Consensus on the use of substituted benzamides in psychiatric patients.

The class of substituted benzamides includes compounds able to modulate dopaminergic neurons selectively and specifically. The first synthetic substituted benzamide was sulpiride, which has been replaced in the clinic by the more modern amisulpride. The compound is very selective for mesolimbic D2 and D3 receptors and, therefore, has a dual mechanism of action, which is associated with two different indications. At low doses (50 mg), amisulpride preferentially blocks presynaptic autoreceptors, producing an increase in dopamine release, and therefore acting as a dopaminergic compound able to resolve the dopaminergic hypoactivity that characterizes depression. At higher doses (400-1,200 mg), the drug exerts its activity on postsynaptic D3/D2 receptors located in the limbic region and prefrontal areas, producing selective dopaminergic inhibition, eliciting antipsychotic effects. In the present review, the clinical use of amisulpride in depressive syndromes is discussed, in particular in dysthymia and in schizophrenia. Based on experimental data, amisulpride is a treatment of choice for dopaminergic transmission disorders, both in depression and in schizophrenia.

Decrease of the D4 dopamine receptor messenger RNA expression in lymphocytes from patients with major depression.

OBJECTIVES: The evaluation of the possible role of dopamine in psychiatric disorders has been limited by the relative inadequacy of tools. A tempting approach to examine alterations of dopaminergic system in major depression is to examine the expression of dopamine receptors in peripheral blood mononuclear cells (PBMC). METHODS: D4 dopamine receptor (D4DR) messenger RNA (mRNA) expression in PBMC from 12 patients with major depressive disorder was examined before and after an 8-week treatment with paroxetine at 20-50 mg/day. Ten healthy subjects were analyzed in parallel. The relative content of D4DR mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). using beta-actin as internal standard. RESULTS: D4DR mRNA levels were significantly decreased in untreated depressed patients as compared to controls. D4DR mRNA expression returned to control levels after paroxetine treatment, when patients achieved a significant improvement of depressive symptoms. CONCLUSIONS: Results of our study suggest the role of PBMC D4DR mRNA expression as a peripheral marker of the central dopaminergic function in major depression.

A comparison of paroxetine and amisulpride in the treatment of dysthymic disorder.

BACKGROUND: The purpose of this study was to provide preliminary data on the effects of paroxetine and amisulpride on depressive dimensions, analyzed by factor analysis, in dysthymic patients. METHODS: One hundred and eighteen patients with DSM IV criteria for DD without concurrent major depression were enrolled in this 8-week, open study, and 100 completed it. Symptom dimensions were identified by principal components analysis with the SAS Factor procedure. RESULTS: Results of the symptom rating scales indicated that both drugs were equally effective. Response rate was 65% both in the paroxetine and the amisulpride group and the proportions of patients achieving a final HRSD score < or =7 were 46.7 and 55%, respectively. MADRS factor analysis identified two factors at baseline: the first corresponding to the global severity of depression and the second to somatic symptoms. After 8 weeks of treatment only one factor could be substantiated. At week 4 both paroxetine and amisulpride produced significant improvements on factor 1 while at week 8 mean changes of factor 1 were greater in the amisulpride-treated patients. LIMITATIONS: The main limitation was the open-label design. CONCLUSIONS: Both paroxetine and amisulpride appear to be effective in the short-term management of DD, improving its most characteristic symptoms.

Refractory obsessive-compulsive disorder: state-of-the-art treatment.

Nonresponse to treatment in obsessive-compulsive disorder is common, associated with substantial impairment, and understudied. Little practical advice is available to clinicians on next-step treatment strategies for patients who have not responded well to 2 trials of selective serotonin reuptake inhibitors (SSRIs). Available options include continuation of SSRI treatment, switching to another SSRI or selective serotonin-norepinephrine reuptake inhibitor, augmenting with atypical neuroleptics or cognitive-behavioral therapy, or utilizing novel treatment approaches. The authors synthesize state-of-the-art treatment and give practical advice for clinicians.

An exploratory study on obsessive-compulsive disorder with and without a familial component: are there any phenomenological differences?

