Depression Esketamine Ketamine

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Study Finds Ketamine Nasal Spray Effective For Treating Depression: What You Should Know

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A new study finds that a nasal spray formulated from the anesthetic ketamine is a safe, fast-acting and effective treatment for treatment-resistant depression. Researchers presented the findings this week at the annual meeting of the American Psychiatric Association.

Esketamine, the intranasal formulation of ketamine, recently received FDA approval as a depression treatment when used with an oral antidepressant, based in part on findings from this study. The results open the door to a potential new alternative for the estimated 30% of depression patients suffering from treatment-resistant depression.

The study included 197 adults from 39 outpatient centers over a two-year period. All of the participants had either moderate or severe depression and hadn’t responded well to at least two antidepressants in the past. Participants were randomly assigned to one of two groups: The first switched from their current antidepressant treatment to esketamine nasal spray and a new oral antidepressant; the other switched from their current treatment to a placebo nasal spray and a new antidepressant.

The results showed significant improvements in depression symptoms among those in the esketamine group compared to the placebo group four weeks into the study, with signs of improvement starting much earlier.

“The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression,” the study concluded.

“Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” said Michael Thase, M.D., one of the study authors. “The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpins just how important this development is for patients with difficult-to-treat depression.”

Depression Esketamine Ketamine

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Study Shows How Ketamine Reverses Depression—and How its Benefits Could Be Extended

The powerful but temporary benefits of ketamine against depression might be extended if the new brain-cell connections it promotes could be preserved, according to a new study published April 12 in Science from researchers at Weill Cornell Medicine.

Depression affects tens of millions of people in the United States alone, which could lead to suicide in severe cases, and ketamine is the only widely-tested antidepressant drug that relieves depression symptoms within hours of taking it—as opposed to weeks for more commonly prescribed antidepressants like Prozac. Ketamine also is effective for many patients who do not improve with standard antidepressants. But ketamine is potentially addictive and has other side effects, and so is typically given in just a single dose or short series of doses, the benefits of which tend to fade within days.

The study reveals that in mouse models of depression, a single dose of ketamine quickly reverses depression-like behavior and extends that effect by promoting the growth of new brain-cell connections, but most of these new connections disappear again in a few days.

“Our findings suggest that interventions aimed at maintaining these new connections could be useful for sustaining ketamine’s antidepressant effects,” said study senior author Dr. Conor Liston, an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute and an associate professor of psychiatry at Weill Cornell Medicine.

Dr. Conor Liston. Photo credit: Rene Perez

Ketamine originally was developed in the 1960s as an anesthetic, and is still widely used in veterinary medicine, though its psychedelic effects in humans have led to its abuse as a party drug. Ketamine also has been used “off label” at a lower dose as an antidepressant, and in March the U.S. Food and Drug Administration for the first time approved a version of ketamine for antidepressant use.

In the Science study, Dr. Liston, who is also an assistant professor in the neuroscience program at the Weill Cornell Graduate School of Medical Sciences and a psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center, and his colleagues sought a better understanding of ketamine’s antidepressant effect on the brain and why it wears off when it does. They used advanced microscopy techniques to observe neurons in the brains of active mice during the induction of depression-like behavior—using a stress hormone, for example—and after ketamine treatment.

The scientists focused on the medial prefrontal cortex (mPFC), a brain region involved in emotion regulation that is known to undergo changes with depression behavior in both mice and humans. They found that the emergence of depression-like behavior in the mice corresponded to the loss, from mPFC neurons, of many of the root-like “dendritic spines” through which these neurons receive input signals from other neurons.

A single dose of ketamine swiftly reversed the depression behavior and prompted the growth of new spines on affected neurons, including the specific restoration of some spines that had been lost. However, within several days most of these newly grown spines disappeared.

Dr. Liston and colleagues also observed that depression-like behavior in the mice corresponded to disruptions of the circuits formed by the affected mPFC neurons, such that the coordinated activity of these neurons was less frequent and involved fewer neurons. However, the researchers noted that the reversal of these circuit disruptions with ketamine, and the reversal of depression-like behavior, occurred just a few hours after treatment; in other words, as rapidly as ketamine benefits human patients. By contrast, the regrowth of dendritic spines was not evident until at least 12 hours after treatment, indicating that these new spines were not required for inducing ketamine’s antidepressant behavioral effects acutely.

However, they went to show that spine restoration was required for the long-term maintenance of the antidepressant effect. In collaboration with Drs. Haruo Kasai and Haruhiko Bito, investigators at the University of Tokyo, who developed a new optogenetic tool for deleting new synapses, the scientists showed that removing these new spines after ketamine treatment caused depression-like behavior to recur within a few days.

Ketamine is known to cause molecular changes in some neurons that can quickly but transiently boost their communications with other neurons through existing connections. Dr. Liston and colleagues suspect that this short-term boost in communications accounts for ketamine’s initial antidepressant effect, and also spurs the growth of new dendritic spines.

The findings show, in any case, that the new spines help sustain ketamine’s antidepressant effect long after the drug is gone from the brain. Increasing the survival of the new spines with an additional intervention thus could prolong the benefits of a single dose or short course of ketamine—improving the lives of many people with depression.

Dr. Liston and colleagues are now preparing to study interventions that could do this. “In principle, we could deliver a drug to the brain to promote the survival of these new connections,” Dr. Liston said. “We might even try a non-drug intervention such as transcranial magnetic stimulation, which is already FDA-approved as a depression treatment, and could potentially be modified to promote synapse survival.”

ost drugs that treat depression don’t work for about one-third of people who take them. That’s why researchers were excited when they found that the anesthetic ketamine was an effective, fast-acting antidepressant for two-thirds of people in that treatment-resistant population. But even though the US Food and Drug Administration approved a version of the drug for treating depression last month, researchers still know little about how it confers its beneficial effects.

