Pharmacogenetics of Antipsychotics: Useful For the Clinician?

Brigitta Bondy; Ilja Spellmann

Curr Opin Psychiatry. 2007;20(1):126-130. 

Abstract and Introduction

Abstract

Purpose of Review: The concept of individualized drug therapy on the basis of pharmacogenetics has become a central focus in psychopharmacology of schizophrenia. This article reviews recent advances in this field with respect to their importance for the clinician.
Recent Findings: First, there is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. Secondly, prediction of response on the basis of variants in candidate genes is incipient and remains elusive. Thirdly, some advances have been made in understanding the pharmacogenetics of weight gain.
Summary: Despite much effort, only a few of the results are now ready for translation into clinical practice. Cytochrome P450 genotyping would be a big step forward towards a more individualized drug treatment based on molecular diagnostics and could improve treatment, reduce adverse effects and increase compliance of the patients. Another promising field may be that of predicting the antipsychotic-induced weight gain and it is hoped that commercially available DNA tests may be available within the next few years. Prediction of response is still hampered by many methodological and clinical problems and is not yet available to the clinician.

Introduction

There is substantial unexplained interindividual variability in treatment with antipsychotics, as a proportion of patients given a regular dose do not respond properly or experience limiting side effects. The nature of drug response is highly complex, involving genetic and nongenetic factors; the latter include age, gender, hepatic and renal status and, additionally, nutrition, smoking or alcohol intake. Within the last decade, the concept of individualized drug therapy on the basis of genetic investigations has become a major issue in psychopharmacology. After early results on an association between the serotonin-2A-receptor (5-HT2A) gene variants and the response to clozapine treatment,[1,2] there was much enthusiasm about the identification of a genetic make-up for an optimally tailored drug treatment in schizophrenia.

Numerous association studies have since been carried out, with genes coding for either the pharmacokinetic (encompassing the processes that influence bioavailability) or pharmacodynamic (targets of drug action) pathways. Most pharmacodynamic studies concerned candidate genes that were proposed either by the aetiopathology of schizophrenia or by the putative pharmacological mechanisms of the drugs.[3**] Despite some advances in various fields, however, the final goal of an optimally tailored therapy remains elusive. This review focuses primarily on recent studies and findings that are already relevant for the clinician, or that might become important in the near future.

Allelic Variants in Cytochrome P450 Enzymes

All antipsychotics are subject to extensive metabolism by various enzymes of the cytochrome P450 (CYP) family, which play a pivotal role in the elimination of these drugs and therefore influence their efficacy and toxicity. Factors that affect CYP function and expression, such as CYP pharmacogenetics and the processes of inhibition and induction, influence the in-vivo rates of drug elimination.[4**]

CYP enzymes show large interindividual differences in activities due to genetic variants constituting multiallelic systems that express a variety of phenotypes. These can be distinguished as poor, intermediate, extensive or ultrafast metabolizers.[5] Mutant alleles differ from normal-functioning alleles by point mutations, gene deletions or gene duplications. Thus the poor metabolizers lack an active form of the expressed enzyme due to an inactivating allelic variant; intermediate metabolizers have at least one copy of an active gene, and ultrafast metabolizers contain duplicated or amplified gene copies, leading to either increased, and possibly toxic concentrations, or decreased, and possibly ineffective concentrations of the drug.[6] It is also noteworthy that considerable differences in allele and genotype frequencies are observed across ethnic groups. For CYP2D6 mutations, the poor metabolizers are more common in the Caucasian and African populations (between 5 and 10%) than in the Asian population (1%). On the other hand, the deficient CYP2C19 alleles are more common in the Asian population.[7] Although many CYP enzymes are known, only a few of them are relevant for phase I metabolism of antipsychotics, mainly CYP1A2, CYP2D6 and CYP3A4 ( ). A possible involvement of CYP2C19, an important enzyme for antidepressant degradation, has been discussed.[8]

Table 1.  Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers

Enzyme Substrate Inhibitor Inducer
CYP1A2 Clozapine, haloperidol olanzapine Fluvoxamine, grapefruit juice, antibiotics Carbamazepine, hyperforin, nicotine
CYP2C19 Diazepam, phenytoin Fluoxetine, valproic acid, fluvoxamine Carbamazepine, phenytoin
CYP2D6 Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics  
CYP3A4 Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine Carbamazepine, hyperforin, phenytoin

