[Impact of personality on the alcohol withdrawal syndrome intensity: a preliminary study with the Cloninger's model]. / Impact de la personnalité sur l'intensité du syndrome de sevrage alcoolique: une étude préliminaire avec le modèle de Cloninger.

INTRODUCTION: The personality of alcohol dependant patients as a factor influencing the intensity of the alcohol withdrawal syndrome has been seldom examined. Cloninger's biosocial model of personality describes four temperaments (novelty seeking, harm avoidance, reward dependence, persistence) which, except for persistence, are admittedly linked to specific central neurotransmitters, and three characters. Novelty seeking is linked with low levels of mesencephalic dopamine, harm avoidance with high levels of serotonin in the septo-hippocampic system and reward dependence with low levels of noradrenaline in the ascending pathways from the locus coeruleus to the limbic system. The same neurotransmitters pathways are known to be involved in alcohol withdrawal, with a decrease of dopaminergic activity in the mesolimbic system, a decrease of serotonergic activity in the nucleus accumbens and an increase of the noradrenergic system. In view of the similarities between the neurobiological systems involved in Cloninger's model and in the neurobiological changes occurring during the withdrawal period, one would expect to observe severe withdrawal symptoms more frequently for patients with high novelty seeking, low harm avoidance and low reward dependence. METHODS: To test this hypothesis, alcohol dependent patients according to DSM IV classification criteria who have drunk in the last twenty four hours were included in the study and received a standardized withdrawal treatment. The withdrawal syndrome intensity was examined with repeated measures of CIWA-Ar, the scores of which were correlated with TCI-R. RESULTS: Twenty eight patients, between 30 et 65 years old and drinking 22,2 +/- 12 standard drinks per day were included. Antidepressant drugs, benzodiazepines and neuroleptics treatment introduced before hospitalisation were stopped or decreased as much as possible. A correlation matrix was carried out between all the variables which could influence withdrawal intensity (age at the hospitalisation, age at the begining of the dependance, ratio between the time of the dependance and the patients' age, the number of alcohol withdrawals carried out and the number of standard drinks per day), and showed a positive correlation between the number of standard drinks per day and withdrawal intensity at day 3 (r=0.7, p<0.000), at day 4 (r=0.52, p<0.005), at day 7 (r=0.41, p<0.036) and at day 8 (r=0.44, p<0.02); as between the ratio between the time of the dependance and the patients' age and withdrawal intensity at day 2 (r=0.43, p<0.03) and at day 5 (r=0.5, p<0.01). Therefore, partial correlations were calculated between the dimensions of personality and withdrawal intensity. The study showed a positive correlation between withdrawal intensity and harm avoidance from day 5 onwards (r=0.6 and P<0.003 at day 5, r=0.59 and P<0.004 at day 6, r=0.56 and P<0.006 at day 7, r=0.66 and P<0.001 at day 8), a negative correlation between withdrawal intensity and reward dependence at day 7 and 8 (r=- 0.45 and P<0.037 at day 7, r=- 0.49 and P<0.02 at day 8) and a negative correlation between withdrawal intensity and persistence from day 6 onwards (r=- 0.5 and P<0.017 at day 6, r=- 0.5 and P<0.019 at day 7, r=- 0.51 and P<0.014 at day 8). No correlation was found between withdrawal intensity and novelty seeking. The same relevant results were found again with the 22 patients without anti-depressant drugs' population. DISCUSSION: Personality dimensions seem to influence alcohol withdrawal intensity once the severe symptomatology is over, while high doses of anti withdrawal treatment in the first days of abstinence may decrease the influence of personality on withdrawal symptoms. The positive correlation between harm avoidance and withdrawal intensity seems to invalidate our neurobiological hypotheses, but can be explained by clinical observations and corroborate studies assessing the influence of personality in benzodiazepine withdrawal intensity and in pain perception. This result encourages the introduction of support therapy during withdrawal and a cognitive-behavioural therapy before withdrawal in order to decrease patients' sensitivity to anxiety. The negative correlation between reward dependence and withdrawal intensity confirms the neurobiological hypotheses, but the weak correlation demands to be cautious in the interpretation of the results. The negative correlation between persistence and withdrawal intensity was expected. CONCLUSION: The characteristics associated with persistence seem to act as protective factors during alcohol withdrawal, whereas those associated with harm avoidance appear to increase the symptoms of alcohol withdrawal. In contrast, the neurobiological hypotheses are only partially confirmed.

