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Biomedical subjects

P Grof

Publications and source records attributed to P Grof.

At least 55 records · Page 3Linked to original sources
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

Mortality of patients who dropped out from regular lithium prophylaxis: a collaborative study by the International Group for the Study of Lithium-treated patients (IGSLI).

Excess mortality has repeatedly been found in patients with recurrent affective disorders. In previous studies our group has shown that during long-term lithium treatment the mortality of such patients is not significantly higher than that of the general population. In the present study, we extended our investigation to 273 patients from the earlier IGSLI cohort who subsequently dropped out from regular lithium prophylaxis. The standardized mortality ratio (SMR) for the whole group was 2.5, significantly higher (P < 0.01) than 1.0, which is the SMR of the general population. Furthermore, the SMR of the patients from each of the participating countries, namely Denmark, Germany and Austria, was significantly higher than 1.0. These findings strengthen the evidence accumulated in previous investigations that regular long-term lithium treatment does in fact markedly reduce the excess mortality of patients with recurrent affective disorders.

Antimanic Agents↗
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↗
PubMed1995

Extended survival of patients on long-term lithium treatment.

OBJECTIVE: Findings from a recent international multi-centre trial are compatible with the idea that long-term lithium treatment extends the survival of patients suffering from affective disorders to match the general population. A similar reduction of mortality was found in Canadian patients, although important questions remained to be answered about cardiovascular and suicide mortality, and patient selection. METHOD: Based on data collected in a study (1) from lithium clinics in Canada, Denmark, Germany and Austria, an analysis was carried out of suicide and cardiovascular mortality in patients who received prophylactic lithium treatment. RESULTS: In patients given lithium for two years or longer (n = 641), both suicide and cardiovascular mortality were the same as, or only slightly higher than, in the general population; in patients given lithium for less than two years (n = 186), both mortalities remained high. The reduced mortality is not likely to be the result of selection because the patients who were treated briefly and those treated for a longer time did not differ in important mortality variables. CONCLUSIONS: In addition to its ability to prevent recurrences, prophylactic lithium treatment appears capable of reducing both the excess suicide risk and excess cardiovascular mortality of affective illness.

Adult↗
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

Designing long-term clinical trials in affective disorders.

Long-term clinical trials in affective disorders have become increasingly important, but their methodology continues to impose a major challenge. An ideal design can be developed but is difficult to implement. The advantages and disadvantages of different designs (mirror image, double-blind study controlled with placebo, and/or standard and discontinuation studies) are described and compared. Shortcuts in design usually carry a high risk of false-negative findings and result in a waste of resources. An abbreviated version was presented at the European Consensus Conference on Long-term Clinical Trials in Zurich, Switzerland, October 1992.

Clinical Trials as Topic↗
PubMed1994

Mortality during initial and during later lithium treatment. A collaborative study by the International Group for the Study of Lithium-treated Patients.

We have previously shown that the mortality of patients with recurrent affective disorders in long-term lithium treatment is not higher than that of the general population. In the present study on 471 patients from Denmark and Germany, we examined mortality during the initial year of lithium treatment and during later lithium treatment. During initial lithium treatment, the total mortality was twice as high as in the general population (difference not significant) and the mortality due to suicide 16 times higher. During later lithium treatment, the mortality rates did not differ from those in the general population. Our results indicate that patients with frequent, often severe recurrences, those chosen for prophylactic lithium treatment, are at risk of high mortality, which then diminishes as the prophylactic action of the treatment takes effect.

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

A Raman spectroscopic study of acetylcholine receptor-rich membranes from Torpedo marmorata. Interaction of the receptor with carbamylcholine and (+)-tubocurarine.

Raman spectroscopy is used to determine structural features of alkali-treated subsynaptic membrane fragments from Torpedo marmorata electric organ, rich in native functional AcChR. Distinct vibrations attributable to the membrane proteins and lipids were identified and studied before and after addition of the agonist carbamylcholine and the competitive antagonist (+)-tubocurarine. The protein secondary structure determined by using amide-I polypeptide vibrational analysis, indicates 47% alpha-helices, 25% beta-sheets, 18% turns and 11% undefined structure. The secondary structure of the AcChR molecule was not subject to large modifications upon addition of carbamylcholine. But, the presence of the (+)-tubocurarine leads to detectable changes in the amide-I region which might be interpreted as reflecting different contributions of alpha-helices and turns in the secondary structure. In addition, Raman spectra provide information about the environment of aromatic amino acids (tyrosine and tryptophan), the (C-C) bonds, the CH2 and CH3 groups of aliphatic side chains, as well as the disulfide (S-S) and cystein (C-S) bonds. The tyrosines seem 'exposed' to the aqueous medium. The Raman spectra of the AcChR-carbamylcholine complex suggest 'exposed' tryptophans, while those of the unliganded membrane-bound AcChR or of the receptor with (+)-tubocurarine are shown 'buried'. The disulfide bridges in the AcChR subunits show identical conformation in the absence and presence of carbamylcholine. On the contrary, considerable changes are found in the AcChR-(+)-tubocurarine complex. Carbamylcholine and especially (+)-tubocurarine decrease lipid fluidity.