Cytochrome P450 Pharmacogenetics, Drug-drug Interactions and Adverse Effects

Some drug oxidations are catalysed by multiple CYPs, but others are substrates for one individual enzyme ( ).[4**] Besides the effect of the respective genotypes on the metabolizing capacity, the processes of CYP induction and inhibition may have tremendous effects on drug elimination. Consequently, in recent years there has been a shift in interest from the influence of the genotype on steady-state plasma concentration towards drug-drug interactions in relation to the genotype, as there is increasing awareness that classical and atypical antipsychotics are susceptible to metabolically based drug interactions with other psychotropic or somatic medication. Thus, inhibition of the metabolizing enzyme might convert an extensive metabolizer to a poor metabolizer or an ultrarapid metabolizer, respectively. Many, if not most, schizophrenics are on a multidrug regimen and the potential for enzyme inhibitory reactions and an increased rate of adverse drug effects is great. Co-medication with antidepressants particularly but also with some antibiotics or ß-blockers might considerably increase the plasma concentrations of the main antipsychotic ( ),[9] and this interaction is extremely important in those patients who are already poor metabolizers due to genetic variants.[10]

Table 1.  Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers

Enzyme Substrate Inhibitor Inducer
CYP1A2 Clozapine, haloperidol olanzapine Fluvoxamine, grapefruit juice, antibiotics Carbamazepine, hyperforin, nicotine
CYP2C19 Diazepam, phenytoin Fluoxetine, valproic acid, fluvoxamine Carbamazepine, phenytoin
CYP2D6 Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics  
CYP3A4 Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine Carbamazepine, hyperforin, phenytoin

Table 1.  Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers

Enzyme Substrate Inhibitor Inducer
CYP1A2 Clozapine, haloperidol olanzapine Fluvoxamine, grapefruit juice, antibiotics Carbamazepine, hyperforin, nicotine
CYP2C19 Diazepam, phenytoin Fluoxetine, valproic acid, fluvoxamine Carbamazepine, phenytoin
CYP2D6 Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics  
CYP3A4 Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine Carbamazepine, hyperforin, phenytoin

On the other hand, some drugs such as carbamazepine, phenytoin or hyperforin are known to upregulate the CYP expression in the liver, and via this enzyme induction the respective substrates are eliminated more rapidly.[10] Important inducible CYPs that have a role in metabolism of atypical antipsychotics are CYP1A2, CYP2C9, CYP2C19 and CYP3A4 ( ).[9] Together with environmental factors such as smoking and/or alcohol consumption, both inducers of CYP activity, genetic factors may lead to different metabolism of a given drug. It is now known that cessation of heavy smoking will increase the concentration of clozapine, accompanied by an increased rate of side effects, especially in poor metabolizers.[11,12*]

Table 1.  Cytochrome P450 Enzymes, Antipsychotic Substrates, Inhibitors and Inducers

Enzyme Substrate Inhibitor Inducer
CYP1A2 Clozapine, haloperidol olanzapine Fluvoxamine, grapefruit juice, antibiotics Carbamazepine, hyperforin, nicotine
CYP2C19 Diazepam, phenytoin Fluoxetine, valproic acid, fluvoxamine Carbamazepine, phenytoin
CYP2D6 Aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol Bupropion, fluoxetine, paroxetine, citalopram, duloxetin, fluvoxamine, fluphenazine, moclobemide, chlorpromazine, haloperidol, perphenazin, propranolol, antibiotics  
CYP3A4 Aripiprazole, clozapine, haloperidol, quetiapine, risperidon, ziprasidone Fluoxetine, fluvoxamine, olanzapine, grapefruit juice, nicotine Carbamazepine, hyperforin, phenytoin

Many antipsychotics have a narrow therapeutic range, with concentration-dependent adverse effects occurring at concentrations similar to or slightly higher than the dose required for the therapeutic effect.[8] Such adverse effects include acute effects, such as postural hypotension, excess sedation, but also more drug-related ones, such as extrapyramidal symptoms or tardive dyskinesia. Although a possible association between the CYP2D6 genotype and antipsychotic-induced movement disorders has been addressed in several studies, the results are inconsistent.[13] There seems to be a trend towards a slight overrepresentation of mutated CYP2D6 alleles in patients with parkinsonism[14,15] or other adverse effects such as over-sedation, and autonomic effects during treatment with classical antipsychotics.[16] The impact of CYP genotypes on the generally higher rate of adverse effects during treatment with risperidone was underlined by a study showing that poor metabolizers for CYP2D6 and CYP2C19 had a longer duration of hospitalization than extensive metabolizers.[17]

