Understanding potential of illicit drug ketamine in treating depression

In continuation of my update on Ketamine 

Advancing the understanding and treatment of psychiatric disorders is
a principal goal of neuroscientists. As mental disorders are the
leading cause of disabilities worldwide, it is concerning that there are
few effective therapeutics on the market due to the lack of knowledge
regarding pathophysiology. In particular, the main treatment for major
depressive disorders are antidepressants, which target the monoaminergic
system and include selective serotonin reuptake inhibitors (SSRIs).
However, these drugs take six weeks on average before symptom relief and
many individuals are unaffected by them.

Ketamine, a synthetic analogue of PCP, has recently taken the
spotlight as a novel, fast-acting antidepressant. The benefits of
ketamine include a one-time, low-dose IV infusion, where symptoms are
alleviated within hours and which lasts for up to two weeks in patients
with depression. Even more compelling is that this regimen affects
patients with treatment-resistant depression, meaning those who do not
respond to current antidepressants. These effects are especially
important in helping individuals with depression who may be experiencing
suicidal ideation because of ketamine's fast-acting nature and it is
the only treatment effective for treatment resistant patients.

However, there are many downsides to the use of ketamine as an
antidepressant, especially with long-term or repeated use. For example,
ketamine is an illicit drug with high abuse potential, commonly known as
the party drug "Special K." Therefore, close clinical monitoring of the
use of this drug is necessary. In regards to neuroscience research in
the past decade, it has been demonstrated that chronic, low-dose
ketamine has been used to study learning and memory deficits in a rodent
model of schizophrenia. The biochemical data from these animals reveal a
change in a specific type of neuron in the brain that is important for
network activity underlying normal cognitive functioning. This begs the
question: Can ketamine work as an antidepressant without producing
cognitive deficits associated long-term use?

In order to address this question, we need to understand the molecular
mechanisms that ketamine is utilizing to produce these beneficial
antidepressant effects. Although researchers do not know exactly how
ketamine works, we know that it is in a different way than current
antidepressants on the market. There is no clear answer yet, but researchers have produced some promising results. Using ketamine to
deepen our understanding of depression will advance the field of neuroscience and ultimately lead to a more effective treatment for the  disorder.

Single dose of psilocybin decreases anxiety, depression in cancer patients

In continuation of my update on Psilocybin

A single dose of psilocybin, the major hallucinogenic component in magic mushrooms, induces long-lasting decreases in anxiety and depression in patients diagnosed with life-threatening cancer according to a new study presented today at the annual meeting of the American College of Neuropsychopharmacology.

Patients who receive a cancer diagnosis often develop debilitating symptoms of anxiety and depression. Reports from the 1960s and 1970s suggest that hallucinogenic drugs such as LSD may alleviate such symptoms in cancer patients, but the clinical value of hallucinogenic drugs for the treatment of mood disturbances in cancer patients remains unclear. In this new study, Roland Griffiths and colleagues from the Johns Hopkins University School of Medicine investigated the effects of psilocybin on symptoms of anxiety and depression in individuals diagnosed with life-threatening cancer. Five weeks after receiving a dose of psilocybin sufficiently high to induce changes in perception and mystical-type experiences, patients reported significantly lower levels of anxiety and depression compared with patients that received a low dose of the drug. The positive effects on mood persisted in the patients at 6 month follow-up.

The authors suggest that a single dose of psilocybin may be sufficient to produce enduring decreases in negative mood in patients with a life-threatening cancer.

Single dose of psilocybin decreases anxiety, depression in cancer patients

Study: Ketamine more effective than common sedative in reducing suicidal thoughts

In continuation of my update on ketamine

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine's anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

"There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm," said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. "Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients."

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine's effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

"This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression," said Dr. Grunebaum. "Additional research to evaluate ketamine's antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments."

Study: Ketamine more effective than common sedative in reducing suicidal thoughts

Hallucinogenic drug offers relief for people with cancer-related anxiety or depression

In continuation of my update on psilocybin

In a small double-blind study, Johns Hopkins researchers report that a substantial majority of people suffering cancer-related anxiety or depression found considerable relief for up to six months from a single large dose of psilocybin -- the active compound in hallucinogenic "magic mushrooms."

