Antidepressants could be expanded in the treatment of migraine

Antidepressants are often used for migraine prophylaxis, but their use is limited to off-license. A high percentage of patients not fully satisfied with their current treatments could justify more research to develop licensed antidepressants to deal with this medical condition.

Main use of antidepressants

The purpose of prescribing antidepressants is to help relieve symptoms of depression, anxiety disorders and other medical conditions that include migraine prophylaxis, at least used off-label. It is important to note that these medicines do not cure the disease but just treat symptoms.

The mechanism of action of these drugs is mainly based on targeting imbalances of neurotransmitters in the brain that could be part or a consequence of the origin of these medical conditions.

Antidepressants in the treatment of migraine

Migraine and depression may share modulatory factors

Chronic stress and depression are frequent in migraineurs and thus seem to share, at least in part, modulatory factors. Just in the United States 8% – 12% of people aged over 12 years old are using antidepressants, with females representing approximately three quarters of patients. It is estimated that around 22% of migraineurs may be suffering from depression, and it seems common that patients are diagnosed with depression or anxiety just after being diagnosed with migraine – this may be influenced by the fact that antidepressants are not always covered by health insurance to treat migraine as a first-line therapy, particularly in the United States.

Migraineur

According to many studies, it seems obvious that serotonin plays a relevant role in migraine and depression.

Serotonin, released from brainstem serotonergic nuclei, is thought to be mediated by its direct action upon the cranial vasculature. Vessel vasodilation seems one of the main causes that result in migraine headaches. Other scientists have suggested that serotonin could intervene in central pain control pathways or could be the consequence of cerebral cortical projections of brainstem serotonergic nuclei. Low levels of serotonin could make easier the activation of the trigeminovascular nociceptive pathways in conjunction with cortical spreading depression.

In any case, serotonin receptors (5-HT receptors) have been one of the main targets in the development of antimigraine drugs. There are at least 7 classes and 14 subtypes of 5-HT receptors, all with varied biological effects. 5-HT1B serotonin agonists in blood vessels known as triptans are the most relevant antimigraine abortive drugs now. Still, triptans are also agonists at the 5-HT1D receptor, which contributes to their antimigraine effect caused by vasoconstriction of blood vessels in the brain.

On the other hand, scientists believe that an imbalance in serotonin levels, particularly diminished activity of serotonin pathways, may influence mood in a way that leads to depression. It is important to notice that this theory has not been fully substantiated though. Some authors suggest that an imbalance in serotonin levels may not be the only cause to suffer from depression and that other factors may also influence, or even be the main cause on their own for certain patients.

SAMe (S-adenosyl-l-methionine), an amino acid-based substance produced naturally throughout the human body, has been postulated as a potent antidepressant that could also be useful to treat migraines due to its modulating effect on serotonin. SAMe has been available as a dietary supplement in the US since 1999, but it has been used as a prescription drug in Germany since 1989.

Studies and experts’ opinions may lead us to think that serotonin levels and imbalances may affect certain individuals under certain circumstances that may prompt migraine and depression or anxiety disorders at the same time. However, it is clear that serotonin is not the only cause for migraine and depression because not all people suffering from migraine have depression and vice versa.

TCAs and SSRIs are the main antidepressant categories used in migraine prophylaxis

Focusing on the prevention of migraine, tricyclic antidepressants (TCAs) and selective-serotonin re-uptake inhibitors (SSRIs) are the most often used categories of antidepressants because these types of product seem to block serotonin reuptake. However, more selective serotonin reuptake inhibitors are not very effective in migraine prevention. Within the TCA category amitriptyline and nortriptyline dominate this segment whilst duloxetine hydrochloride is the leading SSRI drug for migraine treatment.

From a patients’ profiling point of view, as an example, a study showed that migraine attacks after use of tricyclic antidepressants (TCAs) was reduced in all NOS3 genotypes (nitric oxide synthase 3) patients, though there was no significant effect in intensity of headache. Researchers detected an inhibitory role in migraine generation, predominantly in patients with homozygous genotype, due to the decreased frequency of migraine attacks.

Nonetheless, a major concern in the use of antidepressants is their side effects. The use of amitriptyline conveys major worries about suicidality that may not be worth running the risk of their prescription. Patients also report suicidal thoughts with other antidepressants including SAMe.

Serotonin syndrome may also happen in patients that take triptans, TCAs or SSRIs abusively. Symptoms for serotonin syndrome include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea. Under extreme circumstances it may also include seizures and extensive muscle breakdown.

Anyhow, antidepressants should be avoided in elderly migraineurs and patients with comorbid overweight, epilepsy, or concentration and mental psychic performance.