Animals↗
PubMed1993

An open study of oral flesinoxan, a 5-HT1A receptor agonist, in treatment-resistant depression.

Flesinoxan, a full 5-HT1A receptor agonist, was administered (4-8 mg) to treatment-resistant depressed patients in an open study. Safety and tolerance of the substance appeared satisfactory. Headache, dizziness and nausea were the most frequently reported side effects. The observations suggested that flesinoxan is an antidepressant agent and that it may be of particular value in some difficult, treatment-resistant depressions. Based on these observations, a double-blind, placebo-controlled evaluation of flesinoxan's efficacy appears warranted.

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↗
PubMed1993

Length of lithium treatment needed to eliminate the high mortality of affective disorders.

Recent studies have indicated that long-term lithium treatment reduces the expected suicidal activity and overall mortality of patients with affective disorders. Based on the data from the lithium clinics in Berlin and Hamilton (n = 512), a minimum length of two years of continued lithium treatment is needed to reduce the high mortality resulting from affective disorders.

Confidence Intervals↗
PubMed1992

The effect of long-term lithium treatment on the mortality of patients with manic-depressive and schizoaffective illness.

Clinical research centers in Aarhus, Berlin, Hamilton and Vienna collected mortality data for 827 manic-depressive and schizoaffective patients given lithium treatment for more than 6 months. The average duration of the treatment was 81 months and the total time on lithium 5600 patient-years. For each patient, the mortality risk was calculated by entering the appropriate national life tables for the general population. The number of observed deaths was 44; the number of expected deaths was 49.7. The standardized mortality ratio, 0.89, did not differ significantly from 1.0. The mortality of manic-depressive patients is 2-3 times that of the general population. Our data show that the mortality of manic-depressive and schizoaffective patients given long-term lithium treatment does not differ significantly from that of the general population.

Adult↗
PubMed1992

Lithium treatment and memory assessment: methodology.

Clinical observations have suggested that lithium may exert adverse effects on memory. The difficulty in achieving empirical consensus regarding this issue has reflected several methodological problems: diversity of research designs, heterogeneous samples, lack of control groups and the possible confounding of memory test scores by variables such as depression, other acute psychopathologies, organicity, treatment duration, and age. The diversity of memory tests in terms of the complexity and modality of the stimuli as well as the types of memory assessed (immediate, short- and long-term, logical, visuo-practic) has further complicated the comparison of results across studies. Furthermore, the administration of test batteries has been limited by patients' fatigue and the severity of their illness, and by the time required to complete testing. Hence, the use of test norms may be restricted. Suggestions are made for the selection of appropriate memory tests, patients sampling and data analysis. The authors discuss the difficulties inherent in blind studies and in matched-group designs examining the effects of lithium on memory. Conclusions point to the advantages of prospective within-subject designs with repeated testing in which patients serve as their own controls.

Analysis of Variance↗
PubMed1991

A comparative Raman spectroscopic study of cholinesterases.

We report Raman spectra of various cholinesterases: lytic tetrameric forms (G4) obtained by tryptic digestion of asymmetric acetylcholinesterase (AChE) from Torpedo californica and Electrophorus electricus, a PI-PLC-treated dimeric form (G2) of AChE from T marmorata, and the soluble tetrameric form (G4) of butyrylcholinesterase (BuChE) from human plasma. The contribution of different types of secondary structure was estimated by analyzing the amide I band, using the method of Williams. The spectra of cholinesterases in 10 mM Tris-HCl (pH 7.0) indicate the presence of both alpha-helices (about 50%) and beta-sheets (about 25%), together with 15% turns and 10% undefined structures. In 20 mM phosphate buffer (pH 7.0), the spectra indicated a smaller contribution of alpha-helical structure (about 35%) and an increased beta-sheet content (from 25 to 35%). This shows that the ionic milieu profoundly affects either the conformation of the protein (AChE activity is known to be sensitive to ionic strength), or the evaluation of secondary structure, or both. In addition, we analyzed vibrations corresponding to the side chains of aromatic and aliphatic amino acids. In particular, the analyses of the tyrosine doublet (830-850 cm-1) and of the tryptophan vibration at 880 cm-1 indicated that these residues are predominantly 'exposed' on the surface of the molecules.

Acetylcholinesterase↗