Anti-Depression medications – One size does not fit all!

In today’s world ‘stress’ has become a common household phenomenon. Professional, social, economic and personal issues drive people to unimaginable level of stress and the outcome is that 1 in 4 people are afflicted with depression (Mental health statistics, UK). True, happiness is a state of mind but it is also a fact that people have different intrinsic capacities to deal with stressful conditions and not many can cope with a chronic onslaught of ‘stressful’ conditions!

We have come a long way in the field of psychiatry since the time when lithium used to be prescribed for ‘treating’ mental disorders like depression. The older tricyclic antidepressants (Doxepin, Imipramime etc.) have been superseded by the newer SSRIs (Selective Serotonin reuptake inhibitors), SSREs (Selective serotonin reuptake enhancers), atypical antidepressants (Bupropion) and the MAOIs (Monoamine oxidase inhibitors). It would look as if we have a good arsenal to fight this menace. 

But if one scratches the surface, one would realize that in many cases these medications are the problem and not the solution. The side effects of these ‘newer’ class of drugs range from the ‘manageable’ nausea, dry mouth, weight gain/loss to the dangerous cases of increased suicidal tendencies and anxiety. The problem is that still the theories behind the probable cause of depression revolve around the differential levels of neurotransmitters (Serotonin, dopamine) in depressed patients. Although, many scientific reports have validated these claims but doubts persist. To top the level of confusion, both classes of drugs such as SSRIs and SSREs which target the neurotransmitter serotonin level (one increases its level and the other decreases it) have been shown to alleviate symptoms of depression!

Also, unlike other modern medicines, antidepressants take longer time to show their effects (if at all). We do not understand why this is so though there are theories that suggest that the medicines can lead to modifications at the genomic level and hence the time-delay of their action! Psychiatrists themselves try and experiment with different class of medicines to see the best fit for their patients. But in doing so not only crucial time is lost, there are  issues leading to patient compliance and severe side effects and even death (suicide).

The need of the hour is therefore to use modern genomic data to predict the outcome of these medications before embarking on the prescription. As 'mind' is unique to every individual, this is a fit case where the newer field of 'personalized medicine' should kick in with all its technology in its arsenal.We have already started doing the same for oncology drugs with newer drugs being accompanied by companion diagnostic tests. Also, the drug companies need to be more transparent with their data of the side effects of anti-depressants as it has been found of late that many pharma companies did not divulge the true nature of the side effects and later the drugs had a serious ramifications on the patients’ health and many of them were either withdrawn or were forced to have ‘black box’ label warnings!

Effective diabetes treatment gets a nutraceutical pitch!

Type 2 Diabetes is a lifestyle disorder of an epic proportion. It is widely speculated that US, India and China are or are going to be the worst affected by this problem.

Current therapies focus on various strategies to control blood sugar but there is no cure at this stage. The older sulponylureas and metformins to the newer TZDs (thiazolidinediones), GLP-1 analogues and even SGLT2 inhibitors are vying to capture the diabetes market. The whole exercise is to promote medication that can control the HbA1c to controllable levels. 

Dietary extracts containing polyphenols, L-arginine etc. have been shown to have anti-diabetic potential. In a recent publication in the journal Endocrinology(Endocrinology August 19, 2013 en.2013-1529), it has been shown that dietery L-arginine can regulate glucose metabolism indirectly by inducing GLP-1 release in mice. Although the exact mechanism has not been dissected in the paper yet the authors suggest that G protein coupled receptor pathways might be involved. 

Since current strategies involve targeting the GLP-1 system by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using dipeptidyl-peptidase IV-resistant GLP-1 mimetics, it would be interesting to see development of novel approaches like dietary supplement with L-arginine and or L-arginine based therapies to enhance GLP-1 secretion from intestinal L cells. In essence, this study raises the possibility that nutritional-based strategies aiming to improve endogenous GLP-1 release may provide an alternative therapeutic approach to treat patients with metabolic disorder

Bug Therapy to treat Diabetes and obesity in future?