The researchers cautioned that the drug was given in tightly controlled conditions in the presence of two clinically trained monitors and said they do not recommend use of the compound outside of such a research or patient care setting.

The Johns Hopkins team released its study results, involving 51 adult patients, concurrently with researchers from New York University Langone Medical Center, who conducted a similarly designed study on 29 participants. Both studies are published in the Journal of Psychopharmacology on Dec. 1.

The Johns Hopkins group reported that psilocybin decreased clinician- and patient-rated depressed mood, anxiety and death anxiety, and increased quality of life, life meaning and optimism. Six months after the final session of treatment, about 80 percent of participants continued to show clinically significant decreases in depressed mood and anxiety, with about 60 percent showing symptom remission into the normal range. Eighty-three percent reported increases in well-being or life satisfaction. Some 67 percent of participants reported the experience as one of the top five meaningful experiences in their lives, and about 70 percent reported the experience as one of the top five spiritually significant lifetime events.

"The most interesting and remarkable finding is that a single dose of psilocybin, which lasts four to six hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions," says Roland Griffiths, Ph.D., professor of behavioral biology in the Departments of Psychiatry and Behavioral Sciences and of Neuroscience at the Johns Hopkins University School of Medicine. He notes that traditional psychotherapy offered to people with cancer, including behavioral therapy and antidepressants, can take weeks or even months, isn't always effective, and in the case of some drugs, such as benzodiazepines, may have addictive and other troubling side effects.

Griffiths says his team's new study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which found that psilocybin can consistently produce positive changes in mood, behavior and spirituality when administered to carefully screened and prepared participants. The study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

"A life-threatening cancer diagnosis can be psychologically challenging, with anxiety and depression as very common symptoms," says Griffiths. "People with this kind of existential anxiety often feel hopeless and are worried about the meaning of life and what happens upon death."

For the study, the investigators recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic. They were chosen from a total of 566 individuals reached through flyers, web advertisements and physician referrals. Most participants had breast, upper digestive, GI, genitourinary or blood cancer, and each had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female with an average age of 56. Ninety-two percent were white, 4 percent were African-American and 2 percent were Asian.

Each participant had two treatment sessions scheduled five weeks apart, one with a very low psilocybin dose (1 or3 milligrams per 70 kilograms) taken in a capsule and meant to act as a "control" placebo because the dose was too low to produce effects. In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 milligrams per 70 kilograms).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that the participants would receive psilocybin on both sessions, but they did not know that all participants would receive one high and one low dose. Blood pressure and mood were monitored throughout the sessions. Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

In addition to experiencing changes in visual perception, emotions and thinking, most participants reported experiences of psychological insight and often profound, deeply meaningful experiences of the interconnectedness of all people.

The researchers assessed each participant's mood, attitude about life, behaviors and spirituality with questionnaires and structured interviews before the first session, seven hours after taking the psilocybin, five weeks after each session and six months after the second session. Immediately after the sessions, participants completed questionnaires assessing changes in visual, auditory and body perceptions; feelings of transcendence; changes in mood; and more.

Structured clinical interviews, such as the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale, and patient questionnaires, like the Beck Depression Inventory and the State-Trait Anxiety Inventory, assessed depression and anxiety. Other questionnaires assessed quality of life, death acceptance, meaningful existence, optimism and spirituality -- generally defined as a search for the meaning of life and a connection to something bigger than one's self. To measure the changes in attitudes, moods and behavior over time, the researchers administered a questionnaire that assessed negative or positive changes in attitudes about life, mood and behavior.

With regard to adverse effects, Griffiths says 15 percent of participants were nauseated or vomited, and one-third of participants experienced some psychological discomfort, such as anxiety or paranoia, after taking the higher dose. One-third of the participants had transient increases in blood pressure. A few participants reported headaches following the session.

"Before beginning the study, it wasn't clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy," says Griffiths. "I could imagine that cancer patients would receive psilocybin, look into the existential void and come out even more fearful. However, the positive changes in attitudes, moods and behavior that we documented in healthy volunteers were replicated in cancer patients."

Up to 40 percent of people with cancer suffer from a mood disorder, according to the National Comprehensive Cancer Network.