Although it was proposed that the drug-drug interaction could be used to reduce the olanzapine therapeutic dose requirements by addition of low dose fluvoxamine,[18] an increased rate of adverse effects might be more important in clinical practice, as the risk of adverse events is often related to the drug plasma concentrations. This was impressively shown in a recent observation of a marked drug-induced QT interval prolongation after ciprofloxacin administration in a patient receiving olanzapine.[19]

Cytochrome P450 Pharmacogenetics in Clinical Practice

In clinical practice, the dosage of an antipsychotic is primarily adjusted with the aid of therapeutic drug monitoring, by approaching the optimum doses stepwise. Although effective, this may become a tedious process, prolonging the duration of hospitalization, and it does not protect from the devastating effects of drug-drug interactions in poor metabolizers. At the beginning of drug treatment particularly, any knowledge regarding the CYP genotype may be very helpful, as initiation with lower doses in poor metabolizers is liable to decrease the incidence of adverse effects and thus increase the compliance of patients. As an example, it was suggested by Kirchheiner et al. [20**] to reduce the initial dosage of haloperidol by 50% in poor metabolizers. Moreover, the CYP genotype is extremely important in the case of co-medication, as CYP inhibition by various agents may increase the drug concentration - even in steady state - towards toxic concentrations.

In-vivo phenotyping with marker substrates for particular CYPs (caffeine, debrisoquine, mephenytoin) may be a useful and low-cost method in therapy with potent and toxic drugs. On the other hand, this method may also be problematic in patients on existing drug therapy, because of the interactions between the drugs in the phenotyping cocktail and the therapeutic agents.[4**] Genotyping of relevant CYP mutations can now easily be varied out with polymerase chain reaction or the newly developed microarrays. The AmpliChip CYP450 genotyping test analyses the CYP2D6 and CYP2C19 genotypes in one single assay.[21] Although slightly more expensive, this CYP genotyping proved useful in explaining aberrant medication levels in a proportion of patients and could thus be helpful in clinical practice.[22]

Genetic Variants in Pharmacodynamic Drug Targets

Antipsychotics have a wide variety of targets and functions within the central nervous system, ranging from neurotransmitter synthesis, and transporter and receptor function to the signal transduction proteins and other downstream protein polymorphisms. New concepts of mechanisms of drug action are focusing on proteins that are related to synaptic and neuronal plasticity and on adaptive mechanisms as targets of interest.[23,24]

Pharmacogenetic Studies of Response to Antipsychotics

Among the large number of candidate genes, mainly those coding for dopamine and serotonin receptors have been extensively studied in the past. Following the first promising results of a relation between the 5-HT2A receptor T102C polymorphism and the response to clozapine,[1,25] many studies have been carried out with 5-HT2A receptor polymorphisms, but the results were conflicting. Summarizing these studies, Kirchheiner et al.[26] detected only a minor influence of this gene variant on clozapine response. Further investigations concerned polymorphisms in 5-HT2C, 5-HT6 and dopaminergic receptor (D2, D3 and D4) genes. Although there are some positive reports as, for example, an association of the Ser/Ser genotype of the DRD3 receptor Gly9Ser polymorphism and nonresponse to atypical antipsychotics,[27] a reduced frequency of the DRD4 receptor polymorphism five 48-bp repeats allele in clozapine responders,[28] and a variation in the DRD2 promoter region (A-241G) as predictor for sustained response to risperidone and clozapine,[29] the findings are far from convincing.[30*]

A more promising approach might lie in the relation of genetic variants to improvement in either negative or positive symptoms or to improvement of cognitive function, instead of associating them with the overall drug response. This was recently shown for some variants in the 5-HT2A, 5-HT6 and DRD2 and DRD3 receptor genes in patients being treated with risperidone or olanzapine.[29,31,32] Reynolds and colleagues[33] observed a correlation between the 5-HT2C -759C/T promoter polymorphism and negative symptoms and, more recently, an effect of the 5-HT1A receptor polymorphism on response of negative and depressive symptoms to antipsychotics.[32,34*] Several genes, however, apart from the dopaminergic and serotonergic systems, such as neuregulin, dysbindin or the brain-derived neural growth factor, might also be interesting candidates for the prediction of drug response.[30*] Finally, but becoming increasingly important, is the accumulating knowledge that a combination of various genes is more likely to influence the variability in drug response than individual polymorphisms on their own.[35] Thus, systematic studies on gene-gene interactions may be of great help, but are presently missing.