Familial studies on obsessive-compulsive disorders (OCD) have suggested that OCD is a heterogeneous condition, with some cases being familial and others being isolated cases in their families. Nevertheless, no studies evaluated whether there are clinical differences between OCD cases with and without a familial component. The current report presents data on the prevalence of OCD in first-degree relatives of OCD probands and compares phenomenological characteristics of familial and non-familial OCD types. The family study and the family history methods were used to estimate the prevalence of OCD in first-degree relatives of 74 OCD probands. A statistical comparison between OCD probands with and without familial loading was performed using Pearson's chi(2) test, Fisher's exact test, or Student's t test when appropriate. The rate of OCD was 3.5% in directly interviewed first-degree relatives. Eleven percent of the probands had at least one family member with OCD. There were no differences between the two types of OCD (familial vs. non-familial) except for life events prior to the onset of OCD, which were more common and more severe in non-familial OCD subtypes. In conclusion, our results (1) confirm that there is a familial component in the expression of some forms of OCD and (2) indicate that familial OCD patients are not characterized by peculiar clinical features, but appear to have a lower threshold for precipitating events.

Mental deterioration correlates with response of natural killer (NK) cell activity to physiological modifiers in patients with short history of Alzheimer's disease.

Natural killer (NK) cell activity of peripheral blood mononuclear (PBM) cells was measured in 16 subjects with mild to moderate senile dementia of Alzheimer's type (sDAT) chosen for short history of disease and no medication, and in 17 age- and sex-matched controls. Levels of cytotoxicity at baseline and after PBM cell exposure to modifiers either negative (cortisol 10(-6) M) or positive (rIL-2 650 IU/ml and rIFN-gamma 100 UI/ml, respectively) were related to indices of hypothalamic-pituitary-adrenal (HPA) function and Gottfries Bråne Rating Scale (GBS) score for mental deterioration. Spontaneous NK cell activity was not significantly different in sDAT subjects vs controls. In vitro inhibition by cortisol was lower in sDAT (P<0.05); cytokine-induced changes were greater (rIL-2, P<0.02; rIFN-gamma, P<0.05). Percent negative or positive variations from baseline significantly correlated with GBS scores (P<0.05 or less). Serum cortisol and cortisol/DHEAS molar ratio at 0800 h were significantly higher in sDAT (P<0.05 and P<0.02, respectively). Cortisol/DHEA ratio positively correlated with GBS scores (P<0.02). Moreover, the ratios of incremental area of response ACTH/cortisol and beta-endorphin/cortisol after 1 microg/kg ovine-corticotrophin-releasing hormone (o-CRH) positively correlated with percent increase of NK cell activity after rIL-2 (P<0.01). Data indicate that patients with mild cognitive impairment and short history of sDAT show abnormal responsiveness of NK cell activity to physiological modifiers while maintaining normal spontaneous activity. Furthermore, data are compatible with partial glucocorticoid resistance at the immune level. Progressing sDAT longitudinal studies are needed to address: i) the clinical applicability of these abnormalities as prognostic factors; ii) the role played by pro-opiomelanocortin (POMC)-derived peptides and adrenal androgens in the control of NK cell activity.

Paroxetine versus amitriptyline in patients with recurrent major depression: A double-blind trial.

INTRODUCTION: Long-term exposure to antidepressants is required to prevent relapses and recurrences in patients with recurrent major depression. Furthermore, a good pharmacological compliance is the key to successful long-term treatment. Since the early phases of a treatment influence long-term compliance and compliance is adversely affected by poorly tolerated treatments, efficacy and tolerability of paroxetine and amitryptiline over 12 weeks were compared as an introduction to the issue of long-term compliance to these two agents. METHOD: A 12-week, randomized, double-blind, doubledummy, parallel-group trial which involved 129 patients with recurrent major depression. RESULTS: Both paroxetine and amitriptyline were effective in controlling the symptoms of depression, as shown by the reduction in HAMD total score and CGI severity-of-illness score at endpoint compared to baseline. There was no statistically or clinically significant difference between the two treatments in terms of efficacy. However, marked numerical differences were noted in tolerability: the percentage of patients who reported treatment-emergent adverse experiences was greater in the amitriptyline group (40.0% vs 28.1%). This difference was mainly due to anticholinergic adverse events, which were six times more frequent with amitriptyline than with paroxetine. CONCLUSION: When compared with amitriptyline, paroxetine should allow patients with recurrent major depression to receive an equally effective treatment with a relatively lower incidence of adverse experiences.