The long held notion of ‘junk DNA’ has been found to be incorrect (ENCODE project), similarly, characterizing the gut microbiota as bystanders in the intestinal tract is now being widely challenged (Osborn O, Olefsky JM (2012), Nature Med 18(3):363-374).

A recent paper in Proceedings of National Academy of Sciences (PNAS) adds muscle to the fact that a single species of bacteria (Akkermansia muciniphila) can modulate diet induced obesity in mice. A. muciniphila is a Gram-negative bacteria that constitutes 3–5% of the gut microbial community. The paper also highlights the various mechanisms by which this bacterium might exert its effect (Everard A et al. (2013), PNAS)

The study shows dramatic decrease in gut A.muciniphila in diet induced obese mice. On restoring the abundance of this strain in obese and diabetic mice it was found that viable A. muciniphila controls gut barrier function, fat mass storage, and glucose homeostasis via several mechanisms. This study identified an association of obesity with a decrease in mucus thickness that is characteristic of obesity and associated disorders. Interestingly, the authors found that A. muciniphila restored this mucus layer. Strikingly, viable A. muciniphila induces these effects, whereas heat-killed A. muciniphila did not protect the mice from diet-induced obesity and associated disorders. One of the other key findings was that treatment with this bacteria led to increase in acylglycerol levels more specifically 2-OG and 2-AG. Incidentally, 2-OG is known to stimulate intestinal L cells which lead to secretion of GLP-1 (Hansen KB, et al. (2011), J Clin Endocrinol Metab 96(9):E1409–E1417). GLP-1 is known to increase insulin secretion. Also, A. muciniphila treatment completely reversed diet-induced fasting hyperglycemia via a mechanism that was associated with a 40% reduction in hepatic glucose-6-phosphatase expression thereby suggesting a reduction in gluconeogenesis. Hence this association might point to how A. muciniphila exerts its effects on glucose homeostasis. 

Many bacteria (Lactobacilus spp, Bifidobacterium spp etc.) have been shown to have effect on fat mass development during diet induced obesity (Fåk F, Bäckhed F (2012), PLoS ONE 7(10):e46837). However, in this study the emphasis was to study the bacterial strain that is affected during obesity and type 2 diabetes in humans and rodents. It would be interesting to see how this development would enthuse the world of gut microbiome research and interest the pharmaceutical/biotech companies to invest in this field which would then pave the way for not only treatment but prevention of inflammatory, lifestyle and even mental diseases in the near future.

India’s Supreme court ruling on Novartis’s Gleevec – A Perspective

Recently, the Apex court of India rejected the patent application of Novartis’s anti-cancer drug Gleevec (http://www.thehindu.com/news/national/landmark-verdict-gives-big-boost-to-cancer-patients/article4569056.ece?homepage=true)

As per Indian law "ever-greening" of the drugs is not encouraged whereas the big pharma companies keep on doing minor modifications to gain longer patent life in the US and other Western countries. This judgment therefore is in the right direction as it clearly defines what "innovation" is in the Indian drug market context and will give hope to millions of poor patients not only in India but across the world. 

But, I also have a point against the Indian pharma industry which is mostly focused on 'generics'. Indian pharma industry is not too keen on developing new drugs (NCEs) and is looking for major profits once the old drugs come off patent. This is not a healthy trend. Also, the amount being charged by these companies on these drugs can be slashed even more as they have not spent even a penny for the development of these drugs and so there is no point in even charging what they are right now for these drugs!!!

Of course, the above point holds true for NCEs but may not hold true for Biologics!. Biosimilars are a different ball game all together and it would be interesting to see what the future holds for the Indian pharma industry which is betting heavily on generics and biosimilars!

Finally, this verdict is definitely good for the patients and may be also good for the Indian pharma industry in the short run but I feel Indian pharma and Biotech industry need to innovate more and come out of the “profit making with minimal investment mindset"!