Tailormade - antidepressant drug discovery and development

Depression and anxiety are the two neurological conditions into which considerable research effort has been expended but which are currently failing to yield new therapies. Professor Florian Holsboer, co-Director of HMNC Brain Health, gave his opinion as to why this might be and how, in the future, new therapies might be discovered.

Antidepressants work

Surprisingly, there are no data to support that there has been an increase in the incidence of depression over the past 10 years. Rather, it appears that the fight of the stigma of mental illness has begun to be addressed - with the increase in prescription of anti-depressants correlating with the decline in suicides. This suggests that antidepressant drugs do afford great benefit to a great many patients and, contrary to some opinions, such drugs do work. Indeed, according to Professor Holsboer, correctly administered to the right patient, 60-70% of patients enter remission. However, much still remains to be done to improve on the currently available therapies and the management of anxiety and depression.

Neuroscience in depression diagnosis is key to success

Depression is caused by many different mechanisms that make treatment based on diagnosis alone difficult. Most antidepressants work via enhancement of serotonin, noradrenaline and dopamine transmission and the differences between therapies derive from other pharmacologies. Areas ripe for further investigation to find antidepressant therapies include the stress hormone system which Professor Holsboer believes to be a very promising field for investigation. His recommendation, however, comes with the proviso that investigations need to be undertaken in ‘the right patients’ – that is, in those patients in whom the action of the drug matches the ‘pathology’ of the condition.  For this, markers of the underlying condition are needed. Until diagnosis attempts to integrate with neuroscience, Professor Holsboer thinks that physicians will never be guided in making the right drug choices for their patients. 

Stress hormones marking progress

Two stress hormone therapies are promising candidates –corticotrophin releasing hormone receptor 1 (CRHR1) antagonists and vasopressin_1B – receptor (V_1BR) antagonists.  Professor Holsboer went into some detail explaining how only a limited proportion of patients with stress-related depression have persistently raised levels of CRH or vasopressin and how tests or markers for such over-expression are being developed. For example, increased rapid eye movement (REM) density during sleep has been identified as a marker for CRHR1 overexpression. Patents identified in this manner may be those who best benefit from a CRHR1 antagonist. Similarly, those patients with central vasopressin over activity can be identified following administration of a dexamethasone-CRH test and it is these patients who are more likely to respond positively to V_1BR antagonists.

Block-buster approach busted

Clinical trials of CRHR1 antagonists conducted by many pharmaceuticals companies, however, have failed, leading to the apparent wholesale exit of these companies from clinical research into anti-anxiolytics and antidepressants.  Professor Holsboer contends that the whole population approach to clinical trials and the expectation of block-buster success is what has failed – not the compounds. A more personalised approach may well be the solution to discovering new drugs in psychiatry.

Contrary to popular opinion, personalisation of medicine is unlikely to add huge costs to health programmes and it is a common myth that personalised medicine is expensive, affords little added value for patients and gives a poor return on investment for pharma companies. As Prof Holsboer explained, undertaking clinical drug development using the statistically-based methods of the past is all these things but personalised medicine offers a radical departure that counters such criticisms.

Will it pass the BBB?

Already in animal models it is possible to match the antidepressant molecule to the genotype of the custodial p-glycoproteins present in the blood vessels of the brain. This means that candidate drugs, in future, can be tested to see whether they are capable of entering the brain or not via the circulation.  If the custodial glycoprotein genotype indicates that the candidate antidepressant drug cannot gain entrance to the brain, another candidate drug that can do so should be given. Thus, patients’ genotypes will ultimately determine selection of their antidepressant therapy.

More bang for bucks!

More controversially, Professor Holsboer pointed out that with the continued exponential increase in the numbers of scientists, tax-payers are seeking returns on their tax investment – they want to see more effective therapies being developed more rapidly. A more tailored approach to psychiatric medicine would permit this because it could allow any drug that is going to fail to fail sooner, making pharmacological discovery more efficient and, potentially, less costly. 

Do animals suffer from depression?

An interesting question and one about which Professor Holsboer expressed scepticism. If animals don’t experience depression in the same way as humans, why use them to test anti-depressants in preclinical studies? While not advocating the relaxation of toxicity and other important safety studies, introducing therapies to humans sooner might also accelerate clinical development programmes.

Biosignature of the future

In conclusion, the most important research fields for innovative therapies for anxiety disorders and major depression where discoveries might be expected are human genetics and the genome, in the discovery of biomarkers as surrogates for the underlying pathology and in chemical biology. Professor Holsboer predicted that in 2030 drug treatment and disease prevention will be enabled by tailoring therapies according to an individual’s biosignature.