Bianca Nogrady, Oct 1, 2019
Archive for category Pharmacological
The FDA has given the green light to the first major new classes of antidepressant therapies in decades, opening up new avenues for therapeutic development.
As droughts go, the one plaguing the antidepressant drug development landscape for the past few decades has been noteworthy. Since the advent of serotonin and norepinephrine reuptake inhibitors in the 1980s and 1990s, there has been a dearth of new pharmacological therapies for mood disorders, says psychiatrist Samantha Meltzer-Brody, director of the University of North Carolina’s Perinatal Psychiatry Program. “The same medications largely that were there when I went to medical school a long time ago were still the ones we’ve been using.”
Given this state of affairs, Meltzer-Brody says she had the “most modest” of expectations a few years ago when she got involved in the first clinical trial testing a new drug, SAGE-547, for postpartum depression. Developed by Massachusetts-based Sage Therapeutics, SAGE-547 is a solution of allopregnanolone, a neuroactive metabolite of the sex hormone progesterone, which plays key roles in the female reproductive system.
Progesterone and allopregnanolone levels peak during the third trimester of pregnancy, then crash immediately after delivery. Preclinical data suggested the drop in allopregnanolone could be a trigger for postpartum depression in some women. The company-funded trial involved administering SAGE-547 to a handful of patients with postpartum depression as an intravenous infusion over 48 hours.
The response in the first patient treated with SAGE-547 was dramatic. From being withdrawn and depressed with no appetite before treatment, she began smiling, talking, eating, and interacting, Meltzer-Brody says. “After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.” Three more patients were treated, with similar results. Known by the generic name brexanolone, the drug sped through Phase 2 and Phase 3 trials before being approved by the US Food and Drug Administration (FDA) on March 19.
Now marketed by Sage Therapeutics as Zulresso, the therapy is the vanguard of a new wave of antidepressants. Although the path to market hasn’t been straightforward for all drug candidates, these treatments are known for being fast-acting and effective, and have fewer side effects than previous therapies. These improvements are reflected in the price tag: the first of these new antidepressants to reach the market—Zulresso and Janssen Pharmaceuticals’ Spravato (esketamine), approved just two weeks earlier for major depressive disorder—cost up to tens of thousands of dollars for a course of treatment.
But what really sets these new depression-treating drugs apart is the “circuit-driven” approach to their development, says Sage Therapeutics’ chief research officer Jim Doherty. A research focus on basic neuroscience has expanded understanding of how different neural circuits are involved in brain function—and how to target those circuits therapeutically. “The purpose of the brain is as a communication network,” Doherty says. Instead of thinking only in terms of candidate drug molecules and receptors, “we try to think as much as we can at that level [of the whole communication network] to understand what are going to be the circuit-level consequences of our molecules.”
A better understanding of depression
For a long time, the only treatments available for depression were two classes of antidepressants known as tricyclics and monoamine oxidase inhibitors (MAOIs), both of which were discovered in the 1950s. Three decades passed before a new class emerged—the SSRIs, with the first drug Prozac (fluoxetine) launched on the market by pharma giant Eli Lilly in 1988. (See timeline on page 65.) Still the most widely prescribed antidepressants in the world, SSRIs are thought to influence mood by increasing levels of the neurotransmitter serotonin in the brain’s synapses. But their exact mechanism of action is unknown. They’re also ineffective for many people, and even when they help, can require weeks or even months to alleviate patients’ symptoms. Researchers began to ask whether approaches to antidepressant development based on more-recent neuroscience might prove more successful.
“The exciting thing for a clinician-researcher like me is to be able to see that the field is broadening in the understanding of what’s creating depression,” says Jayashri Kulkarni, psychiatrist and director of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, who is involved in a clinical trial of esketamine funded by Janssen. “The move in the last ten years has been to look at causes of depression in terms of brain chemistry as well as brain circuitry or brain physiology, and when you do that, you actually come out with some options that are really good” as potential targets for antidepressant drugs.