AVP- and OT-neurophysins response to apomorphine and clonidine in major depression.

A number of studies have reported abnormalities of neurohypophyseal secretions in major depressive disorder. The purpose of the present study was to test the influence of apomorphine and clonidine injections on plasma vasopressin (AVP)-neurophysins and oxytocin(OT)-neurophysins levels, as direct index of posterior pituitary activation in major depression. Apomorphine and clonidine tests were carried out in 25 medication-free depressive patients and 25 age and gender-matched healthy controls. Blood for neurophysins analysis was drawn by venipuncture at t0, t + 20, t + 40, t + 60 and t + 120. Baseline AVP-neurophysins concentrations were significantly lower in depressives (0.12 +/- 0.14 ng/ml) than in healthy subjects (0.24 +/- 2.15 ng/ml) (p < 0.04). The response to apomorphine test revealed a significant reduced response at 20 (p = 0.01), 40 (p = 0.007) and 60 (p = 0.02) and 120 (p = 0.02)min. Following clonidine test, post hoc tests also revealed a significant decrease at 0 (p = 0.04), 20 (p = 0.01), 40 (p = 0.007) and 60 (p = 0.02) and 120 (p = 0.006)min. Concerning OT-neurophysins, no significant differences were found between depressed and controls in response to clonidine or apomorphine injections. Following clonidine and apomorphine, major depressives exhibited a significantly lower peak GH response than controls. The study supports partially the hypothesis of a reduced vasopressinergic activity in depression. Moreover, we did not find any influence of acute apomorphine or clonidine injections on vasopressin-neurophysin or oxytocin-neurophysin in depressive patients.

Mismatch negativity is not correlated with neuroendocrine indicators of catecholaminergic activity in healthy subjects.

The identification of the brain structures and neurotransmitters responsible for the generation and/or modulation of the mismatch negativity (MMN) may contribute to a clearer understanding of its functional significance, and may have clinical implications. In this context, some findings suggest that the scalp-recorded MMN reflects activity from multiple neuronal ensembles within or in the immediate vicinity of the primary auditory cortex and with possible contribution from the frontal cortex. However, few data are available concerning the influence of neurotransmitter systems on the MMN. In this study, the relationship between both noradrenergic and dopaminergic systems and the MMN were investigated in 34 healthy volunteers. Noradrenergic and dopaminergic activities were assessed with the apomorphine and clonidine challenge tests. The results showed no significant relationship between either growth hormone (GH) responses to apomorphine or clonidine and the MMN amplitude or latency. Therefore, this study does not demonstrate the implication of dopaminergic and noradrenergic activities as assessed by GH response to apomorphine and clonidine for the generation and/or the modulation of the MMN. However, given the complexity of the central neurotransmitter systems, these results cannot be considered as definitive evidence against a relationship between dopaminergic and noradrenergic activity and the MMN.

[Lipids, depression and suicide]. / Lipides, dépression et suicide.

