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Biomedical subjects

M Alda

Publications and source records attributed to M Alda.

At least 55 records · Page 3Linked to original sources
PubMed1998

MN blood groups and bipolar disorder: evidence of genotypic association and Hardy-Weinberg disequilibrium.

BACKGROUND: MN blood groups have been studied in the past as a genetic marker of biopolar disorder (BD). Several previous studies reported an association of the illness with lower frequency of blood group NN. METHODS: We analyzed distribution of MN blood groups in a sample of 174 patients with BD, 176 with unipolar depression, 98 with schizophrenia, and 331 healthy controls. In addition, we tested whether the inferred genotypes. conform to Hardy-Weinberg equilibrium (HWE). RESULTS: The frequency of NN phenotype was significantly lower among the bipolar patients than in any of the other three groups (p < .001). The genotype frequencies in the BD group deviated significantly from those expected under HWE (p < .01). CONCLUSIONS: These results suggest a possible locus on chromosome 4 (4q28-q31.1) associated with genetic susceptibility to bipolar illness.

Alleles↗
PubMed1998

Parental genotype reconstruction: applications of haplotype relative risk to incomplete parental data.

Intended to resolve the problem of constructing a matched population-based control sample, haplotype relative risk techniques frequently suffer from loss of power for late-onset diseases due to unavailability of parental genotypes that are required to form parent-offspring pairs. However, much of this missing information can be reconstructed using the genotypes of the affected individual's siblings. For some cases, an estimate of the marker-allele frequencies for controls is needed. We have developed a technique based upon this idea and call it PGR (Parental Genotype Reconstruction). PGR represents a combination of the internal controls used by haplotype relative risk and controls based upon estimated allele frequencies. Although the latter is just what haplotype relative risk was designed to avoid, PGR has the potential to substantially boost power to detect linkage disequilibrium, for a relatively small increase in type I error. This performance is reasonably robust with respect to errors in the estimated allele frequencies, as we demonstrate by numerical simulation. A PGR software package has been written in FORTRAN and is available from Dr. Martin's web site at http://electro.psi.vcu.edu/rmartin/.

Alleles↗
PubMed1998

Evidence supporting the independent inheritance of primary affective disorders and primary alcoholism in the families of bipolar patients.

BACKGROUND: This study explored the nature of the association between bipolar disorder and alcoholism. METHODS: The authors studied 814 first-degree relatives of 121 bipolar patients, divided on the basis of response to lithium prophylaxis. Logistic regression analysis was used to analyze the contribution of demographic, familial and clinical variables to the risk of primary alcoholism in the relatives. RESULTS: The risk of primary alcoholism in relatives was not related to the degree of affective loading in the family or to the proband's lithium response. CONCLUSION: This study does not support a shared genetic liability between bipolar disorder and alcoholism. LIMITATIONS: This study lacked a control group, but the analysis accounted for this. CLINICAL RELEVANCE: These disorders are not alternative forms of the same illness.

Adult↗
PubMed1998

Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

Adult↗
PubMed1998

Psychiatric symptoms and syndromes among adolescent children of parents with lithium-responsive or lithium-nonresponsive bipolar disorder.

OBJECTIVE: The purpose of this pilot study was to describe the initial course of psychiatric illness in the adolescent children of parents with bipolar disorder who were divided into two groups on the basis of their response to long-term lithium monotherapy. METHOD: Proband parents met Research Diagnostic Criteria for bipolar illness and predetermined criteria for a clear response or nonresponse to lithium prophylaxis. All adolescent offspring were interviewed by a blinded interviewer using the Schedule for Affective Disorders and Schizophrenia for School-Age Children, and final diagnosis was made by blinded consensus. RESULTS: Psychiatrically ill children of lithium-responsive parents tended to have affective disorders that remitted and followed a recurrent course. Psychiatrically ill children of lithium-nonresponsive parents, however, manifested a broad range of psychopathology, had high rates of comorbid illnesses, and experienced nonremitting affective illnesses. CONCLUSIONS: These results suggest that family history and course of illness are important factors to consider in the diagnosis and pharmacological treatment of affective disorders.

Adolescent↗
PubMed1997

Autosomal recessive inheritance of affective disorders in families of responders to lithium prophylaxis?

In this paper we report the results of a study of the mode of inheritance in affective disorders responsive to lithium. Earlier we described a series of 71 families in which the genetic transmission was compatible with a single-gene model. We have now carried out an independent replication study on 25 newly recruited families in a different geographical location. The autosomal recessive model from our original study could not be rejected with the new data. In a subsequent analysis of the pooled sample of 96 families, a recessive model with a common predisposing allele (q = 0.16) and sex-specific penetrance (0.35 in males, 0.66 in females) fitted the data best. On the other hand, X-chromosome and polygenic models could be rejected. The finding of a major-gene effect represents a specific hypothesis that can be tested by molecular genetic techniques.

