Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders.

In a population-based association study, we tested the hypothesis that allelic variants of the human serotonin transporter (5-HTT) gene confer susceptibility to mood disorders. Both a biallelic repeat polymorphism in the 5' promotor region that differentially modulates gene expression and a second intron variable-number-tandem-repeat (VNTR) marker were genotyped in 294 controls and 115 patients with mood disorders. Subjects were of West European descent and included 36 patients with major depressive disorder (MDD) and 79 patients with bipolar I disorder (BD). No significant differences in genotype or allele frequencies were found at either locus between controls and combined patients, nor between controls and MDD or BD patients separately. Thus, our data do not support the association between depressive disorder and a nine-repeat allelic variant of the 5-HTT VNTR marker recently reported by Ogilvie et al. (Lancet 347:731-733, 1996). More importantly, no association between alleles conveying functional differences in 5-HTT gene expression and MDD or BD could be found. Taken together, our data suggest that the 5-HTT gene is not commonly involved in the susceptibility to mood disorders.

Possible involvement of the dopamine D3 receptor locus in subtypes of bipolar affective disorder.

The dopamine D3 receptor gene is of potential interest in the physiopathology of affective disorder because of its expression pattern in brain structures controlling various aspects of behaviour, cognition and emotions. Moreover, it encodes for a receptor protein that is a target for psychotropic drugs, which turn out to be efficient in the treatment of this disorder. Two polymorphisms have been described at this locus (the Bal I and the Msp I Restriction Fragment Length Polymorphisms) that are useful in genetic studies. We therefore researched these polymorphisms in 60 patients suffering from bipolar affective disorder who were compared with 60 healthy volunteers. No statistical difference was observed between the whole patient sample versus the controls. However, one subgroup [homozygous for the (2-2) Bal I polymorphism] exhibits a characteristic clinical pattern consisting of: manic monopolar form of bipolar disorder, low age of onset and initiation by an acute delusional episode. A gender distribution difference for the Bal I polymorphism (chi 2 = 6.61, degrees of freedom = 1, P = 0.01) was then noted, the bipolar females being preferentially heterozygous, and the males homozygous. These results could involve the dopamine D3 receptor locus as a minor effect gene in the manic depression condition.

Technetium-99m ECD single photon emission computed tomography in brain trauma: comparison of early scintigraphic findings with long-term neuropsychological outcome.

OBJECTIVE: The aim of this study was to assess the prognostic value of early brain scintigraphy in head injury in relation to long-term neuropsychological behavior. Twenty-four patients underwent technetium-99m (Tc-99m) ethyl cysteinate dimer single photon emission computed tomography (SPECT) within 1 month of the trauma. Scintigraphic abnormalities were evaluated both visually and semiquantitatively using the brain-to-cerebellum ratio method. The clinical neuropsychological investigation was conducted to evaluate abnormalities related to motor deficit, frontal behavior, and memory and language disorders. All patients had abnormalities on SPECT scan. One year after trauma, 14 patients (58%) had neuropsychological sequelae. The brain-to-cerebellum ratios in the left basal ganglia and brain stem were significantly decreased in patients with memory disorders (P = .03 and P = .02, respectively). Moreover, SPECT visual analysis indicated that low uptake in the basal ganglia, thalamus, and brain stem was associated with subsequent motor deficit, frontal behavior, and language and memory disorders. The authors conclude that brain SPECT can be valuable in predicting the neuropsychological behavior of survivors of severe head injury.

[Emergency EEG and brain injuries]. / EEG en urgence et traumatisme crânien.

The aim of this study is to review indications for emergency EEG in case of brain trauma. The authors emphasize the indication of emergency EEG for the diagnosis of either cerebral death or early post traumatic seizures, and for the monitoring of intensive neurological treatments. Emergency EEG and diagnosis of cerebral death has been reviewed in another issue of this journal. Diagnosis of early post-traumatic seizures may be difficult in case of cranial trauma in either the presence or the absence of coma. Emergency EEG help guide the diagnosis of electrical signs of seizures, thus indicating that treatment with antiepileptic drugs is advisable. Severe post-traumatic coma requires barbiturate impregnation and moderate hypothermia. In this last case, emergency EEG is essential for the monitoring of pharmacological treatments. The authors conclude that continuous EEG monitoring could in the future substitute for standard EEG recorded in emergency.