Polyunsatured fatty acids are made out of a hydrocarbonated chain of variable length with several double bonds. The position of the first double bond (omega) differentiates polyunsatured omega 3 fatty acids (for example: alpha-linolenic acid or alpha-LNA) and polyunsatured omega 6 fatty acids (for example: linoleic acid or LA). These two classes of fatty acids are said to be essential because they cannot be synthetised by the organism and have to be taken from alimentation. The omega 3 are present in linseed oil, nuts, soya beans, wheat and cold water fish whereas omega 6 are present in maize, sunflower and sesame oil. Fatty acids are part of phospholipids and, consequently, of all biological membranes. The membrane fluidity, of crucial importance for its functioning, depends on its lipidic components. Phospholipids composed of chains of polyunsatured fatty acids increase the membrane fluidity because, by bending some chains, double bonds prevent them from compacting themselves perfectly. Membrane fluidity is also determined by the phospholipids/free cholesterol ratio, as cholesterol increases membrane viscosity. A diet based on a high proportion of essential polyunsatured fatty acids (fluid) would allow a higher incorporation of cholesterol (rigid) in the membranes to balance their fluidity, which would contribute to lower blood cholesterol levels. Brain membranes have a very high content in essential polyunsatured fatty acids for which they depend on alimentation. Any dietary lack of essential polyunsatured fatty acids has consequences on cerebral development, modifying the activity of enzymes of the cerebral membranes and decreasing efficiency in learning tasks. EPIDEMIOLOGICAL DATA: The prevalence of depression seems to increase continuously since the beginning of the century. Though different factors most probably contribute to this evolution, it has been suggested that it could be related to an evolution of alimentary patterns in the Western world, in which polyunsatured omega 3 fatty acids contained in fish, game and vegetables have been largely replaced by polyunsatured omega 6 fatty acids of cereal oils. Some epidemiological data support the hypothesis of a relation between lower depression and/or suicide rates and a higher consumption of fish. These data do not however prove a relation of causality. CHOLESTEROL AND DEPRESSION: Several cohort studies (on nondepressed subjects) have assessed the relationship between plasma cholesterol and depressive symptoms with contradictory results. Though some results found a significant relationship between a decrease of total cholesterol and high scores of depression, some other did not. Studies among patients suffering from major depression signalled more constantly an association between low cholesterol and major depression. Besides, some trials showed that clinical recovery may be associated with a significant increase of total cholesterol. CHOLESTEROL AND SUICIDAL BEHAVIOR: The hypothesis that a low cholesterol level may represent a suicidal risk factor was discovered accidentally following a series of epidemiological studies which revealed an increase of the suicidal risk among subjects with a low cholesterol level. Though some contradictory studies do exist, this relationship has been confirmed by several subsequent cohort studies. These findings have challenged the vast public health programs aimed at promoting the decrease of cholesterol, and even suggested to suspend the administration of lipid lowering drugs. Recent clinical studies on populations treated with lipid lowering drugs showed nevertheless a lack of significant increase of mortality, either by suicide or accident. In addition, several controlled studies among psychiatric patients revealed a decrease of the concentrations of plasma cholesterol among patients who had attempted suicide in comparison with other patients. POLYUNSATURATED FATTY ACID AND DEPRESSION: In major depression, all studies revealed a significant decrease of the polyunsaturated omega 3 fatty acids and/or an increase of the omega 6/omega 3 ratio in plasma and/or in the membranes of the red cells. In addition, two studies found a higher severity of depression when the level of polyunsaturated omega 3 fatty acids or the ratio omega 3/omega 6 was low. Parallel to these modifications, other biochemical perturbations have been reported in major depression, particularly an activation of the inflammatory response system, resulting in an increase of the pro-inflammatory cytokines (interleukins: IL-1b, IL-6 and interferon g) and eicosanoids (among others, prostaglandin E2) in the blood and the CSF of depressed patients. These substances cause a peroxidation and, consequently a catabolism of membrane phospholipids, among others those containing polyunsaturated fatty acids. The cytokines and eicosanoids derive from polyunsaturated fatty acids and have opposite physiological functions according to their omega 3 or omega 6 precursor. Arachidonic acid (omega 6) is, among others, precursor of pro-inflammatory prostaglandin E2 (PGE2), whereas polyunsaturated omega 3 fatty acids inhibit the formation of PGE2. It has been shown that a dietary increase of polyunsaturated omega 3 fatty acids reduced strongly the production of IL-1 beta, IL-2, IL-6 and TNF-alpha (tumor necrosis factor-alpha). In contrast, diets with a higher supply of linoleic acid (omega 6) increased significantly the production of pro-inflammatory cytokines, like TNF-alpha. Therefore, polyunsaturated omega 3 fatty acids could be associated at different levels in the pathophysiology of major depression, on the one hand through their role in the membrane fluidity which influences diverse steps of neurotransmission and, on the other hand, through their function as precursor of pro-inflammatory cytokines and eicosanoids disturbing neurotransmission. In addition, antidepressants could exhibit an immunoregulating effect by reducing the release of pro-inflammatory cytokines, by increasing the release of endogenous antagonists of pro-inflammatory cytokines like IL-10 and, finally, by acting like inhibitors of cyclo-oxygenase. THERAPEUTIC USE OF FATTY ACIDS: Data available concerning the administration of supplements of DHA (docosahexanoic acid) or other polyunsaturated fatty acids omega 3 are limited. In a double blind placebo-controlled study on 30 patients with bipolar disorder, the addition of polyunsaturated omega 3 fatty acids was associated with a longer period of remission. Moreover, nearly all the other prognosis measures were better in the omega 3 group. Very recently, a controlled trial showed the benefits of adding an omega 3 fatty acid, eicosopentanoic acid, among depressed patients. After 4 weeks, six of the 10 patients receiving the fatty acid were considered as responders in comparison with only one of the ten patients receiving placebo. CONCLUSIONS: Some epidemiological, experimental and clinical data favour the hypothesis that polyunsaturated fatty acids could play a role in the pathogenesis and/or the treatment of depression. More studies however are needed in order to better precise the actual implication of those biochemical factors among the various aspects of depressive illness.