In a new study, researchers took a close-up gander at neurons in live mice under chronic stress, a condition that models depression in rodents. They found that a dose of ketamine helped first restore electrical activity and then rebuild physical connections between neurons that were lost during stress (Science 2019, DOI: 10.1126/science.aat8078). The observations suggest ketamine has both immediate and more sustained effects on how neurons function in the brain.

Neuroscientist Conor Liston at Weill Cornell Medicine and his colleagues implanted a prism into the frontal region of the rodents’ brains that, combined with a specialized microscope that captures images at extremely high resolution, allowed them to observe branches of nerve cells called dendrites in great detail over several weeks. They could even see tiny nubbins on the dendrites called spines, which form the synapses connecting nerve cells.

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The scientists gave the mice daily shots of corticosterone, the main mouse stress hormone, for three weeks. By the end of that time, the number of spines on the animals’ dendrites decreased significantly. The animals also drank less sugar water and were less keen to explore their cages than before the shots, both signs of depression in mice.

Then, Liston’s team administered a shot of ketamine. Behavioral tests showed that the mice got their pep back within three hours. After 24 hours, spines began reappearing on the dendrites—often in the same locations where they had been before.

Unlike most available antidepressants, ketamine relieves symptoms fast—often within three hours. The fact that the spines didn’t regrow for a full day suggested that their reappearance wasn’t responsible for the short-term behavioral effects, Liston says. Through follow-up experiments, the team determined that the short-term effects resulted from ketamine restoring electrical activity within groups of neurons that had become less active with corticosterone treatment.

To understand the drug’s more sustained effects, the researchers used a light-based technique to delete the newly regrown spines, and found that without them, the mice returned to their “depressed” behavior state. The researchers concluded that synapse formation was required not for inducing, but for maintaining ketamine’s effects, Liston explains. His team next plans to look for ways to enhance those synapses’ survival. In humans, such survival-enhancing methods could involve additional drugs, brain stimulation therapies, talk therapy, or even exercise.

Technologically, the study “was a tour de force,” says Mark Rasenick, a neuroscientist at the University of Illinois at Chicago. “Because they were able to [see spine formation] in real time, they were able to dissociate the rapid and the slower effects of ketamine.”

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Nutrition Uncategorized

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Bacteria and endurance athleticism

Veillonella , which consumes lactate, blooms in marathon runners

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ndurance athletes’ ability to keep going may be thanks, in part, to the bacteria that live in their guts.

By studying the stool samples of men and women who ran in the Boston Marathon, as well as a group of ultramarathoners and rowers, a team of researchers has found that as these elite athletes crunch through mile after mile, they harbor large blooms of an intestinal microbe that seems to convert some of the lactate produced by their muscles into a beneficial compound.

When the researchers seeded the digestive systems of mice with these bacteria, from a genus called Veillonella, they were able to run longer than a control group dosed with bacteria that don’t metabolize lactate. This hints that what Veillonella do with lactate—a byproduct of exercise—might enhance performance (Nat. Med. 2019, DOI: 10.1038/s41591-019-0485-4).

“This is really a big step forward,” says Orla O’Sullivan, a researcher at University College Cork who has studied the microbiome of rugby players. Athletes have a more diverse gut microbiome than the rest of us, she says, but much of what has been reported before was correlation—previous work hadn’t established a connection to athletic performance. “It’s the first time that it’s been shown that a single genus can influence endurance in mice.”

To do the research, Jonathan Scheiman, one of the Harvard Medical School scientists on the team, collected fecal samples from Boston-area people running the marathon in 2015, as well as people who were more sedentary. He gathered samples from one week before the race to one week after the race, roughly every day.

Scheiman previously told C&EN, “I was riding around Boston five hours a day picking up s*** in a Zipcar and putting it on dry ice on the back seat.”

The researchers sequenced the DNA from the stool samples, and found that Veillonella was overrepresented in the samples from the athletes. What’s more, the bacteria seemed to bloom, growing in number after the race.

As people exercise, one of the waste products their muscles produce is lactate. That lactate is mostly metabolized by the liver, but some finds its way into the gut. The team, led by Alex Kostic of the Joslin Diabetes Center and Harvard Medical School, confirmed this by imaging the path taken by radioactively labeled lactate in mice. Veillonella eats the lactate, spitting out small fatty acids, including propionate that have been linked to reducing inflammation and energy creation. He says that if they give mice propionate, they tend to perform about as well on a treadmill test as they do when they are given a transplant of Veillonella.

O’Sullivan says that what metabolites from gut microbes are doing in athletes is an open and interesting question. In her team’s research, rugby players, who are not endurance athletes but are still fit and high-performing, had higher levels of trimethylamine N-oxide, a small molecule linked to heart disease.

She says she went back to her data and saw that the Veillonella species were elevated in her athletic cohort. She is now wondering if the abundance of this microbe is specific to endurance athletics or if it is also found in other elite athletes.

Other microbiome scientists also praised Kostic’s research.

“This was an incredibly well-done study,” says Kjersti Aagaard. She’s a microbiome scientist at Baylor College of Medicine who is also a recreational marathon runner.

She points out that while the team saw performance enhancement in mice treated with Veillonella, she thinks that the microbe may benefit humans particularly during recovery.

