Target Validation in Neuropsychiatric Diseases

Question 1

What proportion of global disease burden is caused by psychiatric and neurological disorders?

Answer 1

Psychiatric and neurological disorders account for ~10% of global disease burden.

Question 2

List 4 difficulties of target identification in neuropsychiatric diseases.

Answer 2

Difficulties of target identification in neuropsychiatric diseases include:

1 - Changing diagnostic criteria.

2 - Broad disease definitions and phenotypes (being resolved by DSM and ICD).

3 - Heterogeneity of disease populations. Neuropsychiatric disease is more of a spectrum rather than black and white so it is unlikely that any two patients have the same form of disease.

• Heterogeneity is due to the complexity of neuropsychiatric disorders and the large number of pathologies involved.
• Heterogeneity makes it difficult to control variables in research without severely restricting patient population numbers.

4 - There is high redundancy in the CNS, owing to its limited repair mechanisms.

• This means that in order for a dysfunction to be manifest clinically, a very large number of neurones have to be affected, by which time there is already significant pathology. An ideal target will be identifiable and targetable before the onset of symptoms.

5 - Targeting neuronal networks means there is a high probability of side effects, because the functional components of the brain are interrelated.

Question 3

List 6 new approaches to drug design in neuropsychiatric diseases.

Answer 3

New approaches to durg design in neuropsychiatric disease include:

1 - Targeting endophenotypes rather than disease.

2 - Taking a systems biology approach to targets, involving molecular and neuronal networks.

3 - Incorporate more objective measures for clinical trial endpoints. Currently, this relies on measuring symptoms, which is difficult to measure consistently. E.g. biomarkers.

4 - If they must be used, reevaluate animal models.

5 - Having more homogenous patient groups in clinical trials - moving away from ‘treatments for all’.

6 - Develop and validate translational biomarkers.