Anticipating wide interest in the psilocybin research from scientists, clinicians and the public, the journal solicited 11 commentaries to be co-published with the study results written by luminaries in psychiatry, palliative care and drug regulation, including two past presidents of the American Psychiatric Association, a past president of the European College of Neuropsychopharmacology, the former deputy director of the U.S. Office of National Drug Control Policy, and the former head of the U.K. Medicines and Healthcare Products Regulatory Authority. In general, the commentaries were supportive of the research and of using these drugs in a clinical setting as tools for psychiatry.

Research produces strong evidence for new class of antidepressant drugs | The University of Manchester

Galanin is a neuropeptide (a small protein) that was discovered and investigated over 30 years ago by various groups including the Swedish scientist Tomas Hokfelt. He is one of the senior authors of the paper published in the journal PNAS.

Professor Hokfelt and others made the fundamental discovery that neurones can release peptides alongside their classical transmitters and that galanin and noradrenaline are one such pair. Both have long been implicated in pain and stress and therefore depression but in the past it had been difficult to study peptides in humans.

The new research by scientists from Sweden, Hungary and the UK demonstrates that galanin is an important stress mechanism in the human brain that influences how sensitive or resilient people are to psychosocial stress.

Lead author Gabriella Juhasz, who is a Research Fellow at the University of Manchester and the Semmelweis University in Budapest, said: “Our research shows that some versions of the gene coding for galanin protect against the risk of depression and anxiety but only in people who have experienced early life neglect or trauma, or recent adverse events.

“Furthermore, the three genes for the three receptors through which galanin acts also influence the risk of depression in people experiencing early or recent life adversity. Crucially, all the galanin related genes are widely separated on different chromosomes and the odds are stacked against four random genes acting in the same way by chance.”

Results from the research indicate that although the results are statistically reliable, galanin effects modify the substantial effects of stress by only a few percent. Indeed the moderate overall genetic influence (about 35%) on depression is likely to be mediated by many small genetic effects interacting with each other and with psychosocial factors converging on stress mechanism in brain.

Co-author Professor Bill Deakin, from the University of Manchester, said: “The findings provide a strong reason to develop drugs that modify galanin functioning as a new class of antidepressant drug. And new drugs are badly needed as almost all commonly prescribed antidepressants act on serotonin and they are often not very effective.

“Our research confirms what previous reports have shown about the variation in the serotonin ‘transporter’ gene and how it influences the risk of depression. We found that the galanin effects are substantially greater than the effects of serotonin.”

Research produces strong evidence for new class of antidepressant drugs | The University of Manchester

Quetiapine fumarate (Seroquel XR) for Major Depressive Disorder (MDD)....

Quetiapine fumarate (see structure) is marketed by AstraZeneca as Seroquel or SeroquelXR and by Orion Pharma as Ketipinor, is an atypical antipsychotic schizophrenia used in the management of, bipolar I mania, bipolar II depression, bipolar I depression, and used off-label for a variety of other purposes, including insomnia and anxiety disorders.

It is sometimes used off-label, often as an augmentation agent, to treat such conditions as obsessive-compulsive disorder, post-traumatic stress disorder, restless legs syndrome, autism, alcoholism, depression, Tourette syndrome, and has been used by physicians as a sedative for those with sleep disorders or anxiety disorders.

Astra-Zeneca, recently  announced that the FDA has approved once-daily Seroquel XR (quetiapine fumarate) Extended Release Tablets as adjunctive (add-on) treatment to antidepressants in adults with Major Depressive Disorder (MDD). Seroquel XR is the only medication in its class approved by the FDA to treat both major depressive disorder as adjunctive therapy and acute depressive episodes associated with bipolar disorder as monotherapy. The company claims that this approval for Seroquel XR provides physicians with a new adjunctive treatment option for patients with MDD who have an inadequate response to their current antidepressant. FDAs approval of Seroquel XR is based on a clinical development program in MDD involving 939 patients randomized across two studies that assessed the efficacy and safety of once-daily treatment with Seroquel XR as adjunctive treatment to antidepressants.....