Brexanolone, for example, is the product of research on how to modulate the function of the brain’s gamma-aminobutyric acid type A (GABAA) receptors, which normally interact with allopregnanolone and other neuroactive hormones. The drug began life as an epilepsy therapy, but Sage soon realized its potential for treating postpartum depression.
Esketamine, meanwhile, is one of another new class of antidepressants, based on a drug that has been in clinical use for half a century. The general anesthetic and painkiller ketamine is one of the World Health Organization’s essential medicines because of its safety and efficacy in both adults and children. A couple of decades ago, with growing awareness of the role that the neurotransmitter glutamate and its interactions with the N-methyl-D-aspartate (NMDA) receptor play in mood disorders, researchers began to investigate whether ketamine, which blocks the NMDA receptor, might also be effective in treating depression.
After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.—Samantha Meltzer-Brody, University of North Carolina
The first clinical study of ketamine for depression, published in 2000, found significant and rapid improvement in depression symptoms in seven individuals with major depression. A second randomized, placebo-controlled, double-blind crossover study in 2006 confirmed the benefits, and showed that they could be delivered within just two hours of an intravenous infusion, based on patient questionnaires. “You don’t have a suicidal patient sitting around for weeks or months trying to see if the next medication is actually going to work,” says psychiatrist and neuroscientist Ronald Duman, director of the Abraham Ribicoff Research Facilities at Yale University School of Medicine who researches ketamine but wasn’t involved in the 2006 study.
Since that research was published, interest has surged in developing new ketamine-based therapies for depression, and esketamine is the first ketamine-derived product on the market. It’s the s-enantiomer of ketamine—one of two mirror-image molecules that together make up ketamine—and is administered in a nasal spray formulation. The drug was approved by the FDA last March as an add-on therapy for treatment-resistant major depression, but not without some controversy. “The FDA gave Janssen quite a bit of flexibility,” says Todd Gould, a neuropharmacologist at the University of Maryland School of Medicine. “They only met their primary outcome in one of three acute studies.”
A typical course of esketamine involves four weeks of twice-weekly treatments, followed by maintenance doses once every one or two weeks in patients who respond, continuing for up to nine months based on clinical judgement. The choice of nasal delivery was deliberate, says Ella Daly, therapeutic area lead for mood in US Scientific Affairs at Janssen. “Unlike the intravenous formulation, the intranasal route is noninvasive, [and] we felt it would facilitate outpatient access and administration,” Daly says.
However, because esketamine, like ketamine, can have cognitive, dissociative, and even psychedelic side effects, the nasal spray must be administered in a supervised medical setting, and the patient has to remain at the clinic for at least two hours after administration. “Generally [side effects attenuate], though, with repeated dosing, so we see that reducing and being less significant,” Daly says.
Neither esketamine nor brexanolone are cheap. The list price for Spravato is $590–$885 per treatment session, or up to more than $30,000 for a full nine months of treatment at maximum dosage, while a one-time, 60-hour intravenous infusion of Zulresso costs around $34,000. But their success has caught the attention of the pharmaceutical industry, which had been moving away from psychiatric drug development due to challenges in translating animal findings into humans, says Duman, who has received fees and grant support from Johnson & Johnson, the parent company of Janssen. “There’s a very renewed interest now because of ketamine and Spravato,” he says. “This is going to help bring big pharma back to the table.”
More new antidepressants on the horizon
Esketamine’s mirror twin, the r-enantiomer of ketamine, is also being investigated as a potential therapeutic molecule. “The preclinical data from our lab and other labs indicates that the r-ketamine is the more potent antidepressant, [but] that remains to be tested in humans,” says Gould. While the s-enantiomer is a more potent antagonist of the NMDA receptor, Gould says that doesn’t necessarily translate to stronger antidepressant effects.
Gould and others are also interested in the metabolites that result from ketamine’s breakdown in the body, after research in animals found that ketamine’s metabolites were not only necessary for its antidepressant effects but could, by themselves, induce ketamine-like responses. One of those metabolites, known as (2R,6R)-hydroxynorketamine and patented by Gould and others, is about to start Phase 1 clinical trials funded by the National Institutes of Health.