The antidepressants market in the treatment of migraine

In the United States no antidepressant is officially approved to treat migraine, but just in the US market amitriptyline may be generating more than $10.0 million annually specifically targeting this indication at manufacturers’ level. Both nortriptyline and duloxetine hydrochloride combined may be around another $10.0 million. In Germany and the United Kingdom amitriptyline is estimated to have sales of approximately $1.60 million and $2.99 million respectively per annum for the prevention of migraine alone.

Some products containing amitriptyline are approved for the treatment of migraine in Germany. In the United Kingdom this active ingredient is used unlicensed for migraine prophylaxis according to the British National Formulary (BNF). In the United States it is used off-label.

Amitriptyline oral tablets and combinations with chlordiazepoxide, a sedative drug, or perphenazine, an antipsychotic drug, are off patent.

Nortriptyline oral capsules and solution and duloxetine hydrochloride delayed release pellets capsules have also lost their patent protection.

Medical devices may treat migraine and depression too

The connection between depression and migraine is also perceived strongly in the interest shown by some companies in the development and use of medical devices.

Patent publication number WO9400189 filed in 1992 by Cyberonics describes alleviation of migraine attacks by selectively applying by electrodes a predetermined electrical signal to the patient’s vagus nerve with an implanted neurostimulator device. Cyberonics markets the Vagus Nerve Stimulation (VNS) Therapy System, which was FDA-approved in 1997 and received CE Mark in 1994 for the treatment of refractory epilepsy and treatment-resistant depression. However, this is just an example as there are a large number of patents related to medical devices describing treatment of depression and migraine that have been filed by many companies.

In Europe, electroCore’s nVNS technology has a CE mark for primary headache (migraine and cluster headache), bronchoconstriction, epilepsy, gastric motility disorders, and anxiety and depression with medical prescription. gammaCore-S® is currently under study for the acute treatment of migraine.

The Fisher Wallace Stimulator received FDA clearance in 1991 for the treatment of insomnia, anxiety, depression and pain, and it is occasionally used off-label for the treatment of migraine.

Antidepressants in personalized migraine prevention may be profitable

In a more personalized medicine in the near future there may be opportunities to develop antidepressants to treat specific subtypes of migraines with ameliorated adverse effects. Understanding serotonin pathways better and improving patients’ genetic profiling will help to find better targets.

The development of a more personalized medicine will force existing products to find their market niches. Improving formulations of existing antidepressants that fit better specific genetic or biochemical patients’ profiles may be profitable for companies and advantageous for these patients. Covering these improved formulations with patents in order to trade them may also be interesting for small companies that do not have the economic muscle to market the product. Prices will be necessarily higher, but a number of patients will increase their quality of life. If these improved formulations are similar enough to the original approved active ingredient the approval process may be shortened and thus costs will also be reduced.

For more information about the antimigraine market in the United States, Germany and the United Kingdom please follow this link

Gene therapy could cure some migraine subtypes

What is gene therapy?

Gene therapy is a disruptive technology that could change the paradigm to treat a disease if it is proven effective.

Up to now, when scientists discovered a new gene potentially involved in the advent of a disease subsequent research mainly evolved around potential development of new products that targeted this new gene as well as associated interacting proteins and biochemical pathways. Nonetheless the future may bring along new approaches as science and technology advance.

Gene therapy in the treatment of migraine

Gene therapy is a technique to transfer genetic material targeting specific cells to repair, replace or inactivate malfunctioning genes that produce either defective proteins or no proteins at all in order to prevent or treat a disease. To transfer a gene, it is necessary to make use of a vector that is generally a genetically engineered virus prepared to cause no harm to the patient. The vector is injected or given intravenously, though in variant techniques a sample from the patient’s tissue can be extracted and exposed to the vector to be returned to the patient afterwards. The viruses infect targeted cells transferring the modified genetic material that will ultimately cause the desired therapeutic effect.

However not everything is as easy as it looks. Gene therapy conveys high health risks and at the moment it is only considered for those diseases that have no cure and whose genes are properly identified. The main barrier to manipulate genes is based on the fact that genes may control many biochemical pathways directly and indirectly, what is known as pleiotropic proteins. These genes often influence in the advent of other potential diseases and / or side effects in the same individual at the same time.

Since 1999 some attempts to use gene therapy have been tried with partial success. In one study conducted by a team of French researchers, eleven children suffering from serious immunodeficiency were treated with limited success, but two of them developed leukemia due to the vector used to transfer the genetic material. Other cases together with opinionated experts have also questioned gene therapy viability.