“Where they were really seeing the changes was in the post-race recovery interval,” she says.

How human endurance runners might take advantage of this knowledge remains to be seen. It will be challenging to do similar experiments in humans: fecal transplants have typically been reserved for people who are ill, and the U.S. Food and Drug Administration recently halted all fecal transplant clinical trials after two people ended up getting antibiotic-resistant strains of bacteria and one died.

Aagaard says that doing fecal transplants to improve athletic performance is too risky.

“While this helps us understand something of what’s going on in these elite, distance athletes,” she says of the Kostic team’s research, “and we can certainly speculate on what it may have to do with performance or post-performance recovery, what we would not want to do is start doing fecal transplants from elite athletes to those wishing to be elite.”

Kostic and other members of the research team are spinning off their findings in a different way. Kostic and others have started a company called Fitbiomics to create probiotics to boost athletic performance.

Kostic shies away from the term “doping” in describing what they are trying to do.

“It might be considered more of a leveling of the playing field,” he says.

Fergus Shanahan, a microbiome scientist also at University College Cork, says that he hopes exercise physiologists will look at this work as evidence that the microbiome should be factored into their research as they plumb the depths of human athleticism.

“Traditionally, exercise physiologists have been blinkered, limited in their thinking to host responses to exercise, and should now broaden their horizons to host-microbe metabolic interactions,” he says.

Depression Esketamine Ketamine Pain

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Denver—Chronic noncancer pain patients may find relief from an unlikely source, according to a team of Canadian researchers. Their retrospective study found that IV infusion of lidocaine plus ketamine significantly reduced the intensity of chronic pain, with few side effects.

“In 2013, we started offering these treatments for patients with neuropathic pain in our clinic,” said Shadi Babazadeh, MD, a clinical research associate with Allevio Pain Management in Toronto. “These patients were not responding to different pain medications, so Ramin Safakish, MD, the senior anesthesiologist at the clinic, decided to give the combination of lidocaine and ketamine to address their pain.

“Many clinicians use lidocaine and ketamine separately, but not as a combination,” Dr. Babazadeh added. “This combination seems to be unique.”

To help assess the safety and efficacy of the treatment, the investigators studied the electronic health records of 670 consecutive patients (mean age, 53.2 years; 508 women) who received the infusion at the clinic between March 2013 and May 2017. The most common diagnoses included fibromyalgia, diabetic neuropathy, postherpetic neuralgia and complex regional pain syndrome.

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Patients underwent a median of three infusions each (interquartile range [IQR], 1-8); 38% of patients received more than five infusions. A total of 3,741 infusions were reviewed.

“Some of these patients have been coming to the clinic every two months for five years,” Dr. Babazadeh explained. “Their quality of life has really improved. They can manage their pain and are almost able to lead a pain-free life.

“That said, demonstrating the change in long-term pain management for these patients was not the goal of this study,” she added.

The primary outcome of the analysis was the proportion of patients achieving reductions in pain scores of at least 30%.

As reported at the 2019 annual meeting of the American Academy of Pain Medicine (abstract 211), the median pain score immediately before the infusion was 8 (IQR, 6-9). After the infusion, it dropped to a mean of 2 (IQR, 0-4). Half of the patients experienced an improvement in their baseline pain score of at least 75% after the infusion.

Of note, patients reported clinically meaningful reductions in pain regardless of age, sex and diagnosis. The overwhelming majority of patients (88%; 3,271/3,741) experienced pain score reductions of at least 30%.

“We believe every infusion should begin with 4.5 mg/kg of lidocaine and 10 mg of ketamine, and then titrated according to the patient’s response,” Dr. Safakish said. “In our clinic, we have a limit of 600 mg lidocaine and 40 mg ketamine over 45 minutes.

“This is the dose where you don’t see side effects in the majority of people,” Dr. Safakish continued. “We’ve had practitioners who increased the ketamine dose to 60 to 70 mg over 45 minutes, and at these doses, people started reporting significantly more side effects.” Nausea and vomiting are the most common adverse events, he added.

The investigators also performed univariable and multivariable analyses regarding the odds of experiencing reductions in pain scores of at least 30%. The univariable analysis revealed that only the combination of lidocaine and ketamine had a statistically significant effect on pain improvement.

Specifically, for each 1-mg increase in lidocaine, the odds of achieving the 30% pain relief benchmark increased by 0.2%. As such, a 100-mg increase in lidocaine dose would result in an 18% increase in the chance of achieving a 30% reduction in pain (odds ratio [OR], 1.18; 95% CI, 1.02-1.37).

Similarly, every 10-mg increase in the ketamine dose was associated with a 21% increase in the odds of achieving a 30% reduction in pain scores (OR, 1.2; 95% CI, 1.09-1.36).

Despite these findings, the researchers acknowledged the potential shortcomings of the retrospective cohort study. Of note, the study did not track patients’ pain levels after discharge from the facility. They also did not have a standard measurement of patients’ quality of life.

To help address these shortcomings, the investigators are performing a prospective observational study. “In that prospective study, we are using a standard questionnaire that will allow us to track how long the pain relief lasts,” Dr. Babazadeh said.

Anecdotally, Dr. Safakish is convinced the combination offers long-term pain relief, the product of his many years of experience treating the same individuals. “The patients who come back, they are all patients for life,” he said in an interview with Pain Medicine News. “I’ve been seeing some of them every two months for the last 12 years.”

