M. Ansseau

Alcohol and withdrawal: From animal research to clinical issues

The withdrawal syndrome in alcohol-dependent patients appears to be a major stressful event whose intensity increases with repetition of detoxifications according to a kindling process. Disturbances in the balance between excitatory and inhibitory neural processes are reflected in a perturbed physical state while disturbances in the balance between positive and negative reinforcements are reflected in a perturbed mood state. Our purpose is to link the different behavioral outcomes occurring during withdrawal with specific biological brain mechanisms from the animal to the human being. Better understanding of the various biological mechanisms underlying withdrawal from alcohol will be the key to design and to apply appropriate pharmaceutical management, together with appropriate therapy aimed at inducing protracted abstinence.

Socio-economic differences in psychiatric in-patient care

Objective:  We seek to investigate socio‐economic differences in psychiatric in‐patient care regarding admission, treatment and outcome.

Belgian normative data of the temperament and character inventory

The Temperament and Character Inventory (TCI) is a 226-item self-questionnaire developed to assess the seven dimensions of personality described by Cloninger and his colleagues. Normative data from 322 representative French-speaking subjects from Belgium are presented and the psychometric properties are discussed. Mean scores of temperament dimensions were appreciably different from those published by Cloninger. In our sample, novelty seeking and self-transcendence scores were lower and harm avoidance scores were higher compared to US norms. The other dimensions were almost identical. The factorial analysis showed that the hypothesized factor structure of temperament and character dimensions was almost confirmed. The present study also confirmed that the TCI scales were weakly related among themselves. The relationships were consistent with those reported by previous reports. Gender differences were also found for different dimensions.

Role of dopamine in non-depressed patients with a history of suicide attempts

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 non-attempters. In the present study, in order to test this hypothesis, GH responses to intravenous apomorphine were measured in non-depressed patients with a history of suicide attempts. The study was performed in 17 non-depressed male patients with a score less than 12 on the 17-item HAMD. The patients were subgrouped into suicide attempters (N = 7) and non-attempters (N = 10). Mean GH peak responses to apomorphine differed significantly between suicide attempters and non-attempters: (mean +/- SD) for GH peak, 10.4 +/- 8.2 ng/mL vs 27.3 +/- 13.1 ng/ml, F = 9.0, P = 0.009. In conclusion, dopaminergic disturbances seem to play a role in the biology of inward-directed aggression in non-depressed patients.

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.

Prediction of Treatment Response to Selective Antidepressants from Clonidine and Apomorphine Neuroendocrine Challenges

Classically, the biochemical pathophysiology of depression is based on central disturbances in catecholaminergic and serotonergic neurotransmission (van Praag, 1980a, b). However, antidepressants are only effective in 60 to 75% of depressive disorders and their success rates are very similar in double-blind studies (Davis, 1985). Recent ‘second-generation’ antidepressants are characterised by their selective activity on neurotransmitter systems. Compounds like zimeldine, fluoxetine, or fluvoxamine selectively inhibit serotonin reuptake, while compounds like nomifensine, maprotiline, or amineptine selectively inhibit catecholamine reuptake. However, it remains quite difficult to define either by clinical or biological parameters which patients would preferentially benefit from one or the other type of antidepressants.

An eight-week, open-label, uncontrolled, multicenter, phase IV study of remission rates in outpatients and inpatients with major depression treated with venlafaxine

Background: Venlafaxine is a structurally novel antidepressant that is believed to potentiate monoamine activity in the central nervous system. In preclinical studies, venlafaxine was shown to inhibit the neuronal uptake of serotonin and norepinephrine and, to a lesser degree, dopamine reuptake, but was without effect on monoamine oxidase (MAO) activity. Clinical trial results from similar to3000 patients suggest that venlafaxine is a safe and effective antidepressant with the potential to invoke an early onset of clinical activity. Objective: The purpose of this 8-week, open-label, uncontrolled, multi-center, Phase IV study was to examine the extent of remission and symptom relief in outpatients and inpatients with major depressive disorder treated with venlafaxine. Methods: This study was conducted at 12 centers across Belgium and Luxembourg. Consecutive, severely depressed inpatients and moderately depressed outpatients aged 18 to 70 years were eligible. Patients were administered open-label venlafaxine for 8 weeks. Dosing was initiated at venlafaxine 75 mg/d (37.5 mg BID), with dose adjustments made throughout the study, to a maximum daily dose of 375 mg for inpatients and 225 mg for outpatients. Results were measured using the Hamilton Depression (HAM-D) scale, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impression (CGI) scale. Results: A total of 149 consecutive patients (84 females, 65 males; mean age, 46.5 years; 88 outpatients, 61 inpatients) were enrolled; the intent-to-treat (ITT) population comprised 144 patients (84 outpatients, 60 inpatients); 111 patients (64 outpatients, 47 inpatients) completed the study. At the week 8 visit, 71.3% of patients (77/108) were considered to be responders according to the HAM-D scale; 73.8% (79/107) according to the MADRS; and 78.7% (85/108) according to the CGI scale. A sustained response was achieved in 33.3% of the ITT population (48/144), and at week 8, 50.8% of outpatients (32/63) and 37.8% of inpatients (17/45) were in remission according to the HAM-D scale. Venlafaxine was well tolerated at all doses, with the most frequently experienced adverse events (AEs) being nausea, sweating, and headache. Fewer inpatients than outpatients reported greater than or equal to 1 AE (57.4% [35/61] and 73.9% [65/88], respectively), despite receiving a higher maximum daily dose of venlafaxine. Conclusion: The results of this study indicate that venlafaxine was a tolerable and effective antidepressant in both outpatients and inpatients, with a significant proportion of patients achieving remission.

Early Clinical Testing of Non-benzodiazepine Anxiolytics

Since the 1960s, benzodiazepines have become the drugs of choice for the treatment of anxiety symptoms. Their advantages are obvious: proven efficacy, immediate activity and very low toxicity. However, over the last few years more attention has been focused on the negative aspects of benzodiazepine therapy. Besides the well-known drowsiness, particularly at the beginning of the treatment, memory impairment is now well demonstrated. But the major drawback of benzodiazepines is their ability to induce psychic or even somatic dependence, particularly after prolonged use (Petursson and Lader, 1984). Therefore, a large body of research has been devoted to new types of anxiolytic compounds, which could lack the negative aspects of benzodiazepines. Pharmaceutical companies have synthetized a huge number of original molecules, with various postulated mechanisms of action, which appeared very promising according to biochemical and animal data. However, most agents did not fulfil the expectations they aroused. Indeed, the actual demonstration of an anxiolytic activity in humans raises a large number of methodological issues owing both to the nature of the illness and to the specificity of the pharmacological effect, which need to be addressed in various types of studies.

Compulsive personality and serotonergic drugs

Abstract Based on the evidence that serotonergic antidepressants are effective in obsessive-compulsive disorder, we found that major depressive patients with an underlying compulsive personality responded significantly better to fluvoxamine than major depressive patients without personality disorder.

Activity of Fengabine, a GABAergic Drug, in Depression

Fengabine is a new γ-aminobutyric acid (GABA)-mimetic drug with atypical antidepressant activity in various models of depression (reduces the behavioral effects of 5-hydroxytryptophan and the behavioral deficits secondary to olfactory bulbectomy and learned helplessness). Like the conventional antidepressants, fengabine delays the appearance of paradoxical sleep and reduces its total duration in rats.1,2 On the basis of these results, the potential antidepressant action of fengabine and its effects on sleep parameters versus the effects of amitriptyline were assessed in a controlled clinical trial.