At dosages that relieve depression-like symptoms in animals, the compound “does not block the NMDA receptor, it does not produce the side effects of ketamine, and it does not appear to have the potential for addiction or abuse,” says clinical pharmacologist Carlos Zarate, chief of the section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health who, with colleagues, also has patents for ketamine and its metabolites for the treatment of mood disorders.
Zarate believes that ketamine-based drugs have great potential, especially if the abuse potential and dissociative side effects are reduced. “What we do know is that ketamine, at least in our research, seems to have more-broad therapeutic effects, called pan-therapeutic effects,” Zarate says. “It seems to work very well in anxiety, [post-traumatic stress disorder] symptoms, anhedonia or lack of pleasure, suicidal thinking, and in fact sometimes even in people who have failed electroconvulsive therapy.”
The drug development pipeline for treatments that, like brexanolone, target the GABA receptor system may also be opening up. Sage Therapeutics is starting Phase 3 trials of another GABAA receptor modulator, called SAGE-217, for adults with major depressive disorder. A recent placebo-controlled Phase 2 study showed that the compound achieved significant improvements in depressive symptoms, without any major safety signals. “That molecule was designed to have the same pharmacology of Zulresso but to have an oral once-a-day pharmacokinetic profile,” Doherty says. The company also has other drugs in early development that target the same NMDA receptor system as ketamine.
It hasn’t all been smooth sailing. Pharmaceutical company Allergan had a high-profile failure of three Phase 3 placebo-controlled clinical trials of its NMDA receptor–targeting drug rapastinel, which did not meet the primary endpoint of preventing relapses of major depression. And both the brexanolone and esketamine Phase 3 trials detected high placebo response rates, a common feature of late-stage trials in depression that can make it difficult to demonstrate that a treatment is achieving a clinical benefit.
In the case of esketamine, one of its Phase 3 trials, carried out in patients aged 65 years and older with treatment-resistant depression, failed to show statistically significant efficacy compared to placebo. “It’s fair to say that studies in the elderly population in depression are more challenging because response rates typically are lower,” Daly says. That study also used a lower starting dose, she notes, adding that an older population may need a longer duration of treatment to show benefit.
Despite the setbacks, there is general agreement that the antidepressant landscape is undergoing a profound change for the better. “It’s going to be the new norm, in that next-generation treatments will be required to have a rapid onset of action unless they’re special or unique in some other therapeutic property,” Zarate says. “Imagine, for every episode of depression you intervene [in] very early, you could significantly reduce the amount of time our patients spend in depression, [are] not able to function, have poor quality of life, and are at risk of suicide.”
A HISTORY OF ANTIDEPRESSANTS
Researchers have been working for decades on new ways to treat depression, but the US market is still dominated by drugs that were developed in the late 1980s and early 1990s.
[Abstract] Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis
The aim of this study is to evaluate a novel composite measure of active range of motion (XA) and determine whether this measure correlates with active function.
Post hoc analysis of two randomized, placebo-controlled, double-blind studies with open-label extensions exploring changes in active function with abobotulinumtoxinA.
Adults with upper (n = 254) or lower (n = 345) limb spastic paresis following stroke or brain trauma.
XA was used to calculate a novel composite measure (CXA), defined as the sum of XA against elbow, wrist, and extrinsic finger flexors (upper limb) or soleus and gastrocnemius muscles (lower limb). Active function was assessed by the Modified Frenchay Scale and 10-m comfortable barefoot walking speed in the upper limb and lower limb, respectively. Correlations between CXA and active function at Weeks 4 and 12 of open-label cycles were explored.