[Joint evolution of erythrocyte membrane transport of tyrosine and tryptophan as a function of the clinical course of depression]. / Evolution conjointe des transports membranaires érythrocytaires de la tyrosine et du tryptophane en fonction de l'évolution clinique des dépressions.

The clinical state and the erythrocyte membrane transports of tyrosine and tryptophan were studied longitudinally during one year (minimum period of 3 months) in 44 depressive patients, 21 men and 23 women of 30 to 77 years of age. According to the DSM III, 18 patients had bipolar disorders (8 with short cycles), 14 had recurrent major depressions and 12 dysthymic disorders. Abnormal values for the membrane transports are found in the majority of patients; the pattern of these abnormalities differs among the nosological groups but decreased ratio of the tyrosine to tryptophan is the predominant finding. The membrane transports normalize as the clinical status improves. In bipolar disorders, the changes observed at the time of switching into mania differ among short and long cyclers. Short cyclers who become manic generally present a short period of normal mood and show values of membrane transports higher than when depressed or euthymic and higher than those of normal controls. Long cyclers directly switch into mania, and when manic have the same ratio of tyrosine to tryptophan than when depressed. Based on these biochemical observations, long cyclers resemble patients with recurrent major depression and short cyclers resemble dysthymic disorder patients, a group for which it has been suggested that one fifth become bipolar within years of evolution.

[Hyperthymic and depressive temperaments study in controls, as a function of their familial loading for mood disorders]. / Etude des tempéraments dépressif et hyperthymique chez 165 sujets contrôles et à risque pour les troubles de l'humeur.