Pharmacogenetics of Weight Gain

Although the newer atypical antipsychotics have many advantages, weight gain together with its deleterious effects on cardiovascular health and glucose and lipid metabolism, became a serious problem in the management of these drugs. Although increase in weight is a well known phenomenon in schizophrenia management and has been reported even for classical antipsychotics, several atypicals such as clozapine and olanzapine, followed by risperidone and quetiapine, have been associated with the highest degree of weight gain.[36] One of the most consistent findings is that patients with a lower body mass index are at higher risk of weight gain and, further, that early and rapid weight gain within the first weeks of treatment appears to be a predictor for long-term weight gain and possibly even for the development of the metabolic syndrome.[37**] Further, in a proportion of patients, this increase in weight seems to be irreversible, as discontinuation of treatment or the switch to another drug does not necessarily reduce weight,[37**] and thus an indicator or marker for patients at risk would be extremely valuable.

There is now evidence that about 200 genes contribute to the regulation of energy homeostasis,[38,39] among them some of the neurotransmitters involved in pathophysiological mechanisms of schizophrenia and drug action, such as the serotonergic and histaminergic system, but also the adrenoceptors or immunological mechanisms.[40,41] Other mechanisms comprise several peptides involved in energy homeostasis, such as ghrelin and adiponectine.[42,43]

Many association studies with genes coding for proteins in these pathways have been performed in the last few years. Overall, most of them failed to demonstrate an interaction between any of these variants and antipsychotic-induced weight gain.[38,39,44,45] For the 5-HT2C receptor, however, several positive results emerged, and most of them concerned the promoter region of the 5-HT2C receptor (-759 C/T).[31,37**,46,47] Although there are also some negative data, there is now compelling evidence that the -759 C/T polymorphism of the 5-HT2C receptor represents a true genetic susceptibility factor for weight gain during treatment with atypical antipsychotics.[37**]

Recently, another approach, apart from the specific neurotransmitter systems, was chosen. In a pilot study investigating genetic variants of the 25 kDA synaptosomal-associated protein (SNAP-25), an association between weight gain and the MnlI and TaiI polymorphisms was found in treatment-resistant schizophrenics.[48*] SNAP-25 is involved in the secretion of neurotransmitters, but there is recent evidence that it plays a role in insulin-responsive tissues and might thus be involved in regulation of hunger and satiety. Interestingly, we were able to replicate the previous preliminary finding using an enlarged sample of schizophrenic patients.[49]

Conclusion and Future Aspects

There have been many efforts in pharmacogenetics to achieve the goal of individualized drug therapy. Although some advances have been made, particularly in understanding the genetic underpinning of side effects, their translation into the clinic has been relatively slow.

There is now increasing agreement that the incorporation of CYP pharmacogenetics into therapeutic decision-making could be a big step forward towards a more individualized drug treatment based on molecular diagnostics.[20**] This method is still only used in some specialized fields, however, and is far from being applied as clinical routine. As DNA chips have started to become commercially available for CYP enzymes, a more widespread application would certainly improve treatment, reduce adverse effects and increase compliance of the patients.

The concept of predicting response on the basis of genotyping is certainly still in its infancy, as all the individual results with transmitters, receptors and transporters cannot easily be formed into a general recommendation. Perhaps one of the limiting factors is the availability of large, well characterized samples and clinically well characterized prospective studies, which leads to difficulties in replicating the findings from diverse populations. On the other hand, response is a complex phenomenon and single mutations in single genes are unlikely to cause the continuous variability observed in response to psychiatric treatment. Therefore, in the future, haplotype analyses and the multigenetic approach with appropriate sample sizes, adequate symptom assessments and improved phenotypic data may reveal the genotypes that predict clinical response.[30*]

The more promising present situation, in principle similar to the response prediction, is that of the genetic basis of weight gain during antipsychotic treatment. So far, the serotonergic system at least (which is far from being systematically investigated) appears to be one of the contributing genes to weight gain. With the results of the genome-wide association studies and the introduction of chip technology, and investigation of a variety of candidate genes in one assay, one is hopeful that a predictive DNA test, similar to that for CYP genotyping, will be available within a few years.

Finally, the field of pharmacogenetics is expanding rapidly; the development of new, fast and cost-effective methods for the investigation of the individual genetic/genomic profile is under way, and the incorporation of novel research areas will lead to better insights into disease and treatment processes.

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