Enas Kandil, MD, an assistant professor of anesthesiology and pain management at the University of Texas Southwestern Medical Center, in Dallas, also has witnessed the efficacy of lidocaine and ketamine in various pain conditions, although she noted that the agents are not typically used together. “I’m in favor of both ketamine and lidocaine infusions,” Dr. Kandil said. “I think they’re great adjuvant medications for patients who have failed opioid interventions.

“We use them quite a bit here for our patients who have neuropathic and cancer pain when we’re trying to limit opioid use or we’ve reached our limit with our other adjuvant medications,” she added.

As Dr. Kandil related, she has only once administered the agents concomitantly, in a patient with intractable pain due to hemophilia. “And the only way we were able to control it was by adding ketamine and lidocaine infusions.”

Nevertheless, she did not see any specific contraindications to using the agents together, unless one or both agents was specifically contraindicated by the case in question.

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Depression Uncategorized

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Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial

Abstract

Background

At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed.

Methods

The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10 mg by mouth administered every 12 h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion.

Results

There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: −13.0±11.5, t 19 =5.0, <0.001), as was QIDS-SR score (mean change: −5.9±6.6, t 19 =4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively.

Limitations

Open-label, proof-of-concept design.

Conclusions

Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10 mg administered every 12 h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

Highlights

  • • Targets for novel antidepressants include the glutamate NMDA and sigma-1 receptors.
  • • Dextromethorphan displays activity at these receptors and other targets.
  • • Dextromethorphan plus quinidine (DM/Q) was tested in treatment-resistant depression.
  • • DM/Q showed acceptable tolerability and preliminary efficacy in this population.

1

Introduction

Major depressive disorder (MDD) represents one of the major sources of disease related disability worldwide, accounting for more than 40% of the 184 million disability-adjusted life years (DALYs) attributed to all mental and substance use disorders in 2010 ( Whiteford et al., 2013 ). It is estimated that only one out of three patients with MDD treated with a first-line antidepressant medication will achieve full symptom remission ( Rush et al., 2006 ), and up to one-third of patients will remain symptomatic despite multiple optimized treatment steps ( Trivedi et al.2006a ). Patients who have failed to respond to two or more antidepressant medication trials of adequate dose and duration may be classified as experiencing treatment-resistant depression (TRD), and as a group these patients suffer a more chronic and severe disease course and account for up to half of the total economic cost of the illness ( Mathew, 2008;Shelton et al., 2010 ). All antidepressant medications currently marketed in the United States (U.S.) act mechanistically by enhancing monoamine signaling in the brain, for example via serotonin or norepinephrine transporter blockade. This mechanistic homogeneity likely contributes substantially to the prevalence of TRD by limiting the pharmacotherapeutic options available to treatment providers.

A critical need in neuropharmacology research is to identify safe and more effective treatments for depression by targeting neural receptors and signaling pathways outside of the monoamine system ( Berton and Nestler, 2006;Mathew et al., 2008;Papakostas and Ionescu, 2015 ). In this context, the discovery of a rapid antidepressant effect of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine now more than a decade ago, has provided a major impetus for drug discovery research focused on the NMDA receptor and other targets linked to glutamate signaling ( Sanacora et al.2008 ). One potentially fruitful research strategy involves the conduct of proof-of-concept (POC) clinical trials of agents with known effects at the NMDAR receptor or other novel molecular targets in patients with TRD, taking advantage of the availability of marketed drugs as tool compounds. This strategy essentially ‘re-purposes’ existing compounds as pharmacological probes in order to gain information concerning the viability of a given target for a new indication (e.g., TRD).

Dextromethorphan (DM) is an antitussive medication with a complex pharmacology that includes inhibition of NMDA receptors, as well as interactions with serotonin and norepinephrine transporters, nicotinic acetylcholine receptors, and sigma-1 (σ ) receptors (reviewed in Taylor et al. (2016) ). A fixed-dose combination product of DM and the cytochrome P450 (CYP) 2D6 enzyme inhibitor quinidine (Q) gained approval for the treatment of pseudobulbar affect (PBA) in the U.S. in 2010 [DM 20 mg/Q 10 mg every 12 h (Nuedexta®, Avanir Pharmaceuticals, Inc.)]. Although early clinical trial experience with DM in neurological disorders showed minimal efficacy, low plasma levels of DM owing in part to substantial first-pass metabolism may have largely limited brain exposure ( Pope et al., 2004;Werling et al., 2007 ). The concurrent administration of Q with DM, in contrast, substantially increases DM plasma levels by reducing the first-pass metabolism of DM by CYP2D6 (Yang and Deeks, 2015 ). Given the unique pharmacology of DM that includes NMDA receptor antagonism, we took advantage of the availability of DM/Q to conduct a phase IIa open-label POC study of DM/Q dosed up to 45 mg/10 mg every 12 h in patients with TRD. Our goal was to examine initial feasibility, tolerability, and open-label antidepressant efficacy of this approach.

5

Discussion

Herein we report on the feasibility, tolerability, and initial antidepressant efficacy of DM/Q dosed up to 45/10 mg every 12 h in patients with TRD in a current MDE. Study patients had failed a median of 2 adequate antidepressant trials in the current episode. We observed acceptable tolerability in this TRD group, with AE frequencies similar to what has been observed previously in studies of PBA ( Doody et al., 2015;Pioro et al., 2010 ). Patients showed a large mean reduction in MADRS score of −13.0 at study end and 50% of patients were classified as ‘improved’ or ‘very much improved.’ Response and remission rates were 45% and 35%, respectively in the ITT sample. The magnitude of improvement was similar between individuals who were taking a concomitant antidepressant medication and those who were not, and between patients with a moderate level of treatment-resistance and those with a higher level. Although direct comparisons between studies are difficult to make, the observed remission rate of 35% in the current study compares to remission rates of 25–39% in level 2% and 8–25% in level 3 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Warden et al., 2007 ). Remission rates following acute treatment with repetitive transcranial magnetic stimulation (rTMS) in patients with moderate levels of treatment resistance are reported to be 15–33% ( Perera et al., 2016 ) .Taken together, the current POC study supports the hypothesis that DM/Q represents a promising pharmacotherapeutic strategy in patients with TRD. Future randomized, controlled trials will be required to further examine the antidepressant potential of this approach.

