The Incorporation of Pharmacogenomics to Drug Development in Neuropsychiatric Disorders -Juniper Publishers
Novel Approaches in Drug Designing & Development (NAPDD)
The global pharmaceutical sales increased from $836
billion in 2014 to $967 billion in 2016 worldwide, from $369 billion to
$446 billion in the USA, and from $179 billion to $201 billion in the EU
[1]. In contrast, the number of new patents for drugs [2,3] and/or FDA drug approvals per year (20-40 drugs/year) remain stagnant or in regression [4]. Furthermore, the health/disease paradigm is changing, with
(i) New pandemics in some geographic locations with potential dissemination to other regions.
(ii) Expansion of chronic/degenerative disorders in
developed countries in parallel with a decrease in infectious diseases
in rich economies.
(iii) An alarming increase of age-related disorders in both developed and developing countries.
(iv) Inequalities in the distribution of health
resources and health-care spending (44% in India; 43% in China; 12% in
UK and USA).
(v) Increase in the cost of health technologies.
(vi) Conflict of interest associated with intellectual property of health products.
Most of these issues demand an urgent revision by
Governments, health-care providers, regulatory agencies, and the
medical/scientific community. In terms of morbidity and mortality,
cardiovascular disorders (25%), cancer (20-30%) and brain disorders
(10-15%) are major problems of health, representing over 60-80% of
mortality in developed countries. These medical conditions account for
over 70% of health costs and about 80-90% of investments in drug
development. However, most drugs on the market are not etiopathogenic,
but symptomatic, with an efficacy rate below 40%. In this context, a
conceptual reconsideration of drug development procedures and
therapeutics is necessary to face the challenges that human health
demands in the present century [6].
Over the past decades, important progress has been achieved in the field of pharmacogenomics [7,8].
However, pharmacogenetics is still in its infancy and its concept has
evolved into a broader spectrum subsequent to the completion of the
human genome project. Pharmacogenomics accounts for 30-90% variability
in pharmacokinetics and Pharmacodynamics [9,10];
however, pharmacogenetics alone does not predict all phenotypic
variations in drug response. Individual differences in drug response are
associated with genetic and epigenetic variability (DNA methylation,
histone/chro matin modifications, miRNA regulation) in pathogenic,
mechanistic, metabolic, transporter, and pleiotropic genes involved in
the pharmacogenomic cascade [11-14].
From a global health perspective, important issues to
be addressed with regard to neuropsychiatric disorders (NPDs) and
Neuropsychopharmocology are
(i) Disease burden (DALYs: disability-adjusted life years;YLDs: years lived with disability; YLLs: years of life lost).
(ii) The costs (direct, indirect) of disease.
(iii) The impact that the identification of pre symptomaticbiomarkers may have on disease burden in the future.
(iv) More immediately, the effect that the
implementationof pharmacogenetic procedures may have on drug efficacyand
safety in NPDs.
NPDs (mental, neurological, substance use disorders)
contribute approximately 10% of the global burden of disease. About 30%
of all YLDs are assigned to NPDs, especially depression (11.8%), alcohol
use disorders (3.3%), schizophrenia (2.8%), bipolar disorder (2.4%),
and dementia (1.6%). The proportion of global disease burden increased
from 7.3 to 10.4% between 1990 and 2010. There was a 41% increase in
absolute DALYs caused by NPDs (from 182 to 258 million DALYs), together
with an increase in excess deaths and suicides. Worldwide DALYs (%) of
major NPDs include the following: 5.3% schizophrenia, 41.9% mood
disorders, 2.2% conduct disorder, 2.3% anxiety disorders, 1.6% autism,
0.2% attention-deficit hyperactivity disorder, 0.4% intellectual
disability, 8.7% migraine, 6.8% epilepsy, 4.4% dementia, 6.9% alcohol
use disorders, 7.8% illicit drug use disorders, and suicide and
self-harm (1.47% of Global Burden of Disease, GBD). NPDs are the leading
cause of disease burden, responsible for 7.4% of global DALYs and 22.9%
of global YLDs. Within NPDs, mental disorders account for 56.7% DALYs,
followed by neurological disorders (28.6%) and substance use disorder
(14.7%) [15].
A global cost of NPDs is projected to be about US$6
trillion by 2030. An estimated 8 million deaths annually are attributed
to mental disorders. Approximately 127 million Europeans suffer brain
disorders. The total annual cost of brain disorders in Europe is about
€386 billion, with €135 billion in direct medical expenditures (€78
billion, inpatients; €45 billion, outpatients; €13 billion,
pharmacological treatment), €179 billion in indirect costs (lost
workdays, loss of productivity, permanent disability), and €72 billion
in direct non-medical costs. Mental disorders represent €240 billion
(62% of the total cost, excluding dementia), followed by neurological
diseases (€84 billion, 22%) [16].
Depression is the third most important cause of
disease burden worldwide, with a prevalence of 5-10% for females and
2-5% for males, and a lifetime risk of 10-25% in women and 5-12% in men.
According to the National Health and Nutrition Examination Survey,
nearly 8% of persons aged ≥12 years (6% of males and 10% of females)
report current depression (suicide deaths per 100,000 population: 13.0).