CXA and active function were moderately correlated in the upper limb (P < 0.0001–0.0004, r = 0.476–0.636) and weakly correlated in the lower limb (P < 0.0001–0.0284, r = 0.186–0.285) at Weeks 4 and 12 of each open-label cycle. Changes in CXA and active function were weakly correlated only in the upper limb (Cycle 2 Week 12, P = 0.0160, r = 0.213; Cycle 3 Week 4, P = 0.0031, r = 0.296). Across cycles, CXA improvements peaked at Week 4, while functional improvements peaked at Week 12.
via Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis – Nicolas Bayle, Pascal Maisonobe, Romain Raymond, Jovita Balcaitiene, Jean-Michel Gracies,
[Abstract] Does Casting After Botulinum Toxin Injection Improve Outcomes in Adults With Limb Spasticity? A Systematic Review – Full Text PDF
Objective: To determine current evidence for casting as an adjunct therapy following botulinum toxin injection for adult limb spasticity.
Design: The databases MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials were searched for English language studies from 1990 to August 2018. Full-text studies using a casting protocol following botulinum toxin injection for adult participants for limb spasticity were included. Studies were graded according to Sackett’s levels of evidence, and outcome measures were categorized using domains of the International Classification of Disability, Functioning and Health. The review was prepared and reported according to PRISMA guidelines.
Results: Five studies, involving a total of 98 participants, met the inclusion criteria (2 randomized controlled trials, 1 pre-post study, 1 case series and 1 case report). Casting protocols varied widely between studies; all were on casting of the lower limbs. There is level 1b evidence that casting following botulinum toxin injection improves spasticity outcomes compared with stretching and taping, and that casting after either botulinum toxin or saline injections is better than physical therapy alone.
Conclusion: The evidence suggests that adjunct casting of the lower limbs may improve outcomes following botulinum toxin injection. Casting protocols vary widely in the literature and priority needs to be given to future studies that determine which protocol yields the best results.
Researchers used electroencephalography and artificial intelligence to identify individuals who would likely respond to sertraline, the antidepressant marketed as Zoloft.
Stanford researchers and their collaborators used electroencephalography, a tool for monitoring electrical activity in the brain, and an algorithm to identify a brain-wave signature in individuals with depression who will most likely respond to sertraline, an antidepressant marketed as Zoloft.
A paper describing the work was published today in Nature Biotechnology.
The study emerged from a decades-long effort funded by the National Institute of Mental Health to create biologically based approaches, such as blood tests and brain imaging, to help personalize the treatment of depression and other mental disorders. Currently, there are no such tests to objectively diagnose depression or guide its treatment.
“This study takes previous research showing that we can predict who benefits from an antidepressant and actually brings it to the point of practical utility,” said Amit Etkin, MD, PhD, professor of psychiatry and behavioral sciences at Stanford. “I will be surprised if this isn’t used by clinicians within the next five years.”
Instead of functional magnetic resonance imaging, an expensive technology often used in studies to image brain activity, the scientists turned to electroencephalography, or EEG, a much less costly technology.
Etkin shares senior authorship of the paper with Madhukar Trivedi, MD, professor of psychiatry at the University of Texas-Southwestern. Wei Wu, PhD, an instructor of psychiatry at Stanford, is the lead author.
The paper is one of several based on data from a federally funded depression study launched in 2011 — the largest randomized, placebo-controlled clinical trial on antidepressants ever conducted with brain imaging — which tested the use of sertraline in 309 medication-free patients. The multicenter trial was called Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care, or EMBARC. Led by Trivedi, it was designed to advance the goal of improving the trial-and-error method of treating depression that is still in use today.
“It often takes many steps for a patient with depression to get better,” Trivedi said. “We went into this thinking, ‘Wouldn’t it be better to identify at the beginning of treatment which treatments would be best for which patients?’”
Most common mental disorder
Major depression is the most common mental disorder in the United States, affecting about 7% of adults in 2017, according to the National Institute of Mental Health. Among those, about half never get diagnosed. For those who do, finding the right treatment can take years, Trivedi said. He pointed to one of his past studies that showed only about 30% of depressed patients saw any remission of symptoms after their first treatment with an antidepressant.
To diagnose depression, clinicians rely on a patient reporting at least 5 of 9 common symptoms of the disease. The list includes symptoms such as feelings of sadness or hopelessness, self-doubt, sleep disturbances — ranging from insomnia to sleeping too much — low energy, unexplained body aches, fatigue, and changes in appetite, ranging from overeating to undereating. Patients often vary in both the severity and types of symptoms they experience, Etkin said.