As noted in the introduction, DM possesses a complex pharmacology that features NMDA receptor antagonism, σreceptor agonism, and effects on serotonin and norepinephrine signaling, among others ( Taylor et al., 2016 ). NMDA receptor antagonism in particular may be an important aspect of DM’s putative antidepressant mechanism of action given the growing evidence that ketamine, a non-competitive high-affinity NMDA receptor antagonist, possess rapid and robust antidepressant effects in patients with TRD ( Caddy et al., 2015;Murrough et al., 2013;Newport et al., 2015;Singh et al., 2016;Zarate et al., 2006 ). More broadly, glutamate signaling via NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and metabotropic glutamate receptors (mGluRs) has been implicated in the pathophysiology and treatment of MDD and other mood disorders (Abdallah et al., 2015;Manji et al., 2003;Sanacora et al., 2008 ). Electrophysiological studies show that DM exerts voltage-dependent blockade of the NMDA receptor, likely binding to a site within the channel pore, similar to ketamine and other channel blockers such as MK-801 ( Ferrer-Montiel et al., 1998 ). DM shows a somewhat lower affinity for the NMDA receptor channel compared to ketamine (K =780 and 200, respectively), but similar to memantine (K =700) ( Taylor et al., 2016 ). Interestingly, a recent study showed that DM exerted an antidepressant-like behavioral effects in the tail suspension test (TST) that were blocked by administration of AMPA receptor antagonist NBQX, similar to ketamine and other glutamate-based antidepressant candidates (Nguyen and Matsumoto, 2015 ).

Sigma-1 receptors are transmembrane proteins located in the endoplasmic reticulum (ER), and constitute a class of receptors distinct from ligand-gated ion channels and G-protein coupled receptors ( Hayashi, 2015 ). These receptors were first characterized in the 1990’s and their potential role in neuropsychiatric disease mechanisms and as potential novel treatments is only beginning to be explored. Several lines of evidence suggest that DM acts as an agonist at σ receptors. For example, the antitussive, anticonvulsant, and neuroprotective effects of DM can be blocked in model systems by administration of a selective σ receptor antagonist ( Shin et al.2005 ). More recently, pretreatment with the σ receptor antagonist BD1063 was shown to attenuate the antidepressant behavioral effects of DM in the forced swim test (FST) ( Nguyen et al., 2014 ). Sigma-1 receptors appear to function as chaperone proteins, and may have a role in regulating the cellular effects of oxidative stress and free radical generation, among other functions (see ( Hayashi, 2015 ) for a recent review).

In addition to PBA, prior clinical trials have examined DM or DM/Q for the treatment of pain, seizure, and traumatic brain injury (TBI), among other neuropsychiatric conditions ( Nguyen et al., 2016 ). In the area of mood disorders, two studies are reported in the literature, both of which involved patients with bipolar disorder (Chen et al., 2014;Kelly and Lieberman, 2014 ). One prior study conducted in patients with bipolar II disorder or bipolar disorder not otherwise specified consisted of a retrospective chart review of the efficacy of augmentation treatment with DM/Q 20/10 mg either once or twice daily ( Kelly and Lieberman, 2014 ). Patients in this study had a predominance of depressive symptoms, and had high levels of treatment-resistance and chronicity. Of the 77 patients met the study eligibility criteria, 19 patients discontinued due to adverse effects attributed to treatment with DM/Q; this discontinuation rate of ~25% compares to a discontinuation rate observed in the current study of 30%. Among the remaining 58 patients, state of illness showed on average between ‘slightly improved’ and ‘much improved’ on a clinical global impression scale. The effect of treatment on depression or other symptoms specifically, however, was not reported. In the second study, patients with bipolar disorder on a stable dose of valproic acid were randomized to adjunctive treatment with DM at a dose of 30 or 60 mg per day (no concurrent Q) or placebo for 12 weeks ( Chen et al., 2014 ). Both depression and mania symptoms improved in both groups to a similar degree.

The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS

Abstract

Background

Dextromethorphan is an over-the-counter antitussive agent that may be a rapidly acting treatment for bipolar depression. Like ketamine, it is an NMDA receptor antagonist.

Methods

We conducted a retrospective chart review of depressed patients with treatment resistant bipolar II or bipolar NOS disorder who were treated with the combination of dextromethorphan 20 mg and quinidine 10 mg (DMQ). One pill of DMQ taken once or twice a day was added to participants׳ drug regimen. No changes were made to the pre-existing drug regimen during the course of treatment with DMQ. The primary outcome measure was the Clinical Global Impression-Improvement (CGI-I) score after 90 days of treatment.

Results

Seventy-seven participants met the inclusion criteria. All had been experiencing depressive symptoms for at least two years, and the mean number of failed medication trials was 21.2. The average CGI-I score at day 90 was 1.66 (1=slightly improved, 2=much improved). Some patients reported improvement within 1–2 days of starting DMQ. Nineteen patients discontinued treatment due to adverse effects, chiefly nausea.