Adult↗
PubMed1997

Bipolar disorder: from families to genes.

BACKGROUND: Genetic factors are known to contribute to the etiology of bipolar illness, but the actual genetic mechanisms remain to be clarified. METHODS: This paper reviews the research undertaken to establish the genetic basis of bipolar illness and to elucidate the nature of its genetic predisposition. RESULTS: The presented findings suggest that bipolar affective disorder is a heterogeneous condition characterized by a complex relationship between the genetic susceptibility and the clinical presentation. Linkage studies have generated promising and replicated findings on chromosomes 18 and 21. CONCLUSION: In spite of the methodological difficulties inherent in the genetic study of psychiatric disorders recent investigations have made important advances and promise to identify specific susceptibility genes.

Bipolar Disorder↗
PubMed1996

Lithium-responsive affective disorders: no association with the tyrosine hydroxylase gene.

Family, adoption, and twin studies have demonstrated the involvement of genetic factors in the etiology of major affective disorders. In an attempt to identify the involved genes, several linkage and association studies have focused on the gene coding for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. The discrepant results to date could be explained by etiological heterogeneity, which may be substantially reduced by selecting patients according to lithium response. Therefore, we investigated 54 patients who had shown definite long-term response to lithium monotherapy in spite of a high risk of recurrence as indicated by the previous clinical course. All the subjects suffered from major affective disorder by Research Diagnostic Criteria (48 bipolar, 6 recurrent unipolar). They were compared to 94 population controls of similar ethnic background to test for association with a penta-allelic microsatellite marker found within the tyrosine hydroxylase gene. No significant differences in allele and genotype frequencies were observed between the two groups, providing further evidence against a major role for the tyrosine hydroxylase gene in the etiology of major affective disorders.

Adult↗
PubMed1996

No association between chromosome-18 markers and lithium-responsive affective disorders.

An allelic association study of excellent responders to lithium was conducted with a candidate gene (Golf, a G-protein receptor gene) and five other chromosome-18p markers. Golf is of special interest because it maps to a region of chromosome 18 where two independent groups (Berrettini et al., 1994; Stine et al., 1995) have found linkage to bipolar disorder. It has been proposed that G proteins are involved in the pathogenesis of bipolar disorder, and lithium, an effective prophylactic agent, is known to impair G-protein activation. To reduce heterogeneity--a common obstacle to genetic investigation--only patients who showed excellent response to lithium prophylaxis were studied. Fifty-five genetically unrelated excellent responders to lithium prophylaxis were compared with 94 normal subjects of similar ethnic background. The groups did not differ in either allele or genotype frequency for the tested markers. The data do not support the hypothesis that the tested loci confer a major susceptibility for affective disorders.

Adult↗
PubMed1996

Age of onset in familial and sporadic schizophrenia.

We have studied the gender and family history differences with regard to age of onset of schizophrenia. These differences have often been viewed as an important clue to the aetiology of the illness. Patients from three centres in Europe and Canada were included in the study. A sample of 1089 subjects was categorized according to the subject's sex, family history of schizophrenia, and the centre. The principal statistical method was analysis of variance. Patients with no family history of schizophrenia had a consistently higher average age of onset. This effect was seen in both male and female subjects across all three groups. These results support the relationship between familial risk and early onset, but no interaction of gender and family history was found.

Adult↗
PubMed1995

Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis.

The mortality of patients suffering from affective disorders is much higher than that of the general population; this excess is due to both suicides and cardiovascular disease. During long-term lithium treatment, the overall mortality has not been found to differ significantly from that of the general population but the question remains whether this lowering, if it is in fact caused by lithium, is due to a reduction in suicide frequency or cardiovascular mortality, or both. We analysed data from 827 previously studied patients and used a procedure that estimated both overall mortality and cause-specific mortalities by single-case analysis. For overall mortality, the ratio of observed deaths (among the patients) to expected deaths (in the general population) was 1.14, which is not significantly different from 1.0; this was also found in our previous analysis. In the whole patient group, comprising 5600 patient years under lithium treatment, seven suicides were observed and 1.3 expected, resulting in a standard mortality ratio of 5.22; this is significantly > 1.0, but markedly lower than that found in patients with affective disorders not given lithium. Cardiovascular mortality was not found to be higher in our patients than in the general population. In view of the fact that a placebo-controlled mortality study under long-term conditions is neither ethically nor practically feasible, our findings cannot prove definitively that long-term lithium treatment counteracts factors responsible for the excess suicide and cardiovascular mortality of affective disorders. However, our observations are compatible with such a notion.

