A. Villeneuve

Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in quebec points to a locus of major effect on chromosome 12q23-q24.

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n approximately 120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes covering the entire genome at an average spacing of 11 cM. GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmation of presumed linkages found in the region of chromosome 12q23-q24.

Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder

Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers on chromosome 12, D12S86 and D12S378, was the most probable genomic region to contain a susceptibility gene for affective disorders. Association studies with microsatellite markers using a case/control sample from the same population (n = 427) revealed significant allelic associations between the bipolar phenotype and marker NBG6. Since this marker is located in intron 9 of the P2RX7 gene, we analyzed the surrounding genomic region for the presence of polymorphisms in regulatory, coding and intron/exon junction sequences. Twenty four (24) SNPs were genotyped in a case/control sample and 12 SNPs in all pedigrees used for linkage analysis. Allelic, genotypic or family‐based association studies suggest the presence of two susceptibility loci, the P2RX7 and CaMKK2 genes. The strongest association was observed in bipolar families at the non‐synonymous SNP P2RX7‐E13A (rs2230912, P‐value = 0.000708), which results from an over‐transmission of the mutant G‐allele to affected offspring. This Gln460Arg polymorphism occurs at an amino acid that is conserved between humans and rodents and is located in the C‐terminal domain of the P2X7 receptor, known to be essential for normal P2RX7 function.

Deanol, Lithium and Placebo in the Treatment of Tardive Dyskinesia

A double-blind crossover study on the effects of deanol and lithium carbonate was conducted on a sample of 29 chronic schizophrenic patients with tardive dyskinesia. In addition to his usual treatment with different neuroleptics, each patient received during an 8-week period either deanol, lithium carbonate or placebo. A 4-week wash-out period was inserted between each of the 8-week periods of experimental treatment of the tardive dyskinesia. The administration of either deanol, lithium carbonate or placebo added to the neuroleptic treatment did not produce a statistically significant improvement of tardive dyskinesia in our patient population as a whole. Favorable and unfavorable responses are discussed.

Support for the presence of bipolar disorder susceptibility loci on chromosome 5: heterogeneity in a homogeneous population in Quebec.

A very large pedigree derived from the Saguenay-Lac-St-Jean region of Quebec contains a branch where a distal chromosome 5q haplotype seems to cosegregate with bipolar affective disorder. The authors used a diagnosis model where Bipolar Types I and II and schizoaffective disorder bipolar type were considered as affected, while single or recurrent episode major depression was classified as unknown and all the others diagnoses as unaffected. Model-free two-point LOD score values of 3.41 and 2.21 were observed at D5S432 in the 5p region with sib_ibd and sib_phase from the ASPEX package, but simulation studies did not permit the conclusion of a significant linkage because associated empirical P values were equal to .0026 and .0037. A parametric LOD score value of 2.15 was obtained at locus D5S412 in the distal chromosome 5q area. In order to investigate heterogeneity in the single multigenerational family, the pedigree was divided into five branches. Our simulation study suggested that the five branches of the Saguenay-Lac-St-Jean bipolar pedigree had low power to detect linkage under intrapedigree heterogeneity in this region.

Lithium, thyroid function and antithyroid antibodies

1. Lithium is known to affect thyroid function. It can cause both subclinical and overt hypothyroidism that may involve in some instances an autoimmune mechanism. 2. Sixty (60) psychiatric patients, already under treatment with lithium for at least 6 months, were administered additional thyroid tests and monitored over a one-year period to study the implication of the autoimmune system in the development of hypothyroidism and thyroiditis during lithium therapy. 3. At the beginning of the study, 16 patients presented biological hypothyroidism (laboratory values under normal limits) and only 4 of them showed some slight clinical symptoms. Initially, antithyroid antibodies were detected in 20% of the patients (6 hypothyroids and 6 euthyroids): 12 had antimicrosomal antibodies and only 8 antithyroglobulin antibodies. 4. During the study, only one additional patient (euthyroid) developed antimicrosomal antibodies. All patients with antithyroglobulin antibodies had antimicrosomal antibodies and 6 hypothyroid patients had both types of antibodies.

Pharmacokinetic interaction between amitriptyline and neuroleptics.

