By:

Dr. Hani Hamed Dessoki, M.D. Psychiatry

Associate Prof. Psychiatry

Acting Head, Psychiatry Department

Beni Suef University

2012

Introduction

Psychiatry has long been a second-class citizen in science and medicine.

Despite much effort, the causes of many psychiatric disorders remain unclear, and it has been difficult even to categorize such disorders precisely.

The identification of genetic biomarkers that predict treatment response can improve current clinical practice in psychiatry.

Introduction

The identification of genetic biomarkers that predict treatment response can improve current clinical practice in psychiatry.

Introduction

This is an emerging field known as pharmacogenetics, which comprises of genetic studies on both the pharmacokinetics and pharmacodynamics of treatment response.

Recent studies on antidepressant-treatment response have focused on both aspects of pharmacogenetics research, identifying new candidate genes that may predict better treatment response for patients.

Introduction

Ultimately, the use of genetic testing which can be considered as a valuable guide in the use of antidepressants and other psychotropics in clinical practice.

The use of biomarkers to predict human behaviors and psychiatric disorders raises social and ethical issues, which must be resolved by collaborative efforts.

Biomarkers

Biomarkers tell us who is sick, who will get sick, which patients should be treated with what and when, how well does the patient respond to treatment, and when has the patient returned to health.

For countless diseases today, biomarkers are providing physicians with valuable information.

It is a long-cherished dream of the medical profession to be able to individually tailor diagnosis and treatment for every patient.

This dream of personalised medicine could come true with the help of biomarkers.

Biomarkers

Measuring biomarkers to identify and assess illness is a strategy growing in popularity and relevance.

Although already in clinical use for treating and predicting cancer, no biological measurement is used clinically for any psychiatric disorder.

Biomarkers in Psychiatry

Here diagnostic tools are restricted to the evaluation of behavioral and clinical phenotypes, a severe limitation for any scientific study.

As in any other disease area a major goal is therefore the identification of markers that can categorize subsets of patients in a consistent manner.

This will allow a more precise definition of psychiatric disorders and in turn facilitate investigations of the pathophysiology and enhance the ability for patient treatment.

Biomarkers in Psychiatry

Biomarkers could predict the course of a medical problem, and aid in determining how and when to treat.

Several studies have indicated that of candidate psychiatric biomarkers detected such as cholesterol and associated proteins, specifically apolipoproteins (Apos), may be of interest.

Biomarkers in Psychiatry

Cholesterol is necessary for brain development and its synthesis continues at a lower rate in the adult brain.

Apos are the protein component of lipoproteins responsible for lipid transport.

There is extensive evidence that the levels of cholesterol and Apos may be disturbed in psychiatric disorders, including autistic spectrum disorders (ASD).

Neuroimaging: Why Important in Psychiatry?

To understand the functional neural basis of psychiatric disorders

To obtain neural markers / disease biomarkers and endophenotypes to aid diagnosis

To identify disease enophenotypes to help predict treatment response

Inflammation and behaviour

There is a relationship between stress, inflammation and different forms of psychiatric pathology.

The way the brain reacts to stress, especially in relationship to personality factors, is still insufficiently known.

One way to look at the brain is to study cerebrospinal fluid (CSF) (Anckarsäter 2005, Söderström 2001), another to look at different markers in blood.

Inflammation and psychiatric disorders

Classical sickness behavior after cytokine therapy (Dantzer et al 2004)

Increased risk of schizophrenia and autism after prenatal maternal infections (Freedman et al 2010)

Inflammatory dysbalance in several psychiatric disorders

Inflammation and aggression

Hostility is associated with increased levels of several inflammatory markers (Marsland et al 2008)

There seems to be a connection between variants of the CRP gene and impulsive personality traits (Suchankova et al 2009)

Measures of hostility/anger are increased in persons undergoing cytokine therapy (Kraus et al 2003)

Pharmacogenetics of Antidepressant Drugs

While antidepressant drugs are widely prescribed to treat depression and anxiety disorders, only one-third of drug-treated patients exhibit a beneficial therapeutic response.

Response and tolerability to medication are highly variable, with some patients responding to one treatment but not another.

Uncertainty in Psychiatry

There are several potential explanations for these poor drug-response rates, including clinical heterogeneity and diagnostic uncertainty, environmental and social factors, and genetics factors.