More recently CRISPR technology, an innovative genetic editing system, has raised great expectations once more. Nevertheless, according to Stanford University, patients receiving this treatment often develop antibodies against Cas9, an enzyme used in this new technology that cuts DNA fragments precisely. According to experts in this field, it is possible, however, to find workarounds such as different nucleases that do not prompt the autoimmune reaction so strongly and / or administration of immunosuppressants. Yet, the autoimmune system is not the only problem to be overcome when dealing with gene therapy and this technique. Further studies seem to show that there is also a risk of developing tumors due to a defective P53 gene. This gene codes for a protein that protects DNA from damaging changes, thus preventing potential tumors and other unwelcome effects. So, when P53 gene does not work properly DNA modification and desired therapeutic effect are easier, but they are also riskier. Some researchers believe that cell culture in a lab could be a solution to this problem, testing those genetically modified cells that have kept a functional P53 gene in a sort of quality control before reimplantation. In conclusion the use of this technique is still far from being implemented soon, and experts believe that it will probably be carried out in a very different way. Targeting RNA instead of DNA could also be another way to overcome DNA-related technical problems.

Migraine genetics

Gene therapy products are considered “biological products”. In the United States, this type of product is regulated by the FDA’s Center for Biologics Evaluation and Research (CBER). Clinical studies in humans require the submission of an investigational new drug application (IND) before clinical trials are conducted in the United States. Marketing a gene therapy product requires submission and approval of a “biologics license application” (BLA).

European Union regulations define “biological medicinal products” as “a protein or nucleic acid–based pharmaceutical substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct extraction from a native (nonengineered) biological source“. The terms “biotechnology medicines” and “biological medicinal products” are also commonly used.

 A quick look at migraine genetics

It is generally accepted that migraine is a multifactorial disorder with multiple genes playing a low penetrance role that is also influenced by environmental non-genetic factors. Thus, migraine is categorized in different subtypes, though it is mainly classified as a neurovascular condition activated from the trigeminovascular system where neurotransmitter pathways apparently play a relevant part, on their turn also controlled by other genes.

Genes that take part in migraine are often categorized as neurotransmitter genes, vascular genes and hormone genes. To get an idea of the complexity of migraine etiology we can give some examples of genes and proteins that take part in this medical condition, but it is far from being an exhaustive explanation for migraine origin, which is still unknown. There is some evidence that trigeminal nociceptive terminals are activated prompting the release of CGRP (calcitonin gene-related peptide), a pleiotropic neurological intermediary. CGRP is a 37 aminoacid peptide which seems to increase the sensitivity of perivascular nociceptors and dilate cranial vessels for some individuals who seem to be more susceptible, eventually known as migraineurs. RAMP1 gene (receptor activity modifying protein 1) codes for a key receptor subunit of CGRP, therefore also playing a relevant role. Still not all migraines are linked to CGRP and therefore not all patients may benefit from treatments targeting this peptide. Other genes may be the essential cause of a migraine, for example pituitary adenylate cyclase-activating polypeptide (PACAP), which is a neuronal messenger molecule thought to influence migraine, or female sex hormones involved in migraine susceptibility. There are many more genes and biochemical pathways suspected of influencing this medical condition.

At the moment, only some hemiplegic migraine subtypes have been accurately identified with causative genes. CACNA1A on chromosome 19p13 (FHM1), ATP1A2 at 1q23 (FHM2), and SCN1A at 2q24 (FHM3). It seems that FHM1, FHM2 and FHM3 mutations increase levels of glutamate and potassium in the synaptic cleft. PRRT2 (proline rich transmembrane protein 2) mutations have also been associated with hemiplegic migraine.

 Are there any clinical trials being conducted to treat migraine with gene therapy?

There are currently a significant number of studies making use of gene therapy to treat hereditary conditions. Examples include several types of cancer, immunodeficiency, sickle cell disease, diabetes concurrent with hepatocellular carcinoma, hemophilia, Alzheimer Disease and others mainly in early stages of development, though some studies have reached phase III trials as it is the case of peripheral arterial disease or spinal muscular atrophy.

We are not aware of any studies being conducted to treat migraine with gene therapy at the moment.

Are there any patents filed related to the treatment of migraine through gene therapy?

Some universities, research institutions and several pharmaceutical companies have filed patent applications related to diagnostic markers or genes involved in migraine such as those concerned with or affecting CGRP among others.

More directly related to gene therapy, there are already thousands of patent applications disclosing vector systems, antibodies, delivery techniques, enhancers, and different methods and techniques targeting specific genes or just genes in general. In particular, there are hundreds of patent applications filed in relation with CRISPR (clustered regularly interspaced short palindromic repeats) technology.