Ref : http://www.astrazeneca.com/media/latest-press-releases/2009/seroquel-us-MDD?itemId=7660757

Omega-3 Fish Oil Supplements Might Boost Antidepressants' Effects

Omega-3 fish oil supplements may improve the effectiveness of antidepressants, new research suggests.

Researchers reviewed the findings of eight clinical trials worldwide, as well as other evidence, and concluded that the supplements appear to help battle depression in people already on medication.

"Omega-3 fish oil -- in combination with antidepressants -- had a statistically significant effect over a placebo," said study leader Jerome Sarris. He is head of the ARCADIA Mental Health Research Group at the University of Melbourne in Australia.

The study looked at the result of trials where patients battling depression took either a standard antidepressant plus a form of omega-3 fish oil, versus the antidepressant plus an inactive placebo.

"The difference for patients taking both antidepressants and omega-3, compared to a placebo, was highly significant," Sarris said in a university news release. "This is an exciting finding because here we have a safe, evidence-based approach that could be considered a mainstream treatment," he explained.

"Many studies have shown omega-3s are very good for general brain health and improving mood, but this is the first analysis of studies that looks at using them in combination with antidepressant medication," Sarris said.

Doctors may be reluctant to prescribe dietary supplements in combination with antidepressants due to a lack of scientific evidence and concerns about safety. But, Sarris noted, the researchers found no major safety concerns in combining the two therapies.

However, the study authors stressed that patients should always talk with their health care provider before taking dietary supplements. In addition, people need to be aware that these supplements can differ in quality.

"We're not telling people to rush out and buy buckets of supplements. Always speak to your medical professional before changing or initiating a treatment," Sarris said.

One expert in the United States believes the findings might be of use to patients.

"The general population is often looking for natural remedies to treat health problems," said Dr. Victor Fornari.

"A large number of individuals with depression do not reach remission with one or two trials of medication," added Fornari. He directs child and adolescent psychiatry at Cohen Children's Medical Center in New Hyde Park, N.Y.

"This may enhance the recovery of individuals who do not respond to antidepressants alone," he said. However, Fornari agreed with the authors that "individuals are cautioned to consult with their medical professional before proceeding."

Omega-3 Fish Oil Supplements Might Boost Antidepressants' Effects  

Antidepressant could do double duty as diabetes drug, study shows

We know that, Paroxetine (also known by the trade names Aropax, Paxil, Pexeva, Seroxat, Sereupin) is an antidepressant drug of the SSRItype. Paroxetine is used to treat major depression, obsessive-compulsive disorder, panic disorder, social anxiety, posttraumatic stress disorder and generalized anxiety disorder in adult outpatients.

Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline. Genericformulations have been available since 2003 when the patent expired.

In adults, the efficacy of paroxetine for depression is comparable to that of older tricyclic antidepressants, with fewer side effects and lower toxicity.  Differences with newer antidepressants are subtler and mostly confined to side effects. It shares the common side effects and contraindications of other SSRIs, with high rates of nausea, somnolence, and sexual side effects. Paroxetine is associated with clinically significant weight gain. Pediatric trials of paroxetine for depression did not demonstrate statistical efficacy better than placebo.

Now University of Texas Medical Branch at Galveston researchers have  discovered that the commonly used antidepressant drug paroxetine could also become a therapy for the vascular complications of diabetes...

"The future potential of this study is that we may be able to 'repurpose' paroxetine for the experimental therapy of diabetic cardiac complications," Szabo said. "We'll need to carefully characterize its safety profile in diabetic patients, but I think there's definite potential here."

Ref : http://diabetes.diabetesjournals.org/content/early/2012/12/03/db12-0789
Antidepressant could do double duty as diabetes drug, study shows

A potential new class of fast-acting antidepressant

Scientists from the University of Chicago have discovered that selectively blocking a serotonin receptor subtype induces fast-acting antidepressant effects in mice, indicating a potential new class of therapeutics for depression. The work was published Oct. 29 in Molecular Psychiatry.

Of the subtypes, serotonin 2C receptors stood out. Selectively blocking these receptors in mice significantly reduced depression-like behaviors in only five days, compared to a minimum of two weeks for a control antidepressant medication.

"We observed fast-acting therapeutic effects in multiple behavioral tasks after we administered compounds that selectively block serotonin 2C receptors," said Mark Opal, a graduate student at the University of Chicago and lead author of the paper. "We began our measurements at five days, but we think there's a possibility it could be effective even sooner than that."

