1.

INTRODUCTION ON
PSYCHOPHARMACOGENETICS

Philip Gorwood, Elizabeth Foot*

‘To wrest from nature the secrets which have perplexed philosophers in all ages,
To track to their sources, the causes of disease,
to correlate the vast stores of knowledge,
That they may be quickly available for the prevention and cure of disease
-These are our ambitions.’

Sir William Osler, 1849-1919

The ultimate goal of psychopharmacogenetics is improved patient health-

care. The following chapters of this book will detail the different mechanisms
potentially involved in psychiatric disorders giving clues for new pharmaco-
genetic studies, and the description of various psychiatric disorders, their
treatment and associated side-effects, that may shed light on the complexities of
the different phenotypes.
The research findings presented will hopefully in the not too distant future,
5- 10 years, form critical knowledge on which future treatment guidelines will
be made, to ensure psychiatry patients are benefiting from these advances in
scientific knowledge and the new insights gained from genetics and pharmaco-
genetics in ravelling the complexities of psychiatry disorders and their treatment.

* Philip Gorwood, INSERM Unit 675 (IFR02) Faculty Xavier Bichat. 16 rue Henri Huchard,
75018 Paris-France.
Elizabeth Foot, Glaxo Wellcome Research and Development Limited, Greenford, Middlesex, UK.

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2 P. GORWOOD ET AL.

1. INTRODUCTION

The idea of the “science of the brain” and that the application of this science
could be used to improve patient health is a belief well rooted in medical thinking.
Indeed, since the time of the Ancient Greeks, the concept existed that psychiatric
illness possessed an underlying neural structure. The last century saw an
evolution of this medical thinking, with a growing body of research conducted
within universities and institutions, to elucidate the chemistry and neurobiology
of the brain and the changes that occur in psychiatric disorders. This pioneering
research set the grounding for now viewing psychiatry as a science-driven
medical field and the prospect of evidence-based treatment for these disorders.
Up until this time, drugs such as opiates had been used as the primary
pharmacological treatment for psychiatry disorders such as depression and
mania. These met with some success, although raised the problem of induced
addiction. One can consider that it was the discovery of the first brain
neurotransmitter, acetylcholine by Otto Loewi and Navrati E. (1926) back in the
1920s, that saw the beginnings of more science-based treatment strategies, with
the end of the century seeing the wide spread use of the selective serotonin up-
take inhibitors in the use of depression and mood disorders, the use of dopamine
antagonists in schizophrenia and lithium for bipolar disorder.
However, despite the enormous advances made in our understanding of
brain chemistry and the development of ground-breaking medicines, there
remains considerable unmet patient need for more effective and better tolerated
drugs (Figure 1). The sequencing of the human genome and the ability to
investigate the genetic variation between individuals now offers a further
window by which to untangle the complexities of psychiatry disorders and
response to drug treatment. Pharmacogenetics, the science of the inherited
component of variability in drug response, is now playing an increasingly
important role to evolve the field of psychiatry medicine from a symptom-based
medicine to a more mechanism and evidence-based field. Psychopharmacogenetics
is the term used to describe pharmacogenetics as it specifically relates to the
genetic understanding of the variability in response to psychiatry drugs.
As we ask the question as to how psychiatry medicine will look at the end
of this century, or indeed in the nearer term, in next 5 to 10 years, a growing
body of data is emerging to believe that new drugs for the future are hidden in
our genes and to support a role for the use of genetic markers as part of a
physician’s decision-making criteria. Understanding the genetic contribution to
the variability in response to drugs is predicted to reduce the reliance on trial and
error prescribing and ultimately lead to more effective medicines and improved
healthcare for patients. This genetic understanding of drug response, or
pharmacogenetics, is also sometimes referred to as “giving the right drug at the
right dose to the right patient at the right time”. The evidence that this belief will
soon become a reality, and the role for pharmacogenetics to support the clinical
development and prescribing of novel psychiatry medicines is growing. Many of
these key findings are described in the subsequent chapters of this book.