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Genetic factors play a significant role in predicting an individual's response to a drug. The response may be the desired therapeutic effect of the drug and also may be the undesirable development of adverse effects. This relationship between genes and drug response interests the pharmacogeneticist. This article aims to give an overview of the exciting discoveries made so far in the field of psychiatry, particularly concerning the response to antidepressants and antipsychotics, as well as to mention some of the more recent findings. The ultimate goal of pharmacogenetics is to provide medication "tailored" to the individual based on their genetic profile, and although this may currently seem a distant target, it has already begun to raise ethical questions, which also are discussed.

CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYPIA2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T-3591G substitution, a G-3595T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P < 0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T-3591G and the G-3595T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T-3591G mutation was shown to be nonfunctional, while although the G-3595T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G-3649C, deltaT-3650, deltaA-4072, and C-4093 ins).

Delta-opioid receptors are known to participate in the protection found following ischemic preconditioning (IPC), but the role of kappa-receptors in IPC is currently controversial. Langendorff-perfused rat hearts received 35 min regional ischemia and 2 h reperfusion. PC (2 cycles 5 min global ischemia) substantially reduced infarct size. Pharmacological PC with the delta-agonist DADLE (10 nmol/L) had similar protective effects. However, higher dose DADLE (1 micromol/L) had a less beneficial effect, and in conjunction with the delta-antagonist naltrindole unexpectedly increased infarct size (61.5 +/- 2.0%, p<0.05 v 45.9 +/- 2.4% in controls) suggesting a non-delta effect. The universal kappa-opioid agonist bremazocine (30 nmol/L) increased infarct size (61.3 +/- 1.6%, p<0.05 v controls), an effect abrogated by the selective kappa1-antagonist nor-binaltorphimine (BNI). Since opiates are known to have anti-adrenergic effects, which hypothetically may help to mediate IPC, cyclic AMP levels were measured in DADLE and in bremazocine-treated hearts. Decreased levels of cyclic AMP at the start of the regional ischemic period were found in low dose DADLE hearts (0.485 +/- 0/020, n = 8, vs controls, 0.654 +/- 0.025 nmol/g wet weight, p<0.001), but not in high dose DADLE nor in bremazocine treated hearts. Thus, in the isolated rat heart kappa1-opioid receptor activation exacerbates infarct size through an as yet unknown mechanism, suggesting that there could be an "antipreconditioned state". In contrast, delta-activity mediates protection which may be associated with a reduction of tissue cyclic AMP levels.

Interethnic variation amongst the drug metabolising enzymes relevant to the treatment of psychosis is reviewed. The frequency of genetically determined variants at the extremes of enzyme activity is seen to vary considerably between different ethnic groups; in addition, a shift in the frequency distribution giving an overall lower population mean activity may occur. The role of dietary and other environmental influences in the generation of interethnic variation in cytochrome activity is also discussed. Clinical studies pertinent to this variation are reviewed. It is suggested that the reason for conflicting data from some clinical studies is the existence of overlapping substrate specificity, so that one cytochrome is able to substitute for another. Individuals deficient for more than one cytochrome would be likely to show much more pronounced clinical effects than those showing single cytochrome deficiency.

Aims: To investigate whether or not there is a correlation between failure to respond to typical antipsychotics and CYP2D6 ultrarapid metaboliser status., Methods: CYP2D6 phenotype (metaboliser status) was assigned following genotyping for gene duplication, as well as for the CYP2D6*3, CYP2D6*4, and CYP2D6*5 null alleles in 235 treatment-refractory patients and 73 nonrefractory patients., Results: Four (1.7%) of the 235 treatment-refractory subjects were positive on the duplication assay, but, of these, two were found to represent duplications of a null allele (CYP2D6*4 ), therefore leaving only two (0.85%) positive for duplication of a wild type allele (ultrarapid metabolisers). Three (4.1%) of the nonrefractory subjects had a genotype consistent with ultrarapid metaboliser status. Fisher's exact test gave a two-tailed P value of 0.091, i.e. a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, which was in the opposite direction to that predicted by our hypothesis., Conclusions: Although the results show a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, the percentages in the two groups of patients are both within the range for ultrarapid metabolisers in Caucasian populations. Our data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.