Regarding p53 gene activity concerns, as an example among many others we can mention MultiVir Inc., an American company, that filed international patent publication number WO2009094647 in January 2009 describing p53 biomarker profiles to be used in anti-hyperproliferative disease gene therapy.

In any case we have not found any patents specifically describing treatment of any migraine subtype through gene therapy yet.

 Is it possible to cure migraine with gene therapy?

For the moment advances in migraine genetics may help identify how genes influence biological pathways to develop more targeted drugs for migraine therapy.

Meanwhile the future treatment of migraine seems better approached with personalized medicine or precision medicine improving the definition of disease subtypes and more precise biomarkers that allow better tailor-made treatments for specific patients. Data mining and analysis in genetics, biochemistry and lifestyle will help to develop this type of personalized medicine.

Certainly, there is hope that gene therapy could cure at least some migraine subtypes in the near future, but gene therapy techniques need a significant improvement together with more advances and better understanding of migraine genetics. Maybe the best migraine subtype candidate to be approached through gene therapy is hemiplegic migraine variants – that is certain types of familial hemiplegic migraine and sporadic hemiplegic migraine.

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Medical devices will lose share in terms of revenues in the total US anti-migraine market by 2022

Anti-migraine medical devices

Anti-migraine medical devices will grab 5% market share in the United Kingdom and 3% in Germany in revenues in 2022

Whilst medical devices will gain two percentage points versus therapeutic drugs from 2018 to 2022 in terms of market share revenues for the total UK and German anti-migraine markets, CR Life Sc predicts that medical devices will lose two percentage points to grab only 7% of the total market to treat migraine in the United States.

During 2017 the medical devices market for the treatment of migraine in Germany has been able to seize approximately 1% share. Meanwhile the UK market for this type of devices has generated twice as much revenues to get 3% share. These devices are mainly available through specialist clinics and neurologists.

Anti-migraine medical devices face significant challenges and many opportunities

93% of revenues are expected to be generated by therapeutic drugs in 2022 in the United States. Abortive drugs (analgesics and antiemetics, specific antimigraine drugs, and more innovative medicines) will still lead the market. Anti-CGRP monoclonal antibodies and gepants together with new preventive drugs will help to drive the anti-migraine therapeutic drugs market. Expected high prices for these innovative products has become a major concern for government payors and insurance companies.

CR Life Sc estimates that neurostimulators and intraoral devices will have growth rates above 16% in revenues by 2022, but still according to the market neurostimulators may be underperforming.

Currently approved anti-migraine medical devices mainly target non-invasive Vagus Nerve Stimulation (VNS), Trigeminal Nerve Stimulation (TNS) and Transcranial Magnetic Stimulation (TMS), but Cranial Electrotherapy Stimulation (CES) devices and Vestibular Neurostimulators could also enter this market. Other invasive devices aiming at occipital nerves, trigeminal nerves, sphenopalatine ganglion, vagus nerve and spinal cord are also under study.

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CR Life Sc Insights has launched the most complete Antimigraine Market Report unravelling many opportunities and some threats

CR Life Sc Insights has produced the most complete market report for the Antimigraine Market. The report conveys a strategic analysis to 2022 for therapeutic drugs, diagnostics and medical devices in the United States, United Kingdom and Germany.

 

An overview of the anti-migraine market as accurate as possible in three relevant countries

 

In order to assess the market properly it is necessary to have an overview as complete and accurate as possible. Most of the reports available on the market just give partial views with a lack of adequate understanding for the whole picture.

 

The treatment of migraine offers many opportunities and some threats for healthcare companies. This report will make the reader an expert in this field.

 

This report is independent and economically unbiased and it is not sponsored by any stakeholder with an interest in the antimigraine market.

 

What you can find in this report

 

CR Life Sc Insights has conducted primary and secondary research involving more than 500 companies and institutions, more than 80 active ingredients and compounds as well as medical devices, and about 200 patents, to produce a report that contains 634 pages, 70 figures and 65 tables.

 

The structure and segmentation of this report makes an interesting and easy reading to reach conclusions and prompt adequate analysis and planning.

 

Who should buy this report

Investors, consultancy firms, professionals and any stakeholders in the pharma, diagnostics and medical devices fields will benefit from reading and having at hand this comprehensive report.

The Antimigraine Market.
The Antimigraine Market.
Therapetic drugs, diagnostics and medical devices. Strategic analysis to 2022. United States, United Kingdom and Germany.

Price: US $6,500

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