UNLABELLED: Since the two last decades, many authors have broadened the scope of mood disorders to include a larger bipolar spectrum which encompasses the sub-affective conditions, including temperaments. According to this view, the latter conditions represent milder or alternative expressions of the classic bipolar episodes. In successive elaborations, Akiskal et al. hypothesized a complex multicausal approach to bipolar disorder, and studied temperamental dysregulations, which could serve as risk factors for major episodes. Until recently, there have been several studies of patients populations, little is known in control populations. The aim of this report is to compare the rates of three affective temperaments (hyperthymic: TH; depressive: TD; irritable: TI) in non-ill subjects with different risk for mood disorders. (The cyclothymic temperament is studied as part of another report). METHODS: We recruited 185 individuals from: a) staff hospital; b) sibling of patients suffering from bipolar disorder, type I. Twenty subjects were excluded: 7 suffered from personal affective trouble; 12 exhibited cyclothymic traits; and one had familial schizophrenia. In the 165 remaining subjects, the temperamental characteristics were assessed by mean of the Akiskal and Mallya's criteria (1987, semi-structured interviews for affective temperaments, TH, TD, TI). Then, the population of controls was divided in 3 groups as a function of the familial loading for affective disorder and bipolar disorders: the first subgroup (AFN) was free of any antecedent ("super-normal controls", n=99); the second subgroup (AFP) had familial antecedents at the first or second degree (normal controls but at risk for affective disorder, n=33); the third subgroup (FBP) was composed of the siblings of bipolar I patients (subjects at high risk, n=33). Statistical procedures included standard and non-parametric methods: means standard deviation, Fisher's test, Mann-Whitney' and Kuskall-Wallis' tests, Spearman's correlation coefficient. As described by Placidi and collaborators (12), we also used the Z-score (temperamental score strictly higher than the second positive standard deviation: m + 2 sd). RESULTS: The general demographic characteristics show a higher frequency of women (p=0.02) but a similar mean age (p=0.296, NS) among the groups. The mean scores of the TH and TD are strongly and negatively correlated (Rho coefficient=- 0.397, p=0.01), exhibiting the internal coherence of the responses. The comparison of the temperamental characteristics among the 3 groups exhibits significant differences for the TH and TI (p=0.003). The mean scores are respectively: for the TH, 9.16 4.18 in AFN, 8.33 4.11 in AFP, and 12.16 5.28 in FBP; and for the TI, 8.94 2.25 in AFN, 9.39 2.63 in AFP, and 10.84 2.76 in FBP. Conversely, the TD scores do not significantly differ: 6.01 3.27 in AFN, 6.76 4.34 in AFP, and 7.94 5.28 in FBP. Beyond these first pass results, we also considered the distribution of the subjects as function of the Z-score and the different groups. We found that hyperthymic traits were almost exclusively among the FBP: 15.1% vs 3.0% in the other groups. For the TD, expressed in mean scores, the groups at risk for affective disorders (AFP and FBP) clearly display a percentage of subjects with a more substantial Z-score than the frequencies observed in the AFN: respectively 12.1%, 18.1% and 4.0% for the TD. Concerning traits of all three temperaments, as function of the demographic variables and the Z-score, they are generally predominant in males; however, the TH is more frequent in males only in the AFP and FBP groups (respectively: 8.3% vs none; 21.4% vs 10.5%). The TD is more prevalent among females in AFP and FBP (respectively: 8.3% vs 14.3%; 21.1% vs 14.8%). CONCLUSION: Our results clearly show temperamental dysregulations in the subjects at risk for affective disorders: (1) the levels of all three affective temperaments under study are significantly higher in subjects at risk for affective disorder, as compared to individuals free of a family antecedent; (2) the depressive temperament is prevalent in both AFP and FBP, whereas the hyperthymic is specific for FBP. As for Akiskal's model on the multicausal origin of the mood disorders, our data supports temperamental dysregulation as an important familial genetic factor in the vulnerability to manic depressive episodes. We further posit that such temperaments--more specifically, the hyperthymic--could serve as proximal phenotypes for full-blown bipolar disorder.

[Choice of antidepressive agents as a function of membrane transport (erythrocytes) of monoamine precursors (L-tyrosine and L-tryptophan)]. / Choix des antidépresseurs en fonction du transport membranaire (érythrocytes) des précurseurs des monoamines (L-tyrosine et L-tryptophane).

In a group of 66 depressed patients, the choice of the antidepressant drug was based upon the result of tyrosine and tryptophan uptake by the membrane of red blood cells. After one month of treatment, 56 subjects were improved, that is 85% of the cases. This result is discussed in comparison with the percentage of improvement described in the literature.

[Erythrocyte membrane transport and plasma levels of tyrosine and tryptophan in depression]. / Transports membranaires érythrocytaires et taux plasmatiques de la tyrosine et du tryptophane dans les dépressions.

L-Tyrosine and L-Tryptophan were studied in 80 depressed patients, hospitalised in Genova and Marseille. After a washout period of ten days, the erythrocyte membrane transports (MT) of L-Tyrosine and L-Tryptophan were measured, as well as their plasma levels; plasma phenylalanine was moreover measured. 33 normal subjects served as control group. In the whole population of patients, the mean of MT's was different compared to controls (MT tyrosine low and MT tryptophan high) and the plasma tyrosine was low. The perturbations of these variables were different according to diagnostic groups (DSM III): MT tyrosine, plasma tyrosine and tryptophan low in bipolar disorders depressed; MT tyrosine low, MT tryptophan high, plasma tryptophan low in major depressions; MT tryptophan high in dysthymic disorders. Phenylalanine was in the normal range compared to controls. The perturbations of MT's involved the part incubated at 37 degrees C for tyrosine, e.g. the facilitated diffusion, and the part incubated at 0 degrees C for tryptophan, e.g. probably the passive and facilitated diffusion. These results were in agreement with the monoaminergic hypothesis of affective disorders and might provide a useful peripheral model.