Pharmacogenetics

Early studies suggested that specific clinical phenotypes, such as melancholic or anxious depression, might predict differential responses to antidepressants; however, the clinical phenotypes were often variable and difficult to translate into clinical practice.

Pharmacogenetics, which is the identification and development of genetic biomarkers that predict therapeutic response and the risk of side effects, takes a different approach to ultimately help the practitioner in choosing effective and safe treatment for patients suffering from psychiatric disorders.

Pharmacogenetics

Pharmacogenetic studies are often subdivided into studies concerned with pharmacokinetics and those concerned with pharmacodynamics of antidepressant medications.

Pharmacokinetics refers to the mechanisms controlling the absorption, distribution, metabolism and excretion of a drug.

Pharmacogenetics

Knowledge of the genetic metabolizer status of a patient may be helpful to the clinician in order to avoid potential side effects and to reach therapeutic levels faster.

However, the well-documented correlations between CYP alleles and plasma concentrations of antidepressants do not translate well to differences in clinical response to the same antidepressants.

Some small studies have found a significant association between CYP2D6 genotypes and antidepressant-treatment response

Pharmacogenetics

The term pharmacodynamics is used to describe the effects a drug has on the body.

Pharmacodynamics includes interactions of a drug with receptors, transporters and downstream targets.

Although the primary mechanism of action for antidepressants is thought to involve predominantly monoaminergic neurotransmitter systems, the exact mechanisms by which antidepressant medications work remain unknown.

Most pharmacogenetic studies in MDD to date have focused on candidate genes involved in monoaminergic neurotransmission.

Future Directions

Future Directions

Molecular genetic predictors of treatmentresponse in Unipolar disorder

5-HTTLPR SSRIs Serretti et al., 2006

HTR2A Citalopram RemissionMc Mahon et al., 2006Horstmann et al., 2009

BDNFSSRIsFluoxetine, DMI

Gratacos et al., 2007Licino, et al., 2009

PDE1A Wong et al., 2006SSRIs RemissionPDE11A

KCNK2 Citalopram Resistance Perlis et al., 2008

SLC6A4 Citalopram Remission Mrazek et al., 2008

5-HTTLPR SSRIs Pediatric Depression Kronenberg et al., 2008

NTRK2 SSRIs Response Dong et al., 2009

U-2-S-TRANSFERASEIL-6, IL-11

SSRIs Response Uher et al., 2010

OPRM 1 Citalopram Response Garriock et al., 2010

FKBP5 Antidepressant Response Zobel et al., 2010

GALANIN Antidepressant Response Unschuld et al., 2010

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TODAY….TODAY….

TOMORROW….TOMORROW….

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Future of Behavioral Health has Arrived

Patients with depression and anxiety are frustrated with drug treatments because of poor response (up to 5 trials).

Also, some of these medications increase anxiety, resistance to treatment, insomnia, and sexual dysfunction.

Sometimes they may quit medications.

It is better to choose psychotropic medications based on the individual genetic characteristics, metabolizing pathways leading to better medication tolerance.

This give the patient the confidence to continue treatment.

Test can done by a simple cheek swab (Assure Rx- GeneSightRx).

Future

The FDA has approved several drug labels to contain information about pharmacogenetic biomarkers.

Currently, approximately 17% of these pharmacogenetic labels are for psychiatric drugs, and most of them contain information about the CYP450 enzymes.

However, most of these labels do not offer any clinical recommendations or require the use of this information before treatment prescription.

The ultimate goal of future studies is to expand the pharmacogenetic information on antidepressant labels and incorporate them into wide clinical use.

However, there are several limitations that need to be considered before the field can advance to this stage.

Problems

The main problem with current pharmacogenetic studies is the lack of standardization, making it difficult to distinguish between positive and negative findings in the same candidate gene.

Current studies often have very different inclusion criteria, use of medications, outcome measures, recording of side effects, ethnicity of study population and genetic coverage.

Furthermore, many of these studies have small sample sizes with limited power and a short-term follow-up of patients, leading to possible false negative or false positive results.

Take Home Massage

The mere existence of biomarkers in psychiatric illness does not mean we should ignore the cultural, psychosocial, and existential components of our patients’ problems, or attribute their psychopathology to biochemical factors alone.

Nonetheless, accurate biomarkers, along with more reliable and valid disease criteria, will help psychiatry achieve greater objectivity in diagnosis.

Even more promising, biomarkers may soon help us diagnose psychiatric disorders in their earliest stages, potentially enhancing the care of our patients.