Neuroendocrine evaluation of 5-HT1A function in male alcoholic patients.

BACKGROUND: Preclinical evidences support the hypothesis of a serotonergic dysfunction in alcohol preference. In human, studies have demonstrated a serotonergic hypoactivity in alcoholism. However, little is known about the role of 5-HT1A receptors. METHODS: We assessed the hormonal (prolactin and cortisol) responses to flesinoxan (a highly potent and selective 5-HT1A agonist) in 12 male inpatients meeting DSM-IV criteria for alcohol dependence, 3 weeks after the last reported use of alcohol and antidepressants. These patients were compared to 10 male controls. RESULTS: There was a highly significant difference between alcoholic patients and controls for the area under the curve relative (AUCr) values of prolactin responses. AUCr values of cortisol responses to flesinoxan showed a trend towards lower values in alcoholics compared to controls. CONCLUSION: These results support the implication of the serotonergic system, and particularly a decreased sensitivity of post-synaptic 5-HT1A receptors, in alcoholism.

5-HT1A dysfunction in borderline personality disorder.

BACKGROUND: A number of challenge studies have reported abnormalities of serotonergic function in borderline personality disorder (BPD). There are, however, problems with the pharmacological probes used in these studies since fenfluramine and m-CPP are not only serotonergic agents but also induce release of catecholamines, particularly dopamine. Therefore, we tested whether subjects with BPD showed a blunted prolactin (PRL) response to flesinoxan, a highly potent and selective 5-HT1A agonist. METHODS: Flesinoxan challenge test was carried out in 20 BPD in-patients and 20 healthy controls matched for gender but not for age. Since 16 BPD in-patients exhibited major depressive co-morbidity, a group of 20 depressed in-patients matched for gender but not for age was also included. RESULTS: BPD in-patients exhibited blunted PRL responses as compared to controls, whereas depressed in-patients did not differ from controls. Moreover, PRL responses were lower among BPD in-patients than among depressed in-patients. Among the BPD in-patients, PRL responses to flesinoxan were lower in patients with past history of suicide attempts (N = 8) than in those with a negative history. CONCLUSIONS: The results show major involvement of serotonergic function in BPD and are consistent with previous studies linking lower serotonergic activity with impulsivity. More particularly, our data suggest that BPD is characterized by lower 5-HT1A receptor sensitivity. Moreover, the data support the involvement of 5-HT1A activity in suicidal behaviour. However, this conclusion is limited because other hormonal responses such as ACTH and cortisol were not assessed, and because BPD was assessed by a self-report questionnaire and not a structured clinical interview.

[Ultra-fast opiate detoxification under general anesthesia: preliminary results of the Liege protocol]. / Le sevrage ultra-rapide des toxicomanes aux opiacés sous anesthésie générale: résultats préliminaires du protocole liégeois.