Nitric oxide and prostacyclin are endothelial-derived vasodilators which inhibit platelet aggregation in a synergistic manner. Experiments were designed to examine whether 3-morpholino-sydnonimine (SIN-1) and iloprost have synergistic cardioprotective actions and whether their effects on infarct size are related to inhibition of platelet aggregation. Anaesthetized rabbits (n = 9-10 per group) were subject to 40 min myocardial ischaemia followed by 3 h reperfusion. Infarct size (percentage of area at risk) was not altered significantly by 3 microg kg(-1) min(-1) SIN-1 (29.7 +/- 1.9%), but was reduced by 0.03 microg kg(-1) min(-1) iloprost (24.6 +/- 1.6%) and to a greater extent by the combination of SIN-1 and iloprost (18.8 +/- 1.7%), compared to controls (33.6 +/- 4.7%). In control rabbits, there were reductions in the ex vivo aggregation of platelets in response to ADP or collagen after ischaemia and reperfusion. SIN-1 and iloprost caused some alterations in platelet responses, but combined administration of both drugs did not produce greater effects. Although the reduction in myocardial infarct size was greatest with both drugs, this did not appear to be a synergistic interaction and was not dependent on the effects of the drugs on haemodynamics or platelet aggregation.

Nitric oxide (NO) and prostacyclin (PGI2) are putative cardioprotective agents. Evidence indicates that there may be a reciprocal relationship involved in the synthesis of NO and PGI2, so that inhibiting the release of one mediator may promote the synthesis of the other. Therefore, we investigated the effects of concomitantly inhibiting NO and PGI2 synthesis, using NG-nitro-L-arginine (L-NOARG) or indomethacin, respectively, on infarct size. Langendorff-perfused rabbit hearts were assigned randomly to one of five treatment groups of n=6: control L-NOARG 100 micromol/l; indomethacin 3 micromol/l L-NOARG 100 micromol/l + indomethacin 3 micromol/l; or L-NOARG 100 micromol/l + L-arginine 1 mmol/l. After 30 min regional ischaemia and 120 min reperfusion, infarct size was assessed by tetrazolium staining. Infarct size was reduced significantly in hearts treated with L-NOARG (20.8+/-1.3%) compared to control hearts (34.7+/-0.4%). This reduction in infarct size was abolished by co-perfusing with a 10-fold excess of L-arginine (30.7+/-1.7%). While indomethacin alone had no effect (33.4+/-2.3%), perfusion with both L-NOARG and indomethacin resulted in a significant increase in infarct size (44.0+/-1.9%) compared to controls. Treatment with L-NOARG alone increased 6-keto PGF1alpha in coronary effluent prior to ischaemia (30.5+/-1.2 vs 16.6+/-1.3 pg/min/g in controls, P<0.05). This effect was reversed by co-perfusion with either L-arginine or indomethacin. These results indicate that the reduction in infarct size by L-NOARG may be due to increased PGI2 release. Concomitant administration of indomethacin negated this effect and revealed an adverse effect of NO synthase inhibition on infarct size., (Copyright 1999 Academic Press.)

Isolated, perfused heart preparations suffer an inevitable peri-operative delay (POD) before retrograde perfusion restores coronary flow. By varying this ischaemic period we investigated the threshold of POD-induced inadvertent preconditioning (PC) in the rat heart. Hearts subjected to POD at 37 degrees C increasing from 1, 2, 3, 5, 10 up to 15 min prior to 20 min retrograde perfusion were further subjected to 30 min global, normothermic ischaemia and 30 min reperfusion (index I/R). The functional recovery was 32 +/- 4.1% in hearts subject to 1 min POD. After 3 min POD functional recovery started to improve and peaked at 10 min POD (78 +/- 7.1%, P < 0.001). At 4 degrees C functional recovery started to improve after 5 min POD and peaked at 10 min POD. To demonstrate that the POD-mediated protection was true PC, two conventional models of PC were established. In both models, hearts were retrogradely perfused within 1 min POD prior to a standard PC protocol (one episode of 10 min ischaemia, or four episodes of 5 min ischaemia). In the conventional PC models protection against the index I/R was abolished using 100 microM 5-hydroxydecanoate (5-HD), the mitrochondrial KATP channel inhibitor. Likewise, 10 min POD-mediated recovery at 37 degrees C (70 +/- 3.2%) was reversed by 100 microM 5-HD perfusion (36 +/- 5.9%; NS v.s. 2 min POD). We conclude: (1) the threshold for PC is greater than 3 min at 37 degrees C and greater than 5 min at 4 degrees C: (2) blockade of the mitochondrial KATP channel abolishes protection in three models of PC in the rat heart, including prolonged POD.

Background: Allelic variation at the CYP2D6 gene has been reported to be associated with Parkinsons' disease (PD) and Lewy body dementia (LBD), but not with Alzheimer's disease (AD). AD has been associated with apolipoprotein E (apoE) epsilon 4 allele loading., Methods: We examined CYP2D6 and apoE polimorphisms in a sample of 259 patients with dementia, 210 of whom had a diagnosis of AD, and 107 healthy controls., Results: We found that the allelic frequency in our AD sample did not vary from that in the controls. The debrisoquine hydroxylase poor metabolize phenotype was not more prevalent among AD cases than among controls in contrast to that reported for PD and LBD. We also found that CYP2D6 status does not modify the risk effect for AD conferred by apoE epsilon 4 alleles., Conclusions: These findings provide some support to the notion that, at a genetic level, at least at this locus, AD could be distinct from PD and LBD.