Depression is the most common type of mental illness, affecting more
than 26% of the U.S. population. It has been estimated that by the year
2020, depression will be the second leading cause of disability
throughout the world, second only to ischemic heart disease [15].
The worldwide prevalence of schizophrenia ranges between 0.5% and 1%,
with the first episode at 21 years of age in men and 27 years of age in
women. Approximately one-third of the cases will attempt suicide and,
eventually, about 1 out of 10 will take their own lives. Global costs
for schizophrenia are estimated to be over $6 billion in the USA.
Anxiety disorders (panic disorder, generalized anxiety disorder,
post-traumatic stress disorder, phobias, and separation anxiety
disorder) are the most common class of mental disorders present in the
general population, with an estimated lifetime prevalence of 10-15%, and
an annual cost of over $40 billion in the USA. Direct treatment costs
for each mental disorder represent 1-2% of total national health care
costs, and serious mental illness is associated with an annual loss of
earnings totaling $193.2 billion [15].
Dementia (Alzheimer's disease, vascular dementia,
mixed dementia) and Parkinson's disease are among the top 15 conditions
with the highest increase in burden. Neurological disorders constitute
5.5% of YLDs (42.9 million YLDs), with migraine, epilepsy and dementia
representing over 50% of neurological YLDs (2.9% of global YLDs) [15-17].
Approximately, 45-50 million people suffer dementia
(75 million in 2030; 145 million in 2050; 7.7 million new cases/year).
The global economic cost for dementia is over US$604 billion, equivalent
to 1% of the global gross domestic product. In terms of costs,
Alzheimer’s disease (AD) accounts for $226 billion/ year in the USA and
€160 billion/year in Europe (>50% are costs of informal care, and
10-20% are costs for pharmacological treatment). It is estimated that in
the USA alone the direct cost of AD in people older than 65 years of
age could be more than $1.1 trillion in 2050 (from 2015 to 2050, the
estimated medical costs would be about $20.8 trillion). Strikingly, no
new drugs have been developed for AD for the past 15 years [18]. Anti-AD drugs are not cost effective and less than 20% of patients can obtain a mild benefit with conventional drugs [19].
Pharmacogenomics of AD has demonstrated to be useful for prediction of
therapeutic outcome and discrimination of responders vs non-responders [9,19-22].
Antidepressants were the third most common
prescription drugs taken by Americans in the past decade. From 1988-1994
through 2005-2008, the rate of antidepressant use in the USA increased
by nearly 400%. Eleven percent of Americans take antidepressant
medication. Prescription of antidepressants varies widely between
European countries despite no evidence of difference in the prevalence
of affective disorders, and only 30-40% of depressed patients treated
with medication achieve full remission [23,24].
Cost-effectiveness of interventions in NPDs ranges
between US$100 and US$2,000 per healthy life year gained. However, drug
effectiveness is lower than 30% in most NPDs [15].
Intervention priorities for NPDs, as proposed by commissioned authors of the World Bank [15]
practically neglect genomic intervention either as prevention
strategies or personalized treatments. However, it seems clear that
multiple genomic defects, interacting with environmental factors and
epigenetic phenomena, are at the basis of the pathogenic mechanisms
underlying most NPDs [9,10,21,25].
Therefore, the elucidation of disease pathogenesis at molecular levels
is a fundamental issue in order to identify suitable biomarkers for an
early diagnosis or, even better, pre symptomatic markers for disease
prevention [26].
Furthermore, 60-80% of psychotropic drugs are metabolized via CYP
pathways; and only 20% of the Caucasian population are normal
metabolizers for the tetragenic cluster integrated by the
CYP2D6-2C9-2C19-3A4/5 genes, this indicating that, by trial and error,
the possibility of prescribing the wrong medication to a particular
patient, ignoring his/her pharmacogenetic profile, is over 70% [7,9].
In fact, over 60% of depressive patients are receiving an inappropriate
medication according to their pharmacogenetic background [23,24],
and community psychiatrists are more accurate in their psychotropic
prescriptions when they know the CYP profile of their patients [27-29].
At the present time, pharmacogenetic testing is currently available for
NPDs and a wide range of medical conditions. Tangible benefits to
patients and reduced total health care costs have been observed.
However, pharmacogenetic-guided therapy faces many barriers to full
integration into clinical practice and acceptance by stakeholders,
whether practitioner, patient or payer [30-34].
In practical terms, biomarkers for early detection/
intervention in NPDs might reduce disease burden by 5-15% during the
first 5-year period of application; and disease-specific pharmacogenomic
procedures would be able to help in (i) reducing acute side-effects by
20-30% and drug-related chronic toxicity by 25-40%, (ii) attenuating
global DALYs by 5-10%, and(iii) developing anti-pathogenic drugs rather
than conventional symptomatic compounds [7,9,10,21,26,35,36].It
is likely that the change in mentality that requires the implantation
of genomic medicine in NPDs will force some reluctant peers to assume
that something is always better than nothing before reaching an
unattainable perfection.
Comments
Post a Comment