Limitations

Because this was a retrospective chart review with no control group, conclusions about causation cannot be made. Nevertheless, the duration of depressive symptoms prior to starting DMQ makes spontaneous recovery less likely.

Conclusions

DMQ, an NMDA antagonist, may be effective in the treatment of bipolar depression. Because its putative mechanism does not depend on the monoaminergic system, it may be appropriate for patients who have not responded to other medications. Unlike ketamine, DMQ does not require IV administration.

AVP-786 (dextromethorphan/quinidine). AVP-786 is an experimental compound developed by Avanir (Aliso Viejo, CA, USA). A combination of deuterium-modified dextromethorphan hydrobromide and ultra-low dose quinidine sulfate, AVP-786 is similar to Nudexta, a medication approved to treat pseudobulbar affect. (Of note, a trial of Nuedexta for treatment-resistant depression (NCT01882829) was recently completed; results are pending). Mechanistically, dextromethorphan is an uncompetitive NMDAreceptor antagonist, as well as a sigma-1 receptor agonist; these properties theoretically have antidepressant effects. Low-dose quinidine (a CYP2D6 enzyme inhibitor) works to increase the bioavailability of dextromethorphan by inhibiting its breakdown. In addition, the deuterium incorporation into dextromethorphan contributes to its bioavailability by strengthening chemical bonds within the molecule, making it less susceptible to metabolic breakdown. Together, this combination may serve to bypass metabolic breakdown of the molecule, allowing for increased NMDA-receptor antagonism by dextromethorphan in the brain. A clinical trial of AVP-786 as adjunctive therapy in MDD was recently completed with results pending (ClinicalTrials.gov ID: NCT02153502). AXS-05 (dextromethorphan/bupropion). In addition to the NMDAreceptor blocking properties of dextromethorphan, AXS-05 contains bupropion (a norepinephrine and dopamine reuptake inhibitor that is currently approved for the treatment of depression), which may also work to increase the bioavailability of dextromethorphan in the brain. Axsome (New York, NY, USA) is currently conducting Phase III trials (ClinicalTrials.gov ID: NCT02741791). Specifically, patients will have a 6-week lead-in period with open-label bupropion, followed by a 6-week, doubleblind treatment period to compare the efficacy of AXS-05 augmentation to bupropion versus bupropion monotherapy in patients with treatment-resistant depression (defined as failure of one to two antidepressant treatments in the current episode and a treatment failure to the lead-in trial of bupropion). Because quinidine can cause cardiac toxicity when used excessively, AXS-05 may offer a theoretical advantage over AVP-786 in patients at a risk of overdose or with cardiac conduction concerns.

Dextromethorphan (DM) may have ketamine—like rapid—acting, treatment—resistant, and conventional antidepressant effects.1,2 This reports our initial experience with DM in unipolar Major Depressive Disorder (MDD). A patient with treatment—resistant MDD (failing adequate trials of citalopram and vortioxetine) with loss of antidepressant response (to fluoxetine and bupropion) twice experienced a rapid— acting antidepressant effect within 48 hours of DM administration and lasting 7 days, sustained up to 20 days with daily administration, then gradually developing labile loss of antidepressant response over the ensuing 7 days. Upon full relapse in DSM-5 MDD while taking 600 mg/day of the strong CYP2D6 inhibitor bupropion XL, a 300 mg oral loading dose of DM was given, followed by 60 mg po bid after an additional dose— finding period, without side effects. DM exhibited a ketamine—like rapid—acting antidepressant effect, thought to be mediated by mTOR activation (related to NMDA PCP site antagonism, sigma-1 and beta adrenergic receptor stimulation) and 5HTT inhibition, resulting in AMPA receptor trafficking, and dendritogenesis, spinogenesis, synaptogenesis, and increased neuronal survival (related to NMDA antagonism and sigma-1 and mTOR signaling). This report appears to be the first report of a rapid—acting effect in unipolar MDD and adds to antidepressant effects observed in the retrospective chart review of 77 patients with Bipolar II Disorder (Kelly and Lieberman 2014). If replicated, there is some reason to think that the administration of other agents with DM, such as lithium or D-cycloserine, might prolong the duration of the rapid-antidepressant effect. Psychopharmacology Bulletin. 2016;46(2):53–58.

Depression Esketamine OCD

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New Horizons in OCD Research and the Potential Importance of Glutamate. Can We Develop Treatments That Work Better and Faster?

First-line treatments for obsessive compulsive disorder (OCD) – cognitive behavior therapy drug therapy with selective serotonin re-uptake inhibitors (SSRIs) or both – are quite effective for many patients. However, approximately one third of patients do not experience a significant reduction in symptoms from these treatments or from established second-line interventions. Even in patients who do respond, symptom reduction usually occurs only over the course of two to three months, and response is often not complete. The development of treatments that work better and faster is a major goal of ongoing research.

Glutamate in OCD

Existing medications for OCD target two neurotransmitters (brain chemicals): serotonin and dopamine. However, there has been substantial interest over the last eight years in the potential involvement of another neurotransmitter, glutamate, in OCD. Glutamate is the most abundant excitatory neurotransmitter in the brain; it is critical to the communication of nerve cells with one another in practically every circuit in the nervous system. An abnormally high level of glutamate can lead to neuron damage, and glutamate-modulating therapies (medications aimed at affecting or normalizing the actions of glutamate in the brain) have been explored in medical conditions, such as “Lou Gehrig’s Disease” (ALS) and in stroke. Evidence from several sources suggests that abnormal levels of glutamate may contribute to OCD. Investigators at the Ruhr University in Germany examined the cerebrospinal fluid (CSF) of patients with OCD who were not on any medication. They found that individuals with OCD had higher levels of glutamate in the CSF than psychiatrically healthy controls. Since the CSF bathes the brain, this suggests that the brain is exposed to high levels of glutamate in patients with OCD. A similar increase of glutamate in the brain has been seen using another technique, magnetic resonance spectroscopy (MRS) by investigators at Wayne State University and elsewhere.