Many studies support the hypothesis of a substantial benefit in inducing an Opiate Receptor Blockade through a Rapid Opiate Detoxification under general Anaesthesia (RODA) in opiate dependent patients. However, prospective studies and long term evaluation of the technique are lacking. In order to evaluate long-term abstinence rates after a RODA among a sample of opiate addicts, a study was started in March 1999 at the University of Liège. To date, 45 patients were evaluated (mean age: 29 +/- 5 years) with a mean opiate dependence duration of 8 +/- 4 years. Most of them were both heroin and methadone dependent; 42.2% of them were included while 31.1% did not complete the whole inclusion procedure and 26.7% were excluded. None experienced severe withdrawal symptoms. At six months, abstinence rate was 67% and 46% at one year. These preliminary results suggest the interest of the procedure in carefully selected patients.

Reduced dopamine function in depressed patients is related to suicidal behavior but not its lethality.

Several lines of evidence suggest a role for dopamine in the control of suicidal behaviour. Previously, we suggested an involvement of D2-dopaminergic function in the biology of suicide by demonstrating a smaller growth hormone (GH) response to apomorphine, a dopaminergic agonist, in depressed patients who later died by suicide. The purpose of the present study was to assess GH response to apomorphine in major depressed in-patients with a history of highly lethal suicide attempt compared to depressed patients with a low lethal lifetime suicide attempt history and non-attempters. The study was performed in a sample of 26 male depressed in-patients with a history of suicide attempt compared to 26 male depressed non-attempters. We observed a significant difference between suicide attempters and non-attempters (for GH peak, 6.3+/-5.1 ng/ml vs 15.8+/-14.2 ng/ml, F=10.3, df=1, 50, P=0.002). Moreover, GH peak responses to apomorphine did not differ between depressed patients with a high lethal lifetime suicide attempt history and patients who made low lethal lifetime suicide attempt. In conclusion, the results of the present study support a role for dopamine in the biology of suicidal behaviour. More specifically, an impaired GH response to apomorphine could be a marker of suicide risk.

Alpha-2-adrenoreceptors in depressed suicide attempters: relationship with medical lethality of the attempt.

Several lines of evidence tend to suggest a role for noradrenaline, and more specifically alpha-2-adrenoreceptors, in the biology of suicidal behavior. The purpose of this study was to assess the growth hormone (GH) response to clonidine, an alpha-2-adrenergic agonist, in majorly depressed inpatients with a history of highly lethal suicide attempt compared to depressed patients with a history of low lethal suicide attempt and nonattempters. Our sample included 20 male depressed inpatients with a history of suicide attempt compared to 20 male depressed nonattempters. We did not observe any significant difference between suicide attempters and nonattempters for GH peak values (2.4 +/- 2.9 vs. 4.1 +/- 3.7 ng/ml; F = 2.52, d.f. = 1, 38, p = 0.12). Moreover, GH peak responses to clonidine were not related to the degree of lethality of the attempt. The results of the present study do not support a major role for noradrenaline in the biology of suicidal behavior.

Reduced dopaminergic activity in depressed suicides.

Several data are available about the implication of the dopaminergic system in the control of inward-directed aggression. Previously, we suggested an involvement of D2-dopaminergic function in the expression of suicidal behavior by demonstrating a smaller growth hormone (GH) response to apomorphine, a dopaminergic agonist, in depressed patients with a history of suicide attempts in comparison to nonattempters. In the present study, the purpose was to analyze GH responses to apomorphine in depressive patients who later died by suicide. Our sample comprised eight male depressive inpatients who died by suicide within one year after hospitalisation. These patients were compared to 18 male major depressed inpatients who never attempted suicide. Mean GH peak responses to apomorphine differed significantly between suicide completers and controls (mean +/- SD): for GH peak, 7.6 +/- 4.1 ng/ml vs 18.9 +/- 14.2 ng/ml, U = 30, Z = -2.33, P = 0.02. Our results tend to confirm the role of dopamine in the biology of suicide in depression.

P300 event-related brain potential and personality in depression.