“As a psychiatrist, I know these patients differ a lot,” Etkin said. “But we put them all under the same umbrella, and we treat them all the same way.” Treating people with depression often begins with prescribing them an antidepressant. If one doesn’t work, a second antidepressant is prescribed. Each of these “trials” often takes at least eight weeks to assess whether the drug worked and symptoms are alleviated. If an antidepressant doesn’t work, other treatments, such as psychotherapy or occasionally transcranial magnetic stimulation, may also be tried. Often, multiple treatments are combined, Etkin said, but figuring out which combination works can take a while.
“People often feel a lot of dejection each time a treatment doesn’t work, creating more self-doubt for those whose primary symptom is most often self-doubt,” Trivedi said.
Looking for a biomarker
The EMBARC trial enrolled 309 people with depression who were randomized to receive either sertraline or a placebo.
For their study, Etkin and his colleagues set out to find a brain-wave pattern to help predict which depressed participants would respond to sertraline. First, the researchers collected EEG data on the participants before they received any drug treatment. The goal was to obtain a baseline measure of brain-wave patterns.
Next, using insights from neuroscience and bioengineering, the investigators analyzed the EEG using a novel artificial intelligence technique they developed and identified signatures in the data that predicted which participants would respond to treatment based on their individual EEG scans. The researchers found that this technique reliably predicted which of the patients did, in fact, respond to sertraline and which responded to placebo. The results were replicated at four different clinical sites.
Further research suggested that participants who were predicted to show little improvement with sertraline were more likely to respond to treatment involving transcranial magnetic stimulation, or TMS, in combination with psychotherapy.
“Using this method, we can characterize something about an individual person’s brain,” Etkin said. “It’s a method that can work across different types of EEG equipment, and thus more apt to reach the clinic.”
Etkin is on leave from Stanford, working as the founder and CEO of the startup Alto Neuroscience, a company based in Los Altos, California, that aims to build on these findings and develop a new generation of biologically based diagnostic tests to personalize mental health treatments with a high degree of clinical utility. “Part of getting these study results used in clinical care is, I think, that society has to demand it,” Trivedi said. “That is the way things get put into practice. I don’t see a downside to putting this into clinical use soon.”
When EMBARC was launched, it was part of a broader effort by the NIMH to push for improvements in mental health care by using advances in fields such as genetics, neuroscience and biotechnology, said Thomas Insel, MD, who served as director of that institute from 2002 to 2015.
“We went into EMBARC saying anything is possible,” Insel said. “Let’s see if we can come up with clinically actionable techniques.” He didn’t think it would take this long, but he remains optimistic.
“I think this study is a particularly interesting application of EMBARC,” he said. “It leverages the power of modern data science to predict at the individual level who is likely to respond to an antidepressant.”
In addition to improving care, the researchers said they see a possible side benefit to the use of biologically based approaches: It could reduce the stigma associated with depression and other mental health disorders that prevents many people from seeking appropriate medical care.
“I’d love to think scientific evidence will help to counteract this stigma, but it hasn’t so far,” said Insel. “It’s been over 160 years since Abraham Lincoln said that melancholy ‘is a misfortune, not a fault.’ We still have a long way to go before most people will understand that depression is not someone’s fault.” (President Lincoln suffered bouts of depression.)
Other Stanford co-authors of the paper are postdoctoral scholars Yu Zhang, PhD, and Jing Jiang, PhD; former postdoctoral scholar Gregory Fonzo, PhD; neuroscience graduate students Molly Lucas and Camarin Rolle; research assistants Carena Cornelssen and Kamron Sarhadi; clinical research coordinator Trevor Caudle; former clinical research coordinators Rachael Wright, Karen Monuszko and Hersh Trivedi; and former neuroscience graduate student Russell Toll. All Stanford authors, including Etkin, are affiliated with Veterans Affairs Palo Alto Healthcare System and the Sierra Pacific Mental Illness, Research, Education and Clinical Center in Palo Alto.