Serotonin 2C receptors normally inhibit the release of dopamine, another neurotransmitter commonly associated with mood, from certain neurons. When 2C is blocked, the researchers believe, more dopamine is released into regions of the brain such as the prefrontal cortex. The team also observed the induction of biomarkers that indicate antidepressant action.

This is the first new biological mechanism that has shown the ability to rapidly alleviate symptoms of depression since ketamine and scopolamine, and it potentially represents a much safer alternative. Some current antidepressants on the market already affect serotonin 2C receptors, although not selectively, and Dulawa believes the safety profile is favorable for human use. The team is now investigating compounds suitable for clinical trials.

"One of the primary advantages to our discovery is that this is much more of an innocuous target than others that have been identified," Dulawa said.

A potential new class of fast-acting antidepressant

Anti-inflammatory drugs may improve severity of depressive symptoms, study finds

Anti-inflammatory drugs similar to those used to treat conditions such as rheumatoid arthritis and psoriasis could in future be used to treat some cases of depression, concludes a review led by the University of Cambridge, which further implicates our immune system in mental health disorders.

Researchers from the Department of Psychiatry at Cambridge led a team that analysed data from 20 clinical trials involving the use of anti-cytokine drugs to treat a range of autoimmune inflammatory diseases. By looking at additional beneficial side-effects of the treatments, the researchers were able to show that there was a significant antidepressant effect from the drugs compared to a placebo based on a meta-analysis of seven randomised controlled trials. Meta-analyses of the other types of clinical trials showed similar results.

When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins known as cytokines. This process is known as systemic inflammation.

Even when we are healthy, our bodies carry trace levels of these proteins - known as 'inflammatory markers' - which rise exponentially in response to infection. Previous work from the team found that children with high everyday levels of one of these markers are at greater risk of developing depression and psychosis in adulthood, suggesting a role for the immune system, particularly chronic low-grade systemic inflammation, in mental illness.

Inflammation can also occur as a result of the immune system mistaking healthy cells for infected cells and attacking the body, leading to autoimmune inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. New types of anti-inflammatory drugs called anti-cytokine monoclonal antibodies and cytokine inhibitors have been developed recently, some of which are now routinely used for patients who respond poorly to conventional treatments. Many more are currently undergoing clinical trials to test their efficacy and safety.

The team of researchers carried out a meta-analysis of these clinical trials and found that the drugs led to an improvement in the severity of depressive symptoms independently of improvements in physical illness. In other words, regardless of whether a drug successfully treated rheumatoid arthritis, for example, it would still help improve a patient's depressive symptoms. Their results are published today in the journal Molecular Psychiatry.

Anti-inflammatory drugs may improve severity of depressive symptoms, study finds: Anti-inflammatory drugs similar to those used to treat conditions such as rheumatoid arthritis and psoriasis could in future be used to treat some cases of depression, concludes a review led by the University of Cambridge, which further implicates our immune system in mental health disorders.

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

In continuation of my update on Rimonabant

A new version of an obesity drug that caused serious psychiatric side effects could help people lose pounds without experiencing the anxiety, depression and suicidal thoughts previously associated with it. The research, published in Bioorganic and Medicinal Chemistry, shows that the new version of the drug can still work without reaching the brain in rats, avoiding the side effects.

The researchers behind the study, from RTI International in the US, say this means the new version of the drug could be used in the future for treating obesity. And their approach could also support the development of drugs to tackle liver disease, metabolic conditions and high blood cholesterol.

In our bodies we have cannabinoid receptors that control appetite, mood, memory and pain. The obesity drug Rimonabant stops these receptors from working. But the drug was found to have serious psychiatric side effects in a small number of the people who took it. Because of this, the drug was never approved in the US and manufacturer Sanofi-Aventis pulled from the European market voluntarily.

In the new study, the researchers altered the drug so it no longer gets into the brain, which stops it from having psychiatric side effects.

Study author Dr. Rangan Maitra, from RTI International in the US, explained: "There is a real need for new medicines to treat metabolic conditions like obesity. We are working with chemists to alter the drug Rimonabant and create compounds that cannot get into the brain. We hope this will help create drugs that can treat people with these conditions, without them having to suffer the side effects."

