Antidepressant may also alleviate multiple sclerosis symptoms

The antidepressant clomipramine may also alleviate symptoms of multiple sclerosis (MS), specifically in its progressive form, i.e. when it occurs without relapses or remissions. As yet, drugs for this type of MS have been virtually non-existent. Researchers collaborating with Prof V. Wee Yong, PhD, from the University of Calgary and Dr Simon Faissner from Ruhr-Universität Bochum screened 1,040 generic therapeutics and, based on preclinical studies, identified one that is suitable for the treatment of multiple sclerosis. They published their results in the journal "Nature Communications" from December 19, 2017.

Today, twelve drugs have been approved for the treatment of relapsing-remitting multiple sclerosis; for the progressive types, on the other hand, only a few therapy approaches exist. "The mechanisms causing damage in progressive MS are not always the same as in relapsing-remitting MS. This is why the latter requires different therapeutic approaches," says Simon Faissner. As postdoctoral researcher of the Department of Neurology at St Josef-Hospital in Bochum, he contributed to a study carried out at the Cumming School of Medicine, University of Calgary as a visiting scholar, funded by the grant for medical research awarded by the Ruhr-Universität's Faculty of Medicine.

Potential side effects already well-documented

The team worked with approved drugs, the side effects of which have already been amply documented. From among those drugs, the researchers selected 249 well-tolerated therapeutics that enter the nervous system safely; this is where chronic inflammation occurs in progressive MS. Using cell cultures, they tested which of the 249 substances are capable of protecting nerve cells from the damaging influence of iron. In MS patients, iron is released due to cell damage, damaging nerve cells in turn.

Following those tests, 35 potential candidates were identified; the researchers subsequently analyzed them with regard to additional properties: investigating, for example, if they can reduce damage to mitochondria - the powerhouses of the cells - or if they minimise the activity of leucocytes that attack the insulation of nerve cells in MS patients. In the process, the drug clomipramine proved promising.

Positive results in preclinical studies

In the next step, the researchers analyzed the substance in mice suffering from a disease comparable with relapsing-remitting multiple sclerosis in humans. The therapy suppressed the neurological disturbances completely; as a result, damages to the nerve cells and inflammation were minimised.

In a subsequent test, they treated mice with a disease that resembles progressive MS in humans. Here, too, the therapy proved effective, provided the researchers applied it immediately after the first clinical symptoms became apparent. Symptoms such as paralysis were thus reduced - unlike in control animals that were treated with placebo drugs.

Clinical studies planned

Simon Faissner returned from Canada to Bochum in January 2017. As a member of Prof Dr Ralf Gold's research group, he is continuously striving to identify new drugs with the potential of protecting from MS and to gain a better understanding of the mechanisms underlying the progressive type of the disease.

"Based on promising preclinical data, our long-term objective is to study clomipramine as well as other therapeutics selected in the screening process on patients in clinical studies," explains Faissner. "An advantage of generic drugs is the fact that there is ample clinical experience regarding their potential side effects." Accordingly, there is no need to perform phase-1 trials to study the tolerance of the drug in healthy volunteers. "The funding of such studies always poses a considerable challenge," concludes Faissner.

Progressive multiple sclerosis

In the Western world, multiple sclerosis is the most common cause of neurological disabilities in young people. In MS patients, leukocytes damage the layer surrounding nerve cells, the so-called myelin sheath. This results in neurological disturbances; in 85 percent of patients, the disease is characterized by clearly defined relapses and may cause e.g. visual impairment, paralysis or numbness. The majority of patients experience gradual deterioration after 15 to 20 years, which is referred to as progression. In ten percent of the patients, the disease is progressive from the outset, without any relapses along the way.

Ref : http://news.rub.de/english/press-releases/2017-12-20-medicine-antidepressant-may-help-combat-course-multiple-sclerosis

Antidepressant may also alleviate multiple sclerosis symptoms

Nasal spray delivers new type of depression treatment -- ScienceDaily

Nasal spray delivers new type of depression treatment

FDA Approves Khedezla for Major Depressive Disorder

We know that, Desvenlafaxine (brand name: Pristiq), also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth (now part of Pfizer). Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (sold under the brand names Effexor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause. 

Now FDA Approves Khedezla for Major Depressive Disorder

New antidepressant acts very rapidly and is long lasting

A first-of-its-kind antidepressant drug discovered by a Northwestern University professor and now tested on adults who have failed other antidepressant therapies has been shown to alleviate symptoms within hours, have good safety and produce positive effects that last for about seven days from a single dose.

The compound, called GLYX-13, (see the structure) is the result of more than two decades of work by Joseph Moskal, research professor of biomedical engineering at Northwestern's McCormick School of Engineering and Applied Science and director of the University's Falk Center for Molecular Therapeutics.

