Pharmacogenetics of dopamine receptors and response to antipsychotic drugs in schizophrenia--an update

A considerable number of pharmacogenetic studies have been performed in recent years to define the association of antipsychotic medication response with dopamine receptor polymorphisms and, despite contradictory results, decisive trends have emerged. For the dopamine D2 receptor (DRD2), a trend toward an association with favorable response seems to emerge for the -141C Ins allele of the DRD2 -141C Ins/Del polymorphism and the A1 allele of the Taq1A polymorphism. In the case of the D3 receptor, the Ser9Gly polymorphism has been extensively investigated and a pattern of association is seen between the Ser9 allele and a response to typical antipsychotics, and between the Gly9 allele and a response to atypical antipsychotics. For the D4 receptor, no convincing association results have been reported to date. These trends are discussed with regard to methodological directives and functional implications.     

Therapeutic monitoring of new antipsychotic drugs

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350-600 ng/mL), risperidone (20-60 ng/mL), and olanzapine (20-80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.     

Antagonism of the amphetamine cue by both classical and atypical antipsychotic drugs

Rats were trained to discriminate the stimulus properties of 1 mg/kg of d-amphetamine sulphate (AMPH) from saline in a two-lever task in which correct responding was reinforced with water under a fixed ratio (FR 32) schedule. Classical antipsychotic drugs from different chemical classes were all able to block the AMPH cue. Doses (mg/kg) inhibiting the cueing effect to 50% (ID50) were 0.035 (haloperidol), 0.04 (spiroperidol), 0.09 (cis(Z)-flupenthixol), 0.12 (trifluperazine), 0.15 (perphenazine), 0.92 (chlorpromazine) and 1.40 (pimozide). The AMPH cue was also antagonized by antipsychotic drugs that are considered atypical due to their relative lack of activity in conventional animal models or inability to produce extrapyramidal symptoms in the clinic. The following ID50 values were obtained: 0.88 (molindone), 1.22 (clozapine), 5.48 (metoclopramide), 15.4 (thioridazine) and 52.8 [-)-sulpiride). In addition, the AMPH cue was blocked by the D-1 selective dopamine (DA) antagonist, SCH 23390 (ID50 = 0.014 mg/kg). The abilities of these drugs to block the AMPH cue were unrelated to the drugs' effect upon the rate of responding. For example, some drugs (e.g. haloperidol, spiroperidol and SCH 23390) blocked the AMPH cue completely without any effect on the response rate. Furthermore, the non-antipsychotic phenothiazine, promethazine (2.5-12.5 mg/kg) failed to affect the AMPH cue although the drug strongly suppressed the response rate. However, the potent DA agonists, apomorphine (0.05-0.33 mg/kg) and lisuride (0.02-0.08 mg/kg), and the DA and norepinephrine agonist, DPI (0.4 and 0.8 mg/kg), did not mimic the AMPH cue or did so only partially. These results suggest that the 1 mg/kg AMPH cue depends on (DA) systems other than those involved in the stereotyped motor behavior commonly produced by high doses of AMPH or DA agonists. Low-dose AMPH discrimination may thus serve as a new model for studying antipsychotic drug action.     

Pharmacogenetics and anesthetic drugs

The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient.     

Pharmacogenetics and immunosuppressive drugs

Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment.     

Effects of classical and atypical antipsychotic drugs on isolation-induced aggression in male mice

A series of classical, atypical and putative antipsychotic drugs were compared for their ability to inhibit isolation-induced intraspecies aggression with affinity for D-2 dopamine receptors and induction of akinesia. The majority of drugs tested significantly inhibited aggressive behavior only after doses that greatly decreased the ability of mice to move. Even though akinesia seemed to account for inhibition of aggression there was no apparent correlation with binding to striatal D-2 receptors.     

Pharmacogenetics of antithrombotic drugs

Antithrombotic therapy has improved the prognosis of patients with venous or arterial thrombosis. However, there is substantial interindividual variability in the response to antithrombotic drugs. This variability is due, in part, to genetics, which may affect the efficacy and safety of drugs used in the treatment and prevention of thrombosis. Pharmacogenetics studies the genetic factors related to interindividual variability in the response to drugs. Various polymorphisms in genes of the hemostatic system that have been reported to be markers of susceptibility to thromboembolic disease also seem to be implicated in the response to antithrombotic therapy. These include polymorphisms in platelet receptors (platelet glycoproteins) and coagulation factors (factors II, V, XII, XIII). There is also growing evidence on genetic polymorphisms affecting the metabolism (cytochrome P450), disposition, transporter proteins or cellular receptors of antithrombotic drugs. This review summarizes current knowledge on the pharmacogenetics of antithrombotic therapy, paying special attention to four therapeutic groups: antiplatelet agents, anticoagulants (vitamin K antagonists and heparin), fibrinolytics and other drugs used for the prevention of cardiovascular risk, such as statins and hormone replacement therapy in the menopause. The potential relevance of pharmacogenetics in the future of antithrombotic therapy and the design of clinical trials is also explored.     