Etkin is a member of the Wu Tsai Neurosciences Institute at Stanford.
Researchers at South China University of Technology, the Netherlands Research Institute, Harvard Medical School, the New York State Psychiatric Institute, Columbia University and the Netherlands neuroCare Group also contributed to the work.
Insel is an investor in Alto Neuroscience.
The EMBARC study data are publicly available through the NIMH Data Archive.
The study was funded by the National Institutes of Health (U01MH092221, U01MH092250, R01MH103324, DP1 MH116506), the Stanford Neurosciences Institute, the Hersh Foundation, the National Key Research and Development Plan of China, and the National Natural Science Foundation of China.
Stanford Medicine integrates research, medical education and health care at its three institutions – Stanford University School of Medicine, Stanford Health Care (formerly Stanford Hospital & Clinics), and Lucile Packard Children’s Hospital Stanford. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu.
CBD. Cannabidiol. No matter what you call it, you may have heard health claims about this little-known part of the marijuana plant, which comes from the plant’s flowers. Some say it treats muscle aches, anxiety, sleeping troubles, chronic pain, and more.
But what does the science say?
We spoke to NIH expert Susan Weiss, Ph.D., to learn more and find out why consumers should be careful. Dr. Weiss is the director of the division of extramural research at the National Institute on Drug Abuse (NIDA).
What is CBD?
CBD (or cannabidiol) comes from the cannabis (or marijuana) plant.
The chemical compound THC [tetrahydrocannabinol] is the part of the cannabis plant that most people are familiar with because that is the part that makes people “high.” Most effects of marijuana that people think of are caused by THC.
Most recreational marijuana has very little CBD in it. CBD products are available through dispensaries, health food and convenience stores, and the internet. It’s a widely used product that’s not regulated—and is not legal to sell for its largely unproven health benefits.
How does CBD work?
Nobody really knows what is responsible for the mental and physical health benefits that have been attributed to it. CBD affects the body’s serotonin system, which controls our moods. It also affects several other signaling pathways, but we really don’t understand its mechanisms of action yet.
How much do we know about CBD as a potential treatment?
There are over 50 conditions that CBD is claimed to treat.
We do know that CBD can help control serious seizure disorders in some children (e.g., Dravet and Lennox-Gastaut syndromes) that don’t respond well to other treatments. Epidiolex is an FDA [Food and Drug Administration] approved medication containing CBD that can be used for this purpose.
There’s also data to suggest the potential of CBD as a treatment for schizophrenia and for substance use disorders. But these potential uses are in extremely early stages of development.
Are there side effects?
We don’t know of any severe side effects at this time. But there were mild side effects reported in the epilepsy studies, mostly gastrointestinal issues like diarrhea. There were also some reported drug-to-drug interactions. That’s why, for safety reasons, it’s important that CBD or any cannabis product go through the FDA review process.
Are there any specific CBD studies that you are focused on?
We are interested in CBD as a potential treatment of substance use disorders.
There is some research looking at it for opioid, tobacco, and alcohol use disorders. If CBD can help prevent relapse in those areas, that would be really interesting. We’re also interested in it for pain management. Trying to find less addictive medications for pain would help a lot of people.
What else would you like people to know?
We are concerned about the health claims being exaggerated or incorrect. The FDA issued warning letters to several companies because of untested health claims. And the CBD products themselves didn’t always contain the amount of CBD that they were reported to have—some actually had THC in them.
Another concern is that people are using CBD to treat ailments for which we have FDA-approved medications. Thus, they may be missing out on better treatments. And when they’re using CBD or other cannabis products for conditions we don’t know very much about, that’s worrisome.
[Abstract + References] Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy – Review
During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine’s active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15–25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.
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The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al., 2006). Young men are consistently over-represented as being at greatest risk for TBI (Langlois et al., 2006). While half of all traumatic deaths in the USA are due to brain injury (Mayer and Badjatia, 2010), the majority of head injuries are considered mild and often never receive medical treatment (Corrigan et al., 2010). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (Baguley et al., 2012). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (Niogi et al., 2008; Rubovitch et al., 2011). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (Faul et al., 2007), demonstrating both the long term financial and human toll of TBI.