"Our study showed that this compound is capable of eliciting a robust and rapid antidepressant effect without the typical side effects seen with other drugs that also modulate the NMDA receptor," said Moskal, who is founder and chief scientific officer of the Evanston-based biotechnology company Naurex Inc., which conducted the clinical study.

GLYX-13 works by modulating the NMDA (N-methyl-D-aspartate) receptor in the brain, as do current NMDA receptor antagonists such as ketamine, but GLYX-13 does not have their serious and limiting side effects, such as hallucinations and schizophrenia-like effects. (An antagonist is a substance that inhibits the physiological action of another.)

The positive effects of GLYX-13 were evident within 24 hours and lasted an average of seven days. The effect size, a measure of the magnitude of the drug's antidepressant efficacy, at both these times after a single dose was nearly double the effect size seen with most other antidepressant drugs after four to six weeks of repeated dosing.

Side effects of GLYX-13 were mild to moderate and were consistent with those observed in subjects receiving a placebo.

GLYX-13 is a four-amino acid peptide that modulates one of a large family of glutamate receptors, the NMDA (N-methyl-D-aspartate) receptor, in the brain. NMDA receptors play a key role in regulating synaptic plasticity -- the quality of the connection between neurons -- and thus are important in regulating learning and memory functions.

GLYX-13 is administered intravenously. Moskal said Naurex also is working on an oral drug with similar properties and potential.

Moskal hopes that these positive GLYX-13 results and the research efforts of his team and colleagues will help shepherd in more research and grant support for studying the role of the glutamate-mediated processes in neuropsychiatric disorders...

Ref : http://www.nature.com/npp/journal/vaop/naam/abs/npp2012246a.html

New antidepressant acts very rapidly and is long lasting

The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

New research conducted by biologists at Texas A&M University suggests that sertraline (see structure below, ZOLOFT®), one of the most widely prescribed antidepressants in the world, also packs a potential preventative bonus  potent mechanisms capable of inhibiting deadly fungal infections. 

C. neoformans is a potentially dangerous fungal pathogen found in many soils throughout the world that may cause systemic infections, particularly involving the central nervous system. In most cases, the microscopic, airborne fungal cells of C. neoformans cause asymptomatic colonization in the lungs. However, Lin says the fungus is particularly aggressive in people with weakened immune systems and can spread to other parts of the body, such as the brain and spinal cord, resulting in cryptococcal meningitis  a condition that, in absence of treatment, is fatal. 

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.....

FDA Acceptance of New Drug Application for Vilazodone for the Treatment of Major Depressive Disorder..

Vilazodone(see structure) is an antidepressant which is currently under  development by Clinical Data for the treatment of major depressive disorder, and as of 2009 has completed two phase III clinical trials with positive results. An NDA was submitted on March 23rd, 2010 in the United States and is currently pending approval by the FDA which, if approved, will likely precede vilazodone's availability on the market by the end of 2010.

Now the company claims that FDA has accepted for filing the Company's New Drug Application (NDA) for vilazodone for the treatment of major depressive disorder (MDD).

Vilazodone is a dual-acting potent and selective serotonin reuptake inhibitor and a 5-HT_1A receptor partial agonist. The NDA will be subject to a standard review. 

“The acceptance of the NDA for review by the FDA is another positive step toward our goal of bringing vilazodone to market, and if approved, vilazodone will offer a novel treatment to the millions of people suffering from depression”  says Carol R. Reed, M.D., Executive Vice President and Chief Medical Officer of Clinical Data.....

Ref : http://www.clda.com/uploads/CLDA%20NDA%20acceptance%20FINAL.pdf

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

 

New cyclopropane derivative as better antidepressant ?

We know that most of the antidepressants have side effects such as  constipation, dry mouth, drowsiness and hypotension, or low blood pressure. Amongst various trypes TCAs, tricyclic antidepressants also have  the above mentioned side effects. 

In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), among others, though they are still sometimes prescribed for certain indications.

Duloxetine, is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and it is as effective as venlafaxine in generalized anxiety disorder. Duloxetine failed the US approval for stress urinary incontinence amidst the concerns about liver toxicity and suicidal events; however, it was approved for this indication in Europe and Canada.

Interestingly, chemists at Oregon State University have discovered and synthesized a new compound  (see the structure) that in laboratory and animal tests appears to be similar to, but may have advantages over Duloxetine. As per the claim by the  lead researcher Dr. James White (Professor Emeritus of Chemistry at OSU),  the new compound has properties similar to (Cymbalta) Duloxetine in some ways, but in laboratory and animal studies does a better job at balancing body chemistry. New compound is 10 times better than Duloxetine at inhibiting the re-uptake of norepinephine and comes close to the perfectly balanced antidepressant with fewer side effects, such as concerns with constipation and hypotension. Though clinical studies are essential to substantiate the claims its a good achievement...

Ref : http://pubs.acs.org/doi/abs/10.1021/jm900847b