Pharmacogenetics of anti-cancer drugs

Toxic side-effects of cytotoxic drugs is a stumbling-block of chemotherapy due to the fact that their therapeutic index is narrow. New approaches are necessary to individualize the treatments. Pharmacogenetic analysis is facilitated by easy access to the patient genome via simple blood samples, by the large number of known genes of interest coding for drugs targets or metabolism enzymes and by the fact that their polymorphism (SNP) is often known. Presently more focused on the prevention of toxic side-effects, pharmacogenetics already provides a good deal of confirmed data for clinical applications, such as the detection of dihydropyrimidine dehydrogenase deficiency by sequencing, or UGT1A1 7/7 genotype detection in Gilbert's syndrome for the prevention of 5-FU and irinotecan-induced severe toxicities. It must be emphasized that a SNP which is deleterious for enzyme activity is rarely a contraindication for the drug, provided that some precautions are taken and appropriate therapeutic advice is given by experts.     

Glutamate hypothesis of schizophrenia and targets for new antipsychotic drugs]

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) and ketamine have been known to cause schizophrenia-like psychosis (positive symptoms, negative symptoms, cognitive dysfunction) in humans. A dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia. In this review, the glutamate hypothesis of schizophrenia, especially the mechanism of neurotoxicity of NMDA receptor antagonist in the posterior cingulate cortex and retrosplenial cortex of the brain, is summarized. Furthermore, the roles of the posterior cingulate cortex and the retrosplenial cortex in the pathophysiology of schizophrenia and Alzheimer's disease are also discussed. Moreover, the glycine site of the NMDA receptor, metabotropic glutamate receptor, AMPA receptor, and antioxidant glutathione as novel potential targets for the treatment of schizophrenia are discussed.     

Differential actions of classical and atypical antipsychotic drugs on spontaneous neuronal activity in the amygdaloid complex

Classical antipsychotic drugs such as haloperidol produce akinesia and catalepsy, whereas clozapine and related atypical antipsychotics fail to elicit these behaviors even at relatively high doses. Despite these behavioral differences, a cataleptic dose of haloperidol (2.0 mg/kg) produces changes in neuronal activity in the neostriatum and nucleus accumbens comparable to those produced by a non-cataleptic dose of clozapine (20.0 mg/kg). To further elucidate the brain mechanisms underlying the differential behavioral response to these drugs, an electrophysiological analysis was extended to neurons in the rat amygdaloid complex. Whereas an intraperitoneal injection of 2.0 mg/kg haloperidol generally failed to alter the firing rate of amygdaloid neurons, 20.0 mg/kg clozapine typically produced a prolonged increase in activity. Similarly, clozapine, but not haloperidol, reversed the depression of firing rate produced by 1.0 mg/kg d-amphetamine. The results suggest that neurons in the amygdaloid complex are more responsive to antipsychotic drugs devoid of extrapyramidal side effects than to antipsychotics which elicit parkinsonian-like motor dysfunctions.     

Pharmacogenetics of new analgesics

Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B(1) (BDKRB1) and 5-HT(1A) (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information.     

Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine

Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients.     

Haematological safety of antipsychotic drugs

Many clinicians have become concerned about the safety of new antipsychotics particularly in view of the association of agranulocytosis with clozapine and of aplastic anaemia with remoxipride. The Committee on Safety of Medicines and Medicines Control Agency 'yellow card' post-marketing surveillance data were analysed for reports of haemopoietic disorders with the 16 antipsychotics in common use. Corrections for relative risk were made in three separate ways: (i) control for degree of use, using Northern Ireland prescribing data for 1995; (ii) percentage of total reports from 1963 to 1996; and (iii) examination of the first 5 years' post-marketing data only. After clozapine and remoxipride the highest risks of haemopoietic reactions appeared to be associated with the aliphatic phenothiazine derivatives thioridazine and chlorpromazine. There is therefore no evidence of any increased risk with high-potency drugs such as haloperidol or pimozide or with the newer drugs such as sulpiride or risperidone. Continued vigilance, however, is necessary as more new atypicals become available and begin to be widely prescribed.     

Pharmacogenetics/pharmacogenomics and antirheumatic drugs in rheumatology

Genomic medicine has raised many expectations with regard to individualized therapies. Drug response is a complex function of many genes interacting with environmental and behavioral factors. In addition, poor prescribing, interactions between drugs and an incomplete understanding of the metabolism of many drugs, which are administered simultaneously to treat concomitant morbidities, are leading causes of the occurrence of adverse drug reactions in chronic non-inflammatory and autoimmune rheumatic diseases. Symptomatic non-steroidal anti-inflammatory drugs, as well as disease-modifying drugs, are complicated by drop-outs (poor patient compliance) in a large percentage of patients. Even though intensive and careful monitoring is always clearly advisable, preliminary data suggest that typing of genes controlling the effects, metabolism and response of drugs might be of clinical utility to define the 'at-risk' genotype.     

Haematological safety of antipsychotic drugs

Haematological abnormalities are frequently encountered during treatment with antipsychotic drugs. Most of these are mild and of no clinical significance. In the case of many, there is often difficulty in establishing a cause-and-effect relationship between the drug and the abnormality. However, in a small minority of patients, hazardous, potentially life-threatening haematological effects can occur due to a combination of pharmacological and host factors. These include leucopenia and agranulocytosis. Although such effects are rare, it is essential that they are diagnosed and managed promptly. In this paper, the authors review the haematological adverse effects and safety of antipsychotic drugs and present a strategy for prevention.