the accumulation of Lewy bodies. When healthy astrocytes and healthy neurons are co-cultured there is no evident accumulation of Lewy bodies. To see if astrocytes with PD could drive disease a co-culture was done with PD astrocytes and healthy neurons. In this experiment not only were Lewy bodies detected but the survival of dopaminergic neurons was decreased. This suggests that dysfunctional astrocytes contribute to the development of PD. A final co-culture was set up using PD neurons and healthy astrocytes to see if astrocytes were able to offset the dysfunction of diseased neurons. This resulted in a significantly lower accumulation of Lewy bodies and increased survival of neurons⁴.

     At the time of writing this blog there are only a few studies that have been published studying astrocyte interactions with dopaminergic neurons in PD. There is evidence that astrocytes actively exchange α-synuclein, the main component of Lewy bodies, with dopaminergic neurons and degrade it. PD astrocytes have varying degrees of impairment in autophagy and lysosomal function meaning that they are not as able to destroy and discard unwanted or dysfunctional proteins and cellular components⁵. Astrocytes have also been shown to be mitochondrial donors to neurons in another model of PD. Dysfunctional mitochondria are often implicated in PD and the donation of healthy mitochondria to dopaminergic neurons significantly offset PD related phenotypes in dopaminergic neurons⁶.

    The evidence of astrocyte involvement in PD opens the doors to new research into drug development. We may design drugs to target astrocytes to slow or stall the progression of not only PD but other neurodegenerative diseases. The co-culture system using iPSC also allows us a more compete picture for study neurodegenerative diseases.

By Meagan Medley, a Master of Medical Science Student at the University of Kentucky

  References

 1.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

2.  Chaudhuri, K. R., & Schapira, A. H. (2009). Non-motor symptoms of Parkinson's disease: Dopaminergic pathophysiology and treatment. The Lancet Neurology, 8(5), 464-474. doi:10.1016/s1474-4422(09)70068-7

3.   Booth, H. D., Hirst, W. D., & Wade-Martins, R. (2017). The Role of Astrocyte Dysfunction in Parkinson’s Disease Pathogenesis. Trends in Neurosciences, 40(6), 358-370. doi:10.1016/j.tins.2017.04.001

4.   Domenico, A. D., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J. P., Richaud-Patin, Y., . . . Consiglio, A. (2019). Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease. Stem Cell Reports, 12(2), 213-229. doi:10.1016/j.stemcr.2018.12.011

5.  Aflaki, E., Stubblefield, B. K., Mcglinchey, R. P., Mcmahon, B., Ory, D. S., & Sidransky, E. (2020). A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease. Neurobiology of Disease, 134, 104647. doi:10.1016/j.nbd.2019.104647

6. Cheng, X., Biswas, S., Li, J. et al. (2020) Human iPSCs derived astrocytes rescue rotenone-induced mitochondrial dysfunction and dopaminergic neurodegeneration in vitro by donating functional mitochondria. Transl Neurodegener 9, 13. https://doi.org/10.1186/s40035-020-00190-6