The development of management protocols in major trauma centers (Brain Trauma Foundation et al., 2007) has improved mortality and functional outcomes (Stein et al., 2010). Monitoring of intracranial pressure is now standard practice (Bratton et al., 2007), and advanced MRI technologies help define the extent of brain injury in some cases (Shah et al., 2012). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy (Bullock et al., 2006) which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (Sahuquillo and Arikan, 2006). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (Stiver, 2009). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies (Meyer et al., 2010) and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data (Lu et al., 2007; Mbye et al., 2009; Sen and Gulati, 2010) plagued by translational problems once reaching clinical trials (Temkin et al., 2007; Tapia-Perez et al., 2008; Mazzeo et al., 2009).
The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.
The Endocannabinoid (eCB) System
Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (Mechoulam and Goani, 1967). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in Gertsch et al., 2010), synthetically produced cannabinoids used as research (Wiley et al., 2014) or recreational drugs (Mills et al., 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995).
These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 (Devane et al., 1988) and CB2 (Munro et al., 1993). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (Alger and Kim, 2011), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (Mackie, 2006). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (Herkenham et al., 1991). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (Cabral et al., 2008). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (Atwood and MacKie, 2010). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in Di Marzo, 2008) many of which are impacted following TBI.
Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (Siegel, 1999). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described (Porter et al., 2002; Chu et al., 2003; Heimann et al., 2007) the two most studied are anandamide (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (Béquet et al., 2007). Additionally, their receptor affinity (Pertwee and Ross, 2002; Reggio, 2002) and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (Hillard, 2000a). In addition, anandamide binds and activates TRPV1 receptors (Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000), whereas 2-AG also binds GABAA receptors (Sigel et al., 2011). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.
Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (Cravatt et al., 1996, 2001), localized to intracellular membranes of postsynaptic somata and dendrites (Gulyas et al., 2004), in areas such as the neocortex, cerebellar cortex, and hippocampus (Egertová et al., 1998). Inactivation of 2-AG proceeds primarily via MAGL (Dinh et al., 2002; Blankman et al., 2007), expressed on presynaptic axon terminals (Gulyas et al., 2004), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (Dinh et al., 2002). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.
[Abstract] Exploratory Randomized Double-Blind Placebo-Controlled Trial of Botulinum Therapy on Grasp Release After Stroke (PrOMBiS)
Background. OnabotulinumtoxinA injections improve upper-limb spasticity after stroke, but their effect on arm function remains uncertain.
Objective. To determine whether a single treatment with onabotulinumtoxinA injections combined with upper-limb physiotherapy improves grasp release compared with physiotherapy alone after stroke.
Methods. A total of 28 patients, at least 1 month poststroke, were randomized to receive either onabotulinumtoxinA or placebo injections to the affected upper limb followed by standardized upper-limb physiotherapy (10 sessions over 4 weeks). The primary outcome was time to release grasp during a functionally relevant standardized task. Secondary outcomes included measures of wrist and finger spasticity and strength using a customized servomotor, clinical assessments of stiffness (modified Ashworth Scale), arm function (Action Research Arm Test [ARAT], Nine Hole Peg Test), arm use (Arm Measure of Activity), Goal Attainment Scale, and quality of life (EQ5D).
Results. There was no significant difference between treatment groups in grasp release time 5 weeks post injection (placebo median = 3.0 s, treatment median = 2.0 s; t(24) = 1.20; P = .24; treatment effect = −0.44, 95% CI = −1.19 to 0.31). None of the secondary measures passed significance after correcting for multiple comparisons. Both groups achieved their treatment goals (placebo = 65%; treatment = 71%), and made improvements on the ARAT (placebo +3, treatment +5) and in active wrist extension (placebo +9°, treatment +11°).
Conclusions. In this group of stroke patients with mild to moderate spastic hemiparesis, a single treatment with onabotulinumtoxinA did not augment the improvements seen in grasp release time after a standardized upper-limb physiotherapy program.