Dr. Maitra and colleagues modified the original Rimonabant compound by changing its weight, polarity and other properties to try to stop it from getting into the brain.

Tests in rats found that one of the versions, called 8c, blocks the target receptor and is much less likely than the original drug to get into the brain and affect the central nervous system.

The researchers found that 8c mostly stays in the blood and works on cannabinoid receptors found in parts of the body other than the brain. In comparison, more than half of the original drug Rimonabant entered the brain.

It's early days for the research, and the new version of the drug will need to go through testing before it can be used to treat people, but the researchers say it's a step in the right direction. Their study also outlines how scientists can test drugs designed to target cannabinoid receptors to make sure they are working outside the brain.

"Drug development is a long and arduous process," said Dr. George Amato, co-author of the study. "You have to develop hundreds, if not thousands, of compounds before you get the right one. The challenge is that some medicines that are absorbed in the gut also get into the brain. We set out to find compounds that absorb across the gut barrier but not the brain barrier. We've identified some, and they'll now serve as lead structures for further refinement."

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

MIF (Macrophage migration Inhibitory Factor) - a new molecular target for the treatment of depressant and anxiety...

Clinical depression affects 121 million people around the world,  according to the World Health Organization, but only 60% to 80% of cases are effectively treated with current medication and psychotherapy.  Now researchers from Ecole Polytechnique Fédérale de Lausann, (EPFL), have come up with an interesting target, i.e., macrophage migration inhibitory factor, MIF. 

MIF(see strucutre : wikipedia : a pro-inflammatory cytokine that is expressed in the CNS) is normally thought to play a role in tissue swelling (inflammatory mediator possibly associated with rheumatoid arthritis,  RA-severity) and even cancer development (metastatic potential in speculative models of cancer), but its precise location and function in the brain remained a mystery before Carmen Sandi's (lead researcher) study. 

 The research team, first detected a concentration of MIF protein in stem cells in the hippocampus, (a key area for memory formation and neuron generation during adulthood). New neurons are thought to be linked to the creation of new memories but they may also play an important role in curbing anxiety  (previous studies have shown that prolonged periods of stress reduce neurogenesis, and many anti-depressants actually boost the production of new neurons).

By genetically and pharmaceutically manipulating the level of MIF in the hippocampus of rats, the researchers discovered that the absence of MIF significantly reduced the production of neurons and increased anxiety They also found that the lack of MIF decreases the ability of anti-depressants to stimulate neurogenesis. 

Researchers, identified  MIF expression in neurogenic cells  (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1 - see (right side) chemical structure : (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid, methyl ester) approaches. 

As per the claim by the researchers,  genetic deletion of MIF resulted in increased anxiety and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Researchers conclude that,   MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition....

Ref : Carmen Sandi et. al., Molecular Psychiatry, 23 February 2010

 

FDA Acceptance of ALKS 3831 New Drug Application for Treatment of Schizophrenia and Bipolar Disorder

 Alkermes plc (Nasdaq: ALKS) announced that the U.S. Food and Drug Administration (FDA) has accepted for review the company's New Drug Application (NDA) seeking approval of ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and for the treatment of bipolar I disorder. ALKS 3831 is an investigational, novel, once-daily, oral atypical antipsychotic drug candidate designed to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The NDA has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of Nov. 15, 2020. [(Olanzapine/samidorphan - developmental code name ALKS-3831) is a combination of the atypical antipsychotic olanzapine and the opioid modulator samidorphan

                             

                                                                                             Samidorphan

olanzapine

"The acceptance of the NDA for ALKS 3831 marks an important milestone toward our goal of offering a new treatment option to people living with schizophrenia or bipolar I disorder. The ALKS 3831 development program builds on Alkermes' commitment to developing new therapeutic options that seek to address unmet needs of patients in large therapeutic areas," said Craig Hopkinson, M.D., Chief Medical Officer at Alkermes. "We believe ALKS 3831 has the potential to be a meaningful new offering for patients with these serious and complex mental health disorders, and we look forward to engaging with the FDA throughout the NDA review process."