The influence of amitriptyline on the plasma level of various neuroleptics was studied in 25 chronic schizophrenic patients. The study lasted 20 weeks. Patients were kept first 4 weeks on their former neuroleptic medication, with amitriptyline added for 12 subsequent weeks, and withdrawn during the last 4 weeks when only the neuroleptic medication was continued unchanged. The plasma level of neuroleptics was assayed by gas-liquid chromatography, once weekly throughout the study. The amitriptyline plasma level was also evaluated once weekly during the 12 weeks of its administration. The mean neuroleptic plasma values for each 4-week period were pooled together in three groups: aliphatic, piperdine and piperazine phenothiazine derivatives. Amitriptyline provoked some increase of the plasma level of all phenothiazine derivatives. This augmentation was significant only transitorily, however. The putative mechanisms of this neuroleptic tricyclic antidepressant interaction are discussed.

Therapeutic trials in tardive dyskinesia.

The search for a treatment of tardive dyskinesia has generally been guided by the putative biochemical mechanisms underlying the extrapyramidal disorders, but no markedly effective treatment has yet been found. The currently postulated mechanism in tardive dyskinesia involves namely an imbalance between the central dopamine-acetylcholine systems whose balance may also be influenced by neuroendocrine factors. The agents reported having some clinical efficacy in the management of this neurological complication act on these systems. The clinical investigation for the treatment of tardive dyskinesia is laborious and raises several problems that could account for the unpredictability and the discrepancies in results. These problems can be divided into three broad categories: patient variables, experimental treatment variables and methodological variables. These variables are discussed and some suggestions made.

THERAPEUTIC DILEMMA IN NEUROLEPTIC-RESISTANT PSYCHOTIC DISORDERS

Abstract According to the classical approach the neuroleptic-resistance in schizophrenic patients is related to such factors as poor pre-morbid history, lack of precipitating factors, insidious onset, hebephrenic or simple types of schizophrenia and more advanced stage of illness. The question of neuroleptic-resistance is recently studied from the point of view of different rates of metabolism of different neuroleptics by different schizophrenic patients. Some neuroleptic-resistant patients are fast metabolizers and the neuroleptics are metabolized so rapidly, mostly in the gut wall, that the brain levels of neuroleptics can be quite ineffective. In these cases oral meganeuroleptic therapy or even better parenteral administration of long-acting neuroleptics can be the adequate strategy. The neuroleptic resistance can be related also to the manner in which neuroleptics are metabolized. It was demonstrated, for instance, that patients who metabolize chlorpromazine predominantly to 7-hydroxychlorpromazine are chlorpromazine responders, and patients who convert chlorpromazine predominantly to chlorpromazine sulfoxide are chlorpromazine resistant. The levels of neuroleptics are lower in patients receiving antiparkinson drugs and also polypharmacy seems to contribute to treatment resistance. The relation between the classical approach to the problems of neuroleptic-resistant schizophrenics and the metabolic problems is not yet clear and this important question should be studied. From the practical point of view one should not evaluate recent schizophrenic patients as neuroleptic-resistant before 3 months of treatment. There are some rules elaborated for the treatment of chronic schizophrenic patients (e.g. the rule of crescendo in the intensity of the drug applied) but this subject needs much more research and some critical remarks are presented.

Neuroendocrinology and the extrapyramidal system.

Abstract Endorphins are involved in the neuroendocrine regulation of the pituitary functioning, namely increasing the levels of prolactin and growth hormone, presumably through dopamine. This interaction of endorphins with dopamine could effect the extrapyramidal system, probably indirectly, their decrease potentially leading to an intensification of dyskinetic movements like tardive dyskinesia and an improvement of parkinsonian symptomatology. In fact, naloxone administered to 20 subjects of both sexes (10 o and 10 o) produced an increase in the intensity of tardive dyskinesia in man. In this connection, it has been reported that in rats the effect of naloxone is antagonized by prior administration of a synthetic estrogen (moxestrol) and this could explain the differential clinical response in males. Indeed, estrogens have previously been shown to possess an antidopaminergic activity. In other respects, a neuroendocrine theory has been proposed in an attempt to explain the therapeutic effect of ECT and the hypothesis that endorphins could be involved in this effect, at least in part, has already been raised to explain the mechanism of action of ECT, as well as its effect on extrapyramidal symptomatology.