The presence of abnormally high levels of glutamate in the brains of individuals with OCD does not prove that it contributes to the disease – problems with glutamate could be a consequence of the illness rather than a cause. However, recent genetic findings lend support to the idea that glutamate imbalance may be an important causal factor in at least some cases of OCD. Two independent groups from the University of Toronto and the University of Chicago published evidence in 2006 that a protein that carries glutamate in the brain is linked to OCD in some cases; more recent studies from groups at the Massachusetts General Hospital and Johns Hopkins University have found the same thing. Although it is not yet clear whether these genetic linkages correspond to a functional problem with this protein, problems with these glutamate transporters can increase the amount of glutamate found outside neurons, which might explain the increased glutamate seen in the brain, and possibly lead to OCD symptoms.

Recent findings in mice further support the idea that changes in glutamate in the brain can produce behaviors that resemble OCD. Researchers at Duke University have described a mouse that is anxious and grooms itself compulsively They genetically altered the mouse so that it is missing the SAPAP3 gene. The SAPAP3 gene is a critical piece in structure of the glutamate receptor. The anxiety and compulsive grooming behavior of these mice decreased when they were given an OCD medication – a selective serotonin re-uptake inhibitor (SSRI). A few doses of an SSRI did not decrease compulsive symptoms; the medication has to be given over a long period of time to have an affect – the same pattern seen with patients taking SSRIs to treat their OCD.

Although it remains unclear whether this gene (SAPAP3) is involved in OCD, the one genetic study performed to date in humans with OCD from researchers at Duke and Johns Hopkins, showed preliminary evidence of a relationship to grooming disorders, such as Trichotillomania, but no links to OCD. Regardless, further work in this and related animal models will increase our understanding of how changes in the brain, glutamate, and how neurons respond to it, can lead to compulsive behavior patterns.

Glutamate-targeting Medications

Is it possible then that medications that affect glutamate in the brain will benefit patients whose OCD does not respond to existing therapies? This hope has guided research in our clinic over the past several years, and early results from our group and elsewhere are promising – although the evidence for such drugs is not yet conclusive.

Fortunately a number of medications that affect glutamate levels are already FDA approved for other medical conditions and are therefore readily available for research and clinical use .One such medication is riluzole (Rilutek®), which has been marketed since 1996 for Lou Gehrig’s disease (ALS). Riluzole affects glutamate levels in several ways. In an initial open-label study in 2005, and a case series in 2008, we found that approximately half of the severely ill treatment refractory patients who have not responded to other treatments improved significantly when riluzole was added to their SSRI. Researchers at the National Institute of Mental Health have found similar results using riluzole in children with OCD. Controlled double-blind studies (the best way to test the effectiveness of a medication) for riluzole in adult and pediatric OCD have already begun.

A second drug that is already available and affects how neurons respond to glutamate is memantine (Namenda®). Several case reports and two recent open-label case series suggest that the addition of memantine to standard medication therapy can benefit both children and adults with OCD. As in the case of riluzole these studies are uncontrolled and need to be replicated in larger placebo-controlled studies.

There is also some limited evidence suggesting that a third medication – N-acetylcysteine or NAC – also has benefit in the treatment of OCD. NAC is available without a prescription. It is an antioxidant and is used in cases of acetaminophen (Tylenol®) overdose to protect the liver from damage. However, animal studies by researchers at the Medical University of South Carolina have found that NAC can affect levels of brain glutamate as well. We worked with a patient with OCD who improved significantly after we added NAC to her existing medications. Unpublished clinical experience, from our group and elsewhere, further suggests that the agent may be of benefit in at least some patients with OCD. Well controlled studies have shown benefit from NAC in a variety of other disorders of compulsive and impulsive behaviors, including pathological gambling, Trichotillomania, and drug craving. Because it is inexpensive, has no significant side effects, and is available over-the-counter, this drug is a potentially attractive therapeutic option, though the evidence for benefit in OCD remains extremely thin.

Glutamate in Depression and the Possibility of a Rapidly-acting Anti-obsessional Drug

Abnormal glutamate levels may also play an important role in major depressive disorder. All of the medications discussed above (riluzole, memantine, and N-acetylcysteine) have been investigated in depression by researchers at Yale, the National Institutes of Health, and elsewhere. Indeed an important question for future research is how the glutamate problems in these two disorders which often occur together, differ from one another.

Glutamate is a neurotransmitter – a chemical that communicates from one nerve cell to another. A neuron can respond to glutamate when it binds to a specific kind of protein, a receptor (a receiver of a brain chemical message like your cell phone receiving a phone call). So, alterations in glutamate affect nerve cells by changing the activation of these receptors, and targeting the receptors with medications can change how the neurons respond to glutamate.