P300 is an event-related brain potential (ERP) particularly interesting to the study of cognitive processes in normal subjects and in psychopathology. P300 has been applied in depression with controversial results. A major source for these controversial results could result from the diversity of depressed patients included in the different studies. Supporting this assumption, impulsivity, blunted affect, suicidal behavior and psychotic features significantly influence P300 amplitude. However, no data are available on the possible influences of the personality of depressed patients on P300. Since personality is related to P300 in normal subjects, the aim of the present study is to investigate the relationship between ERPs (P200, N200, and P300) and the Temperament and Character Inventory (TCI) in 54 depressed patients. The main results of the study concern the absence of major correlations between personality dimensions as assessed by the TCI and ERP parameters among depressed patients. Only weak partial positive correlations relate N200 latency with harm avoidance, and P300 amplitude (Pz) with the self-directedness dimension. N200 amplitude is also negatively correlated to persistence. However, the preliminary nature of the presented results with respect to the weak statistical significance should be underlined.

[Guidelines for the treatment of depression]. / Recommandations dans le traitement de la dépression.

Depression is a common psychiatric disorder with a lifetime prevalence estimated of 17%. About 25% of the patients develop chronic depression. Diagnosis and treatment are not easy to establish. The authors summarize the latest data on this topic, and suggest Guidelines based upon Consensus Conferences and Evidence-Based Medicine.

[Guidelines for the treatment of opiate addiction]. / Recommandations dans le traitement des toxicomanies aux opiacés.

Over the past 20 years, scientific progress have revolutionised our understanding of the nature of opiate addiction and its various possible treatments. Addiction is a chronic illness treatable if the treatment is well-delivered and tailored to the needs of the particular patient. There is indeed an array of treatments that can effectively reduce drug use, help manage drug cravings, prevent relapses and restore people to productive social functioning. The treatment of drug addiction will be part of a long-term, medical, psychological and social perspective.

[Specific phobias in women]. / Les phobies spécifiques chez la femme.

Specific phobias are common, leading to a high level of suffering and disability when subjects have to face the phobic stimulus. According to the epidemiologic survey of Liège, one fifth of the population exhibits some phobic disorder during lifetime. Women are more affected than men (2:1). This article reviews definitions, etiopathogeny and treatments of specific phobias, and tries to explain the reasons why the trouble is more frequent in women.

Temperament and character inventory (TCI) and depression.

Although several studies have assessed the relationships between the temperament dimensions of the Cloninger model of personality and depression, little is known about the role played by the character dimensions proposed by the seven-factor model of Cloninger in depression. In this study, the relationships between the Temperament and Character Inventory (TCI) and depression were examined in a sample of 40 major depressive patients and 40 healthy controls. Depressed patients exhibit higher harm avoidance and self-transcendence scores as well as lower self-directedness and cooperativeness scores as compared to healthy controls. However, the three other dimensions do not differ between depressive patients and controls. Among the depressive group, harm avoidance, self-directedness and cooperativeness dimensions are related to the severity of depression as assessed by the Hamilton scale. This study confirms the state dependence of the harm avoidance dimension and suggests a relationship between the character dimensions of the Cloninger model and depression.

Dopamine 'D2-like' receptor agonists in combination with cocaine: absence of interactive effects on locomotor activity.

This study examined interactions between cocaine and drugs that act as direct agonists at subtypes of "D2-like" dopamine receptors. The drugs 7-OH-DPAT, quinpirole and RU24213 were studied alone and in combination with cocaine for their effects on locomotor activity in non-habituated mice. Locomotor activity was measured by photobeam crossings over 140 min. At the doses given (7-OH-DPAT: 0.006-6.4 mg/kg; quinpirole: 0.001-1 mg/kg; RU24213: 0.008-8 mg/kg) all three direct agonists dose-dependently reduced locomotor activity throughout the test, whereas cocaine (0.6-20 mg/kg) produced dose-related hyperactivity. Next, for each direct agonist, a series of doses was selected (up to threshold behaviourally-active doses) as pretreatments to a sub-maximally stimulant dose of cocaine (15 mg/kg). 7-OH-DPAT and quinpirole did not modulate the effects of cocaine; RU24213 produced, at best, a very modest attenuation of the effects of cocaine. Finally, a series of cocaine doses (below stimulant threshold) was given before a single dose of each direct agonist (the lowest dose to reduce activity significantly). Cocaine did not reliably alter the hypoactivity produced by any of the D2-like agonists. By demonstrating negligible interactions between cocaine and D2-like agonists, the results fail to demonstrate any necessary involvement of D2-like receptors in one of the behavioural effects of cocaine.