Atypical antipsychotics are claimed to show advantages in efficacy and tolerability when compared with older, typical drugs. However, the purchase cost of atypicals far exceeds that of typical drugs. Pharmaco-economic evaluations of the use of atypical agents are used, in essence, to determine whether or not the benefit gained by using atypicals is greater than the extra cost of their acquisition. Several forms of pharmaco-economic evaluation have been developed, but none provides definitive, unarguable findings. In psychiatry, the most commonly used method is the mirror-image technique, which retrospectively compares costs and outcomes before and after the use of a particular drug. Despite the large number of phamacoeconomic evaluations undertaken and published, the cost-effectiveness of atypical drugs remains unproven. Data relating to clozapine are the most compelling, but they remain ultimately equivocal. However, ethical considerations may prevent conclusive research being conducted. Some data support the cost-effectiveness of olanzapine and risperidone, but, again, the overall picture is far from clear. Little or nothing is known of the pharmaco-economics of other atypicals. Further research is needed before any atypical can be said to be cost-effective.

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.

Fifty-two ovine strains of Pasteurella haemolytica and P. trehalosi representing serotypes 1-16 were examined for the presence of [copper, zinc]superoxide dismutase DNA sequences. This was done using a combination of polymerase chain reaction with degenerate primers based on the sequence of the [Cu,Zn]superoxide dismutase gene (sodC) in related species and Southern hybridization using a fragment of sodC from P. haemolytica A2 serotype as a probe. Both detection methods identified a fragment of the sodC gene in 9/9 strains of P. haemolytica serotype 2 examined and in 5/8 strains of serotype 7. No evidence of this gene was found in any other serotype of P. haemolytica or in any P. trehalosi serotype. Comparison of DNA sequence showed near identity between sodC from the A2 and A7 serotypes of P. haemolytica and substantial similarity (70%) to sodC previously sequenced in P. multocida, Haemophilus parainfluenzae and H. influenzae. Analysis by gel electrophoresis of the superoxide dismutase activity present in cell lysates showed that one or more superoxide dismutase is present in all serotypes. However, cyanide-inhibitable activity, corresponding to [Cu,Zn]superoxide dismutase, was detected only in those strains of serotypes A2 and A7 which showed evidence of the sodC gene fragment.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

We examined a Ser-9-Gly polymorphism in the dopamine D3 receptor gene for allelic association with schizophrenia in 133 patients currently treated with clozapine and 109 controls. Allele 1 (Ser-9) was significantly more frequent in the patients (69%) than in the controls (56%) (P = 0.004). The 1-1 genotype was more common (43% vs 30%) and the 2-2 genotype less common (5% vs 18%) in patients than in controls. When the patient group was subdivided on the basis of clinical response to clozapine, using a 20-point improvement in the global assessment scale as cut-off, genotype 1-1 was found to be more frequent among the non-responders (53% vs 36%, P = 0.04). To place our results in the context of previous studies of this polymorphism and schizophrenia, we performed a meta-analysis of all published data including the present sample. The combined analysis shows evidence for a modest association between genotype 1-1 and schizophrenia (odds ratio 1.25, 95% confidence interval 1.05-1.49, P = 0.01). These results suggest that the Ser-9 allele, or a nearby polymorphism in linkage disequilibrium, results in a small increase in susceptibility to schizophrenia.

A transcultural comparison of the attitudes of hospital dental practitioners and final year dental students in Glasgow, Scotland and Los Angeles, USA was made to assess their attitudes towards treatment of AIDS and hepatitis B patients. Almost all of the respondents were aware of the facts related to spread of AIDS via saliva and blood and the major oral manifestations of AIDS. Surprisingly, a significant proportion of respondents in both countries said they will not attend their dentist if the latter treats AIDS patients and significantly more Americans thought that AIDS transmission was likely in the dental clinic. An overwhelming majority thought specially trained dentists should be employed to treat AIDS patients while the majority of Americans, as compared with Scots surmised that AIDS is a serious threat to public health. In general, the attitudes of the two survey populations towards the AIDS epidemic and attendant problems was similar although the Scots were more complacent than their American counterparts, probably due to the less immediacy of the AIDS problem in Scotland.

In a consanguineous pedigree in which a severe type of osteogenesis imperfecta was segregating as an autosomal recessive trait, analysis of genetic markers for both collagen I structural loci COL1A1 and COL1A2 showed that the phenotype was unlinked to either locus.