There are several receptors for glutamate; a particularly important one is called the NMDA receptor. Drugs that affect these NMDA receptors have recently been found to produce a remarkably rapid antidepressant response. This contrasts starkly with the delayed response typically seen with SSRIs in both depression and OCD. This observation was first made by researchers at Yale who reported in 1998 that depressed patients receiving a single dose of the NMDA-targeting drug, ketamine, became rapidly better and stayed better for up to a week. Ketamine can produce a short “high,” lasting 1 or 2 hours. However, the improvements of mood were greatest at 24 hours and lasted in some subjects for as long as seven days, making it clear that they were not just a result of this high. This striking and unexpected effect was reproduced in a double-blind study at the National Institutes of Health in 2006. Memantine also affects NMDA receptors, but its effect is much weaker than that of ketamine. Unfortunately, a controlled study of memantine in depression from the National Institute of Mental Health did not show benefit. Newer medications that act on this NMDA receptor are under development.

Ketamine is by no means the answer for major depression. The antidepressant effects of ketamine usually wear off by a week or two. Furthermore, ketamine’s addictive and abuse potential, and the fact that it needs to be administered intravenously, limit its long-term use. Potentially unpleasant psychological symptoms, such as anxiety, sadness, disorientation, flashbacks, and hallucinations can sometimes emerge during ketamine administration, and also limit its potential for widespread use. However, a limited trial of ketamine may be useful to help a patient break out of a particularly severe or treatment-refractory depression. In addition, the rapid antidepressant effect of ketamine opens a window into an entirely new way of thinking about how to treat depression. A better understanding of how this drug works in the brain could lead to the development of new drugs that do not have ketamine’s drawbacks, but do have its advantages – in particular a more rapid effect than any standard antidepressants.

These observations raise exciting new possibilities for the field of OCD research. If glutamate contributes to both depression and OCD, and if ketamine can produce a rapid antidepressant effect, would this medication, or similar drugs that affect glutamate or the NMDA glutamate receptor, also be effective treatments for OCD? Depression frequently occurs along with OCD – could drugs that affect the NMDA receptor like ketamine be of benefit to both? Most excitingly, the antidepressant effects of ketamine are remarkably rapid – much more so than traditional medication or psychotherapy. It has long been possible to rapidly treat severe depression using ECT; but ECT is not effective in the treatment of OCD, and no rapid treatments have been available. Perhaps this unfortunate limitation will change.

In sum, increasing evidence indicates that abnormal levels of the neurotransmitter glutamate contribute to OCD and may be a fruitful target for new therapies. Ketamine’s unexpected rapid antidepressant effect suggests that similar anti-obsessional effects are a real possibility, since the disorders frequently occur together and problems with glutamate appear to be associated with both.

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How Ketamine Opens a New Era for Depression Treatment

Not for clubbers only.
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Researchers have discovered that ketamine, a drug of choice for club-goers for decades, can be used to fight severe cases of the blues. For more than three decades, patients seeking treatment for depression in the U.S. have been steered primarily to one family of pharmaceuticals. Doctors have been looking for more treatments, particularly for patients who haven’t had success with drugs or who have had suicidal thoughts. (The U.S. suicide rate increased 30% from 1999 to 2016.) Could a party drug be the key to solving the nation’s suicide crisis?

1. What’s ketamine?

It’s an anesthetic approved in 1970 as a safer alternative to phencyclidine, better known as PCP or angel dust. Ketamine became a common battlefield anesthetic during the Vietnam War, and by 1971 it was being used in much higher doses as a recreational drug. By the mid-1980s, ketamine was linked with dance culture in the U.S. and Europe, where it became a popular party drug that can produce euphoria and put users in a dreamlike state. At higher doses it can cause hallucinations and disassociation, a state in which users feel as if their mind and body aren’t connected, sometimes called the “K-hole.”

2. Why is it getting another look?

In March, Johnson & Johnson won approval for esketamine, a close cousin of ketamine, for patients with treatment-resistant depression, who make up one-third of the estimated 17.3 million Americans who have experienced depression. Administered via nasal spray, the drug, Spravato, is being billed as the first major therapeutic advance for depression since the introduction of Prozac in 1987. Spravato is undergoing additional studies, and the drugmaker hopes to win approval to use it for treatment of suicidal depression by 2020. (U.S. President Donald Trump expressed optimism that the drug can succeed in reducing suicides by military veterans.) Janssen, a subsidiary of Johnson & Johnson, filed marketing applications for esketamine in in the EU, UK, Canada, Switzerland, China, Japan, Australia, New Zealand and Colombia.

3. How is ketamine different from other antidepressants?

Most depression drugs, including Prozac, are part of a class known as selective serotonin reuptake inhibitors, or SSRIs. They work by blocking the re-absorption of the neurotransmitter serotonin, increasing the supply available in the brain. Ketamine works on the neurotransmitter glutamate, which is considered crucial in learning and memory formation. While SSRIs can take weeks or months to take effect, ketamine has been shown to begin working in as little as a few hours, making it the first rapid-acting depression drug. Another psychedelic drug that’s long been frowned-upon, so-called magic mushrooms, or psilocybin, also being studied as a potential treatment for depression.

4. When will it be available?

Some patients have already started taking Spravato for depression. Because of concerns about abuse, the drug is available to patients only under supervision at several hundred medical centers that Johnson & Johnson has certified.

The Reference Shelf

  • Bloomberg Businessweek on how esketamine can transform the treatment of suicidal patients.
  • President Donald Trump is impressed with Spravato’s potential.
  • Spravato has life changing potential, but may not be a surefire hit, Max Nisen argues in Bloomberg Opinion.
  • An academic paper detailing ketamine’s historyas a recreational drug.
  • Johnson & Johnson’s Spravato website, featuring a database of centers certified to give the treatment.
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