The ALKS 3831 NDA includes data from the ENLIGHTEN clinical development program in patients with schizophrenia, as well as pharmacokinetic (PK) bridging data comparing ALKS 3831 and ZYPREXA^® (olanzapine), to support an indication for the treatment of schizophrenia, and an indication for the treatment of manic or mixed episodes associated with bipolar I disorder as a monotherapy or adjunct to lithium or valproate and for maintenance treatment of bipolar I disorder. Alkermes is seeking approval of fixed dosage strengths of ALKS 3831 composed of 10 mg of samidorphan co-formulated with 5 mg, 10 mg, 15 mg or 20 mg of olanzapine.

About the ENLIGHTEN Clinical Development Program

The ENLIGHTEN clinical development program for ALKS 3831 includes two key studies in patients with schizophrenia: the ENLIGHTEN-1 study, which evaluated the antipsychotic efficacy of ALKS 3831 compared to placebo over four weeks, and the ENLIGHTEN-2 study, which assessed weight gain with ALKS 3831 compared to olanzapine over six months. The program also includes supportive studies to evaluate the pharmacokinetic and metabolic profile and long-term safety of ALKS 3831, and pharmacokinetic bridging studies comparing ALKS 3831 and ZYPREXA.

About ALKS 3831

ALKS 3831 is an investigational, novel, once-daily, oral atypical antipsychotic drug candidate for the treatment of schizophrenia and bipolar I disorder. ALKS 3831 is composed of samidorphan, a novel, new molecular entity, co-formulated with the established antipsychotic agent, olanzapine, in a single bilayer tablet.

About Schizophrenia 

Schizophrenia is a serious brain disorder marked by positive symptoms (hallucinations and delusions, disorganized speech and thoughts, and agitated or repeated movements) and negative symptoms (depression, blunted emotions and social withdrawal).An estimated 2.4 million American adults have schizophrenia, with men and women affected equally.

About Bipolar I Disorder

Bipolar disorder is a brain disorder that causes shifts in a person's mood, energy and ability to function. Patients with this brain disorder may experience debilitating mood shifts from extreme highs (mania) to extreme lows (depression). Bipolar I disorder is characterized by the occurrence of at least one manic episode, with or without the occurrence of a major depressive episode, and affects approximately one percent of the adult population in the United States in any given year.

About Alkermes plc

Alkermes plc is a fully integrated, global biopharmaceutical company developing innovative medicines for the treatment of central nervous system (CNS) diseases and oncology. The company has a diversified commercial product portfolio and a clinical pipeline of product candidates for diseases that include schizophrenia, depression, addiction, multiple sclerosis, and cancer. Headquartered in Dublin, Ireland, Alkermes plc has an R&D center in Waltham, Massachusetts; a research and manufacturing facility in Athlone, Ireland; and a manufacturing facility in Wilmington, Ohio. For more information, please visit Alkermes' website at www.alkermes.com.

https://en.wikipedia.org/wiki/Olanzapine

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Antidepressant Wellbutrin linked to long-term modest weight loss

Group Health researchers have found that bupropion (marketed as Wellbutrin) is the only antidepressant that tends to be linked to long-term modest weight loss.

Previously, Group Health researchers showed a two-way street between depression and body weight: People with depression are more likely to be overweight, and vice versa. These researchers also found that most antidepressant medications have been linked to weight gain.

Prior research on antidepressants and weight change was limited to one year or shorter. But many people take antidepressants--the most commonly prescribed medications in the United States--for longer than a year. So for up to two years the new study followed more than 5,000 Group Health patients who started taking an antidepressant. TheJournal of Clinical Medicine published it: "Long-Term Weight Change after Initiating Second-Generation Antidepressants."

"Our study suggests that bupropion is the best initial choice of antidepressant for the vast majority of Americans who have depression and are overweight or obese," said study leader David Arterburn, MD, MPH. He's a senior investigator at Group Health Research Institute (GHRI), a Group Health physician, and an affiliate associate professor in the University of Washington (UW) School of Medicine's Department of Medicine. But in some cases, an overweight or obese patient has reasons why bupropion is not for them--like a history of seizure disorder--and it would be better for them to choose a different treatment option.

Could 'Magic' Mushrooms Ease Depression?

