Clinical Impact of Pharmacogenetic Testing on Antidepressant Therapy

Special Article - Major Depressive Disorders

Ann Depress Anxiety. 2017; 4(1): 1085.

Clinical Impact of Pharmacogenetic Testing on Antidepressant Therapy

Holsboer F*

HMNC Holding GmbH, Germany

Corresponding author: Holsboer F, HMNC Holding GmbH, Maximilianstr. 34, 80539 Munich, Germany

Received: July 14, 2017;Accepted: September 01, 2017; Published: September 08, 2017


Optimization of antidepressant treatment can be achieved by administration of gene tests that inform about pharmacokinetics. While the CYP450 gene test has merit in special cases the ABCB1-test informs about penetrance of a given drug into the brain. In both cases the prediction can be improved if combined with measurement of plasma drug concentrations. The implementation of gene tests targeting pharmacodynamics is not warranted until we know more about pathology of depression and antidepressants mode of action.

Keywords: Blood-Brain Barrier; CYP450 Enzymes; ABCB1 Test; Personalized depression treatment


Current pharmacotherapy of depression follows a “trial-anderror” approach rather than a schedule where the first-line treatment is based on laboratory diagnostic that indicates the underlying pathology. Reasons that have fostered this sobering development include: (1) diagnostic categories are entirely based on mental symptoms; (2) patients fulfilling criteria for a certain category may have different disease mechanisms; and (3) in the absence of specific disease mechanisms „one-for-all“ drugs were developed that engage with multiple disease targets in the hopes that the disease causing mechanism is hit.

Clinicians tend to select their treatment according to past experience and according to specific side effects, e.g. sedation or activation, which may be useful in an individual case. Once a drug is selected, a treatment regimen is applied following the officially recommended guidelines. The adequacy of treatment and dosing is limited to what is called “therapeutic drug monitoring” to ensure that the administered drug dosage results in plasma drug concentrations that are within the appropriate range [1,2]. Prospective, controlled clinical trials where different patient groups were stratified according to fixed plasma drug levels and where clinical outcome is monitored to identify the perfect “therapeutic window” are yet not available. Instead, for each of the marketed antidepressants reference ranges were published that are largely based on expert consensus and not on studies. These ranges have considerable merit as guidance, but there is obviously room for further improvement.

In contrast to biomarkers that are physiologically and timely associated with the disease gene tests have the advantage of clinical feasibility as they are easily performed, independent from disease episodes and need no replication as gene variants are fixed. Thus, the main interest of all parties involved (patients, doctors and payers) currently focuses on gene tests [3].

Cytochrome P450 test

Cytochrome P450 proteins, predominantly located in the liver, have enzymatic properties and constitute the principal metabolic profile for most drugs in clinical use [4]. It is known from clinical observation and measurement of plasma drug levels that in some patients even moderate drug dosages result in high plasma concentrations while the same dosage in other patient’s results in very low drug levels. Obviously, some patients metabolize the administered drug very rapidly and are termed „ultra metabolizes“, while others having high plasma drug levels despite recommended dosages define as “poor metabolizes” [5]. Often also intermediate and extensive metabolizes between these extremes exist depending on the combination of CYP alleles they carry. As a result of different metabolize status “ultra metabolize” may be insufficiently dosed and therefore not responding to the drug while “poor metabolizes” may suffer from peripheral side effects secondary to the high plasma drug levels achieved by a standard dose.

Roche Diagnostics were the first to launch an oligonucleotide chip that measured genetic variations in two cytochrome p450 genes, CYP2D6 and CYP2C19, with limited commercial success. Today, the CYP2D6 and CYP2C19 genotyping is pursued by other companies, including STADA. While at first glance plausible, this test has some disadvantages as actual enzymatic activity is not precisely determined by gene polymorphisms. Enzyme activity, in general, is influenced by both, the substrate to be metabolized and the product that results from the chemical synthesis. More specifically, monotherapy among psychiatric patients is a rarity and some psychotropic drugs may impair CYP 450 enzyme activity while others can stimulate this activity. In pharmacokinetic studies administration of CYP2D6 inhibitors (e.g. paroxetine, fluoxetine) it was shown that individuals with non-poor metabolize genotype converted to a poor metabolizer phenotype. Larger studies, e.g. with venlafaxine, confirmed that phenoconversion to CYP2D6 poor metabolizer status among patients with non-poor metabolize genotype is occurring in around one quarter of patients [6]. Clearly, such phenotype conversions may have impact on clinical efficacy of a given drug. A prominent example where inhibition of a CYP 450 enzyme has considerable clinical implications is the inhibition of CYP1A2 by fluvoxamine that increases about threefold the plasma drug level of concomitantly administered clozapine which is also a CYP1A2 substrate [7]. There are other drugs that induce enzyme activity, e.g. carbamazepine, also smoking of tobacco induces CYP 450 enzyme activity.

In the light of these ambiguities treatment decisions guided by CYP 450 genotyping alone bears the risk of in proper dosing particularly if co medications are in place. In that case the individual patient is potentially either over- or under dosed. Such a risk can be avoided by continuous measurements of plasma drug levels which justify CYP genotyping only in special cases.

ABCB1 test

Endothelial cells of brain capillaries have tight junctions constituting the physical barrier whose paracellular transport of substances is negligible. Only passive diffusion, receptor-mediated transcytosis and specific carrier systems allow molecules to penetrate into the brain. Like all drugs used to treat brain disorders, including also antidepressants, regardless of clinical indication, must be able to penetrate to their site of action [8].

This biochemical efflux transporter, called ATP-Binding Cassette (ABC) transporters carries substrates across cell membranes including the endothelial cells of the blood-brain barrier. The phosphorylated glycoprotein, Pgp, is encoded by the ABCB1 gene and localized in the luminal (apical) cell membrane [9]. In mice where the ABCB1 gene is deleted the absence of Pgp results in enhanced neurotoxicity of various drugs supporting that ABCB1 expression is protecting the brain from exposure to potentially harmful lipophilic compounds that in the absence of the efflux transporter would diffuse into the central nervous system [10]. This applies only for antidepressants that are substrates of Pgp, i.e. they are bound at the Pgp binding domain, which induces a structural change of the Pgp molecule that leads to the drugs return transport into the blood circulation (Figure 1). Whether or not a given antidepressant is a Pgp substrate has been extensively studied using transgenic mice that carry an ABCB1 gene deletion. If the antidepressant concentration in the brain is much higher in ABCB1-knockout mice than in wild-type mice the antidepressant is a Pgp substrate. If the blood: brain ratio is unchanged by the absence of Pgp the drug is a non-substrate [11,12].