Cardiovascular Diseases↗
PubMed1995

Clinical course of affective disorders: were Emil Kraepelin and Jules Angst wrong?

Returning to the original problem of 'correcting' the earlier findings, it appears that it is not a question of who is right and who is wrong. Kraepelin outlined, and Angst clearly specified, the basic characteristics of the clinical course of unipolar and bipolar affective disorders which unfolds in patients without other pre-existing psychiatric disorders and which is typically episodic. The criteria for diagnosis applied not only cross-sectionally but also longitudinally. Recent studies, on the other hand, have put more emphasis on the standardized cross-sectional approach, and deal with a much broader population in which episodes of affective syndromes develop mainly on the basis of preexisting and chronic psychiatric disturbance, with more frequent recurrences and cycling. In a nutshell, Kraepelin and Angst provided us with a natural history of affective disorders whereas recent studies provide us with the clinical course of a broadly defined cluster of affective syndromes.

Comorbidity↗
PubMed1994

Lithium response and genetics of affective disorders.

The authors have carried out an investigation of psychiatric morbidity in families of patients who responded and failed to respond to long-term lithium treatment. The study included 121 probands with RDC primary affective disorders and 903 first-degree relatives and spouses. Seventy-one probands were responders and 50 were nonresponders to long-term lithium treatment. Extended to 20 years, the follow-up of patients and their families provided substantial information relevant for the diagnosis and reliable assessment of lithium response. The diagnoses were based on all available information, SADS-L interviews and RDC criteria. The principal statistical methods were survival analysis and Cox regression analysis. The results revealed a significantly higher frequency of bipolar disorder in the relatives of lithium responders (3.8% vs. 0%). Schizophrenia was more common in the families of nonresponders (2.4% vs. 0.3%). There were no significant differences in the rates of other psychiatric disorders. Both family history and the proband's diagnosis contribute independently to predicting response to long-term lithium.

Adult↗
PubMed1994

Mode of inheritance in families of patients with lithium-responsive affective disorders.

A better understanding of the role of genetic factors in affective disorders is likely to result from investigating more homogeneous populations. To achieve this goal, we have systematically studied patients who are excellent responders to long-term lithium treatment and their relatives. In the families of 71 such probands, we have analyzed the mode of inheritance by comparing the observed morbidity risks with the risks expected under different genetic models. The results demonstrate major-gene effects in the transmission of primary affective disorders; the polygenic model with sex-specific thresholds could be rejected. Discrimination between the autosomal and X-chromosome models was not possible, but the autosomal recessive model predicts more realistic, gender-specific frequencies of affective disorders in the general population. These results suggest that autosomal recessive inheritance deserves serious consideration in molecular genetic investigations.

Adult↗
PubMed1993

The challenge of predicting response to stabilising lithium treatment. The importance of patient selection.

Lithium treatment, an approach with well documented efficacy, has recently been losing its treatment value. Lithium continues working, however, for those patients for whom it was proven efficacious; that is, most patients with primary episodic affective disorders. Such responders to lithium prophylaxis can be reliably identified beforehand by a comprehensive clinical assessment. The explanation for the paradox of lithium's lost efficacy lies mostly in the educational bias against a comprehensive patient assessment, and in the shift in diagnostic fashion favouring affective disorders and the treatment methods associated with them in the clinicians' minds.

Depressive Disorder↗
PubMed1992

A double-blind placebo-controlled comparison of moclobemide and amitriptyline in the treatment of depression.

The objective of this study was to determine if moclobemide is an effective treatment for depression and if it is well tolerated by patients. A randomized, double-blind placebo-controlled trial was conducted in a tertiary ambulatory clinic which treats depression. Fifty-five patients participated. They fit the DSM-III-R criteria for major depressive episode, scored at least 18 on the 17 item Hamilton Rating Scale for Depression (HRSD), were between the ages of 18 and 65, and were not suffering from a major medical illness. After a one week washout period, patients were randomly selected to receive placebo, amitriptyline or moclobemide for up to six weeks. Moclobemide is a well-tolerated medication at therapeutic doses; it is globally as effective as amitriptyline in the treatment of major depression.

Adult↗
PubMed1989

Neuroendocrine response to clomipramine and desipramine--the evidence of partial determination by heredity and sex.

A single dose of clomipramine, 10 mg i.v., or desipramine, 25 mg i.m., was administered to seven healthy young sibling pairs in a randomized cross-over experiment. The response of serum growth hormone, prolactin and cortisol was measured. The main findings were (1) sex differences in the growth hormone and cortisol response to desipramine and (2) a significant genetic component of the prolactin and cortisol response to desipramine as indicated by significantly (p less than 0.05) lower within-pair than between-pair variance in the sibling pairs but not random pairs of the experimental subjects.

Adult↗