[7 years study of erythrocyte membrane transport of monoamine precursors. 395 patients (335 depressed, 60 schizophrenic patients)]. / Sept ans de détermination du transport membranaire érythrocytaire des précurseurs des monoamines. 395 patients (335 dépressifs, 60 schizophrènes.

According to the monoaminergic hypothesis of affective and schizophrenic syndromes, a perturbation of influx of precursors of monoamines such as tyrosine (TYR) and tryptophan (TRYP) into the brain might be correlated with the clinical syndromes. The measure of blood cell membrane transports of TYR and TRYP is an interesting peripheral model for the study of these syndromes. This work concerns 395 patients (335 depressed and 60 schizophrenics); 215 of depressed patients were followed after the antidepressant therapy. The transport of TYR and TRYP into erythrocytes was measured as followed: erythrocytes were incubated in plasma for 10 min. at 0 degree and 37 degrees C with radiolabeled TYR and TRYP; facilitated diffusion was calculated by subtracting from the total amount of radioactivity taken up by the cells at 37 degrees C (total uptake) that accumulated at 0 degree C (passive diffusion). The results showed that: 1) The depressive syndromes were characterised by a decrease of facilitated diffusion of TYR, an increase of facilitated diffusion of TRYP and a decrease of the index diffusion of TYR/TRYP. 2) The means of variables were different according to the diagnostic sub-groups (DSM III). In the depressions with alcoholism, the facilitated diffusions were increased compared to depressive syndromes without others diagnosis. The depressions with dementia were in intermediate position. 3) After treatment with antidepressant drugs, the biological variables improved with the clinical improvement, without complete normalization compared to controls. The patients without clinical improvement showed no change in the biological measures. 4) Patients for whom the choice of antidepressant drug was done according to the facilitated diffusions showed a 87% rate of clinical improvement, while this rate was 60% in the other patients. 5) In schizophrenic patients, the biological variables were different than in depressed or normal controls and showed a little decrease of facilitated diffusion of TYR, a marked decrease of diffusion of TRYP and an increased index of diffusion TYR/TRYP.

[Head injury and pregnancy]. / Traumatisme crânien et grossesse.

Even mild, head injury during pregnancy can threaten either the maternal or the fetal life. Traffic accidents are the main causes so head injury is often associated with other lesions, frequently abdominal trauma. Among all these possible lesions, head injury and hemorrhagic shock are the main sources of fatality in pregnant women. All kinds of trauma and especially head injuries have a potentially deleterious effect on fetal viability. This risk is associated with systemic and cerebral consequences of post-traumatic arterial hypotension, anoxia or anemia. Moreover, diagnostic procedures and medications can add their noxious secondary effects, contributing more or less to poor fetal outcome. Decision making is necessarily dictated by the severity of the consciousness disorders and/or the encephalic lesions. A convergent discussion between the intensive care physician, the neurosurgeon, the obstetrician and the anesthesiologist is needed. Severe or prolonged traumatic coma is highly dramatic situation because the maternal outcome remains largely unknown for days or weeks. Technically, for these severe comas, there are no substantial differences with what is usually done in a similar case without pregnancy. Neurosurgical indications follow the usual rules, except that some non-urgent indications should be delayed for a while. Usually, this simple rule of independency in indications also applies to the obstetrician. Special care must be taken for fetal monitoring required throughout the initial critical phase.

[Efficacy of antidepressants selected as a function of erythrocyte membrane transport and plasma levels of L-tyrosine and L-tryptophan]. / Efficacité des antidépresseurs choisis en fonction des transports membranaires erythrocytaires et des taux plasmatiques de L-tyrosine et L-tryptophane.

