Why Big Pharma is not addressing the failure of antidepressants

May 18, 2015 by Colin Hendrie And Alasdair Pickles, The Conversation
Changing views on depression. Credit: Shutterstock

Around a quarter of people experience depression at some point in their lives, two-thirds of whom are women. Each year more than 11m working days are lost in the UK to stress, depression or anxiety and there are more than 6,000 suicides. The impact of depression on individuals, families, society and the economy is enormous.

Front-line therapies usually include medication. All the commonly prescribed are based on "the monoamine hypothesis". This holds that is caused by a shortage of serotonin and noradrenaline in the brain. Existing antidepressants are designed to increase the levels of these chemicals.

The first generation of antidepressants were developed in the 1950s and a second generation came in the 1980s. Products such as Prozac and Seroxat were hailed as "wonder drugs" when they first came onto the market.

In the roughly 30 years since, these kinds of drugs have come to look tired and jaded. Patents have expired and there are doubts about their efficacy. Some scientists even argue the drugs do more harm than good.

Broken model

There has been no third generation of antidepressants. This is despite there having been moon-landing levels of investment in research. The antidepressant discovery process that gave rise to the earlier drugs is clearly broken. It is also apparent that this process had never worked that well, since the only real improvements over the previous 60 years were a reduction of side-effects.

By the mid-2000s the major pharmaceutical companies started disinvesting in this area. Government funding for basic research into depression and charitable funding followed a similar pattern. In 2010 GSK, AstraZeneca, Pfizer, Merck and Sanofi all announced that they had stopped looking for new antidepressants altogether. Professor David Nutt, the former government drug advisor, declared this to be the "annus horribilis" for psychiatric drug research. The likelihood now is that there will be no new antidepressants for decades.

Why Big Pharma is not addressing the failure of antidepressants
Brain ventricles. Credit: Shutterstock

However, there continues to be an urgent and pressing need for more effective treatments. The question the drug companies now need to ask themselves is, did they fail because the task was impossible, or did they fail simply because they got things wrong? Our view is that there was a systems failure.

The monoamine hypothesis was not correct. There is little to no clinical evidence to support the notion that depression is associated with low levels of monoamines and predictions based on it were not borne out by research. The drug discovery process built around it was equally flawed and contained at its very heart a basic logical error which meant it was only ever capable of producing drugs with similar effects to the drugs we already had.

However, these failures still give reason for cautious optimism about the development of new drug treatments because they mean depression can now be looked at in ways that weren't previously possible.

New ideas

We have proposed a new theory of depression we call the "third ventricle hypothesis". The ventricles of the brain are a network of interconnected spaces filled with a liquid known as cerebrospinal fluid.

The third ventricle hypothesis links the behavioural features of depression, such as sleep disturbance or disruption of appetites for things like food and sex, with the brain structures that contact this space. Other behavioural features associated with depression include hunched posture, avoidance of eye contact and social withdrawal.

Our hypothesis says that this kind of behaviour developed in response to situations where an individual's survival depends on them remaining in a social group that has become hostile to them. Behaving in this more defensive way helps reduce the probability of further attack by others. The hypothesis goes on to say that this effect is produced by the explosive release of inflammatory substances known as cytokines into the third ventricle.

The third ventricle hypothesis ties in with clinical evidence showing that this ventricle is enlarged in depressives, that depression is associated with elevated levels of cytokines in blood, and other theories of depression that relate to the release of stress hormones. If developed, it could give new insights into the nature of depression and lead to novel approaches to the development of drugs that are used to treat it.

However, it has not proved possible to take this theory forward because its publication in 2010 coincided with the drug companies pulling out of psychiatric drug research. This disinvestment has impacted on all such work in this area. Guy Goodwin, former head of psychiatry at the University of Oxford has warned of a "generational crisis" in terms of capacity to develop new antidepressants unless the withdrawal of pharmaceutical funding is addressed.

A government review of funding for basic research into depression is now needed to revitalise drug company interest in developing new antidepressants, similar to the recent review of the development of new antibiotics. If new funding structures could be proposed, they might provide hope for the millions affected by depression.

Explore further: The science behind many antidepressants appears to be backwards, researchers say

Related Stories

The science behind many antidepressants appears to be backwards, researchers say

February 18, 2015
The science behind many antidepressant medications appears to be backwards, say the authors of a paper that challenges the prevailing ideas about the nature of depression and some of the world's most commonly prescribed medications.

Discovering why antidepressants don't work well for kids

April 1, 2015
Depression is a major health problem for which most patients are not effectively treated. In particular, depression is an increasing problem in children and teenagers. The most commonly prescribed antidepressants are selective ...

New study links antidepressants with improved cardiovascular outcomes

March 5, 2015
A new study by researchers at the Intermountain Medical Center Heart Institute has found that screening for and treating depression could help to reduce the risk of heart disease in patients with moderate to severe depression.