Psychedelic mushrooms (see above picture) may point to new ways to treat depression, suggest two small brain imaging studies that seem to show how psilocybin (see right structure) the active ingredient in such mushrooms -affects the brain. 

One study included 30 healthy people who had psilocybin inserted into their blood while magnetic resonance imaging (MRI) scanners measured changes in their brain activity. The scans revealed that psilocybin caused decreased activity in what the researchers described as the brain's "hub" regions -- areas especially well-connected with other areas.

The second study included 10 healthy volunteers and found that psilocybin boosted their recall of personal memories and their emotional well-being for up to two weeks. The researchers said this suggests that psilocybin might prove useful as an adjunct to psychotherapy.

"Psychedelics are thought of as 'mind-expanding' drugs, so it has commonly been assumed that they work by increasing brain activity, but surprisingly, we found that psilocybin actually caused activity to decrease in areas that have the densest connections with other areas," Nutt said....

Researchers lead by Dr.David Nutt, add that result is consistent with earlier finding that psilocybin decreases mPFC activity, as many effective depression treatments do. The effects need to be investigated further and this study was only a small study, and  are interested in exploring psilocybin's potential as a therapeutic tool.....

CGP3466B compound may effectively treat depression

We know that, Omigapil (TCH346 or CGP3466) is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD). Omigapil was first synthesized at Ciba-Geigy, Basel, Switzerland. Santhera Pharmaceuticals has since taken over production of omigapil and preclinical trials for CMD. In May 2008, omigapil was granted orphan designation to commence clinical trials for. Pharmacokinetic trials are scheduled to commence enrollment in the second half of 2012 to determine the appropriate pharmacokinetic profile of the drug for children with laminin-α2-deficient congenital muscular dystrophy (MDC1A) and collagen VI related myopathy. Santhera Pharmaceuticals will use the phase 1 clinical trial to determine if the drug is safe and acts with the same pharmacokinetic profile in children as it does in adults. The impending clinical trial will take place in the United States at the National Institute of Neurological Disorders and Stroke/National Institute of Health(NNDCS/NINDS) (Bethesda, Maryland) and in the United Kingdom at Great Ormond Street Hospital (UCL

The compound CGP3466B, already proven nontoxic for people, may effectively and rapidly treat depression, according to results of a study in mice. The Johns Hopkins Medicine neuroscientists who conducted the research say that the compound -- previously shown to block cocaine craving in the brains of rodents -- delivers antidepressant effects to mice within hours instead of weeks or months, like currently available antidepressants. The results of the study will be summarized Jan. 12 online in the journal Molecular Psychiatry.

"One of the promising things about CGP3466B is that it targets a new network of proteins," says Solomon Snyder, M.D., professor of neuroscience at the Johns Hopkins University School of Medicine. "That means it may work in patients who are unresponsive to other types of drugs and it lays the foundation for the development of a new class of fast-acting antidepressants that target the same network."

The team's discovery came out of investigations into the workings of a different drug, ketamine, long used primarily at high doses to induce anesthesia during surgery but known, at lower doses, to be a fast-acting antidepressant. Unfortunately, Snyder says, ketamine is addictive and can produce schizophrenialike symptoms, making it unsuitable for prolonged use, but his team hoped it could shed light on how to make a better fast-acting antidepressant.

CGP3466B compound may effectively treat depression: 

Dietary supplement could be promising therapeutic target for seizure disorders

We know that, Glucosamine  is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, as well as the cell walls of fungiand many higher organisms. Glucosamine is one of the most abundant monosaccharides.

Seizure disorders -- including epilepsy are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group to proteins is a well-known regulator for many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation.

A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function.

Since neural excitability in the hippocampus is a key feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, "Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus." The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham.

"Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics," they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complex.

Research details

Glucose, the major fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels.

In experiments with hippocampal brain slices treated to induce a stable and ongoing hyperexcitability, UAB researchers found that an acute increase in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability.

In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation -- synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1.

Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments -- this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice. 

Ref : http://www.uab.edu/news/innovation/item/8796?utm_source=eurekaalert&utm_medium=referral&utm_campaign=&utm_content=

Dietary supplement could be promising therapeutic target for seizure disorders