The present study concerned 69 depressed patients (26 men, 43 women). The antidepressant drug was prescribed in accordance with perturbations of tyrosine and tryptophan membrane transports (MT) across the red cell, measured in vitro after a wash-out period of ten days. After two to four months of treatment, the clinical results were divided into two groups: normal mood (AMDP - Depression Scale less than 6) and no recovery (AMDP - Depression Scale greater than 6). The initial criteria (e.g. MT) was completed by using plasma tyrosine, tryptophan and the product MT by plasma level. Indeed, the success of this treatment was corresponding to precise abnormalities of variable: (i) tyrosine and tryptophan values for imipramine, (ii) tyrosine values, plasma tryptophan and tryptophan product for desipramine, (iii) tryptophan variables and plasma tyrosine for fluvoxamine (and indalpine). The analysis of clinical failures permitted to complete our previous choice of antidepressant drug.

Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase.

The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without alpha-thalassemia. Using a vectorette strategy, we have identified and sequenced the intron/exon boundaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases identified three zinc finger motifs within the 5' end of the gene. Expression analysis in different tissues indicated that an alternative splicing event that involves exon 6 is occurring. One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. These data led us to search for mutations in the 5' region in ATRX patients without other mutations in the 3' region. In one patient a mutation was found in which part of exon 7 was removed from the XNP transcript, as a result of a mutation creating a novel splice site that is substituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predominantly found in the helicase region as well as in the zinc finger regions and leads us to propose a large screening of additional patients.

[Erythrocyte membrane transport of L-tyrosine and L-tryptophan in 66 patients with depressive syndromes. Preliminary results]. / Transports membranaires érythrocytaires de la L-tyrosine et du L-tryptophane chez 66 sujets atteints de syndromes dépressifs. Résultats préliminaires.

The transport of Tyrosine and Tryptophan by the membrane of red blood cells has been studied in a group of 66 depressed patients (DSM-III: 27 major depressions, single episode or recurrent; 17 bipolar disorders, depressed; 22 dysthymic disorders). Anomalies were observed: tyrosine transport was decreased in the bipolar disorders and in the major depressions; tryptophan transport was increased in the major depressions and in the dysthymic disorders. These results suggest that membrane transports are disturbed in depressed syndromes, and may be related to dysfunction in the monoaminergic balance.

A multivariate analysis of red blood cell membrane transports and plasma levels of L-tyrosine and L-tryptophan in depressed patients before treatment and after clinical improvement.

The purpose of this study was to examine whether biological variables, such as erythrocyte membrane transports and plasma levels of monoamine precursor amino acids (tyrosine, tryptophan and phenylalanine), exhibit a particular pattern relatively to DSM-III depressive subgroups (dysthymic disorders, major recurrent depression and biopolar depression), when they are treated synthetically by a stepwise discriminant analysis. We conducted two tests in 97 subjects (64 depressed patients vs. 33 controls): the first before any antidepressant treatment, and the second after pharmacotherapy and clinical improvement. Our results clearly indicate a satisfying homogeneity for the controls and bipolar depressed patients as opposed to dysthymic disorders and major recurrent depression in both tests. The most informative biological variables are the erythrocyte membrane transports before treatment, tryptophan parameters after clinical improvement. Evidence is provided that multivariate analysis constitutes an interesting approach in biological psychiatry.

The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia.

Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. We have previously identified the human small conductance calcium-activated potassium channel gene (hSKCa3) which has two tandemly arranged CAG repeats in its 5' region. Here we have isolated the first genomic clones containing the gene and have shown that both repeats are in exon 1. Homology to the previously localized sequence tagged site G16005 indicated that the gene may be on chromosome 22q, however using polymerase chain reaction amplification of somatic cell hybrid DNA and fluorescence in situ hybridization of two P1 artificial chromosome clones, we physically localized the gene to chromosome 1q21.3. We previously found an association between the highly polymorphic second (more 3') CAG repeat and schizophrenia in 98 patients and 117 controls. We have now genotyped an additional 19 patients with schizophrenia and have performed statistical analyses on the entire group of patients and controls to investigate the possible effect of age of onset, family history, and gender of the patients on the observed association. None of these factors were found to influence the results. Both CAG repeats have been typed in 86 bipolar I disorder patients, and no significant difference in allele distribution was observed between our bipolar disorder patients and controls.