Depression during pregnancy linked to child's asthma risk

March 9, 2015
(HealthDay)—A child may face an increased risk of asthma if the child's mother experienced depression during her pregnancy or she took an older antidepressant to treat her condition, new research suggests.

A fast-acting antidepressant appears within reach

May 1, 2014
For someone with depression in the midst of a crisis, there is no time to waste. Yet time is exactly what currently-available antidepressants require to take effect—often on the order of weeks.

Why some antidepressants may initially worsen symptoms

December 17, 2014
New research helps explain a paradoxical effect of certain antidepressants—that they may actually worsen symptoms before helping patients feel better. The findings, highlighted in a paper publishing online December 17 in ...

Recommended for you

Researchers show that category learning can be influenced by where an object is in our field of vision

August 15, 2018
We humans are pros at category learning—the process by which we classify things, whether objects, concepts or events, into groups that share certain features that are relevant to us. We do it when we distinguish friends ...

Researchers link animosity in couples to inflammation, bacteria in bloodstream

August 15, 2018
Married people who fight nastily are more likely to suffer from leaky guts—a problem that unleashes bacteria into the blood and can drive up disease-causing inflammation, new research suggests.

Male tobacco smokers have brain-wide reduction of CB1 receptors

August 15, 2018
Chronic, frequent tobacco smokers have a decreased number of cannabinoid CB1 receptors, the "pot receptor", when compared with non-smokers, reports a study in Biological Psychiatry.

Unwanted or unplanned babies likely have more troubled close relationships

August 15, 2018
Findings appearing in the Journal of Social and Personal Relationships show people who believe they resulted from unwanted or unplanned pregnancies tend to have more insecure relationship styles as adults.

How we explain the behavior of others depends on our beliefs about their 'true selves'

August 14, 2018
Why did they do that? It's a question we ask every day in attempting to understand the behavior of others and make meaning of the world around us. How we answer the question, however, varies depending on our moral attitudes ...

Potent psychedelic DMT mimics near-death experience in the brain

August 14, 2018
A powerful psychedelic compound found in ayahuasca can model near-death experiences in the brain, a study has found.


Adjust slider to filter visible comments by rank

Display comments: newest first

4 / 5 (2) May 18, 2015
Perhaps we should stop looking at *drugs* as a first-line defense against extreme states of being altogether in the first place? (No matter how much "promise" new research shows)
1.5 / 5 (2) May 18, 2015
Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

A single amino acid substitution (Val158Met) links what is currently known about the biophysically constrained nutrient-dependent chemistry of RNA-mediated protein folding from the honeybee model organism to human life history transitions.

"The honeybee already serves as a model organism for studying human immunity, disease resistance, allergic reaction, circadian rhythms, antibiotic resistance, the development of the brain and behavior, mental health, longevity, diseases of the X chromosome, learning and memory, as well as conditioned responses to sensory stimuli (Kohl, 2012)." -- see: http://www.ncbi.n...3960065/

Big pharma failed because theorists never learned about the biological basis of RNA-mediated amino acid substitutions and cell type differentiation.

5 / 5 (1) May 19, 2015
Ketamine based meds are on the way.....
not rated yet May 19, 2015
The process of research must go on for the sake of interest of entire mankind. Depression will be the second most severe threat to mankind after 2020 according to World Health Organisation.
2 / 5 (2) May 19, 2015
The process of research must go on...

Until researchers lean the cell type differentiation is nutrient-dependent and occurs via RNA-mediated links between metabolic networks and genetic networks, the results of research will continue to be meaningless and have no explanatory power.

They might just as well be presented as ridiculous misrepresentations of facts as if the experimental evidence was based on population genetics instead of biologically-based cause and effect.
not rated yet May 23, 2015
Why does ketamine seem to work so well, and so quickly? The most interesting approach to me is likely connected with the new work involving olfactory receptors, see http://medicalxpr...rug.html and refs therein.

As to the authors speculations, in order to even begin to take it seriously, please ask him to provide a reference.
not rated yet May 23, 2015
See http://www.ncbi.n...2a80cc55 for a few refs.
However, this is a complicated area about which we know little.

For example see http://www.ncbi.n...18083105 for the connection of components of inflammation pathways with the ordinary pathways of synapse elimination. This is all in the arena of fundamental, publicly funded very basic research for now, which might well be seriously increased. The pharma companies are themselves likely rational and right to hold back for now. They have nothing to work with. They might contribute something to the basic research, I suppose, but it is not what they are designed to do. Without knowing this field at all, they would seem to need actionable targets with solid preclinical work, about 4 stages later than the hunches being proposed.
not rated yet May 24, 2015
Cytokines and excessive stress aside, dopamine, opioid, and cannabinoid targets seem to have been grossly neglected for depression. And unfortunately for us, the natural solutions providing coca, morphine, and marijuana have all been idiotically outlawed. Lastly, active B vitamin forms and magnesium have also been grossly underused.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.