Peripheral benzodiazepine receptor messenger RNA is decreased in lymphocytes of generalized anxiety disorder patients.

BACKGROUND: The aim of this study was to assess whether the decrease of peripheral benzodiazepine receptor (pBR) number in peripheral blood mononuclear cells (PBMC), previously observed in patients with generalized anxiety disorder, is paralleled by changes in the relative content of messenger RNA (mRNA) encoding pBR. METHODS: Eight patients with a DSM-III-R diagnosis of generalized anxiety disorder were examined before, during, and after 2'-chloro-N-desmethyl-diazepam treatment. Eight healthy subjects were analyzed in parallel. The relative content of pBR mRNA was determined by reverse-transcriptase-polymerase chain reaction, using beta-actin as internal standard. Kinetic binding properties of pBR were measured using 3H-PK11195 as a ligand. RESULTS: pBR and pBR mRNA were significantly decreased in untreated generalized anxiety disorder patients as compared to controls (by 45% and 70%, respectively). Both pBR density and mRNA levels returned to control values during treatment or after withdrawal, which also coincided with recovery from anxiety. CONCLUSIONS: These results suggest that the turnover rate of pBR is reduced in PBMC of generalized anxiety disorder patients, and that this change occurs at the transcriptional level.

Altered cAMP-dependent protein kinase A in platelets of patients with obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to assess cAMP-dependent protein kinase A in patients with obsessive-compulsive disorder (OCD). METHOD: The levels and the activity of protein kinase A were evaluated in whole platelets obtained from 12 unmedicated patients with OCD and 15 healthy comparison subjects. RESULTS: The immunolabeling of protein kinase A regulatory subunits type I and II were significantly greater but that of the catalytic subunit significantly lower in patients with OCD than in healthy subjects. The cAMP-stimulated activity in patients with OCD was significantly lower than that in healthy subjects. CONCLUSIONS: These data suggest a possible role of protein kinase A in the pathophysiology of OCD.

[3H]N-methylscopolamine binding to muscarinic receptors in human peripheral blood lymphocytes: characterization, localization on T-lymphocyte subsets and age-dependent changes.

The properties of the binding of the muscarinic receptor ligands, [3H]quinuclidinyl benzilate ([3H]QNB) and [3H]N-methylscopolamine ([3H]NMS) in human mononuclear cells were compared. The binding of [3H]QNB showed a high, non-specific component and lack of saturability in both intact mononuclear cells and preparations of lysed mononuclear cell membranes. Conversely the specific binding of [3H]NMS had a high affinity and was saturable at concentrations greater than 30 nM in both intact and broken cells. Classical muscarinic receptor antagonists displaced specific binding of [3H]NMS binding according to the law of mass action, while displacement curves for pirenzepine and muscarinic agonists were very shallow (nH less than 1), suggesting the presence of more than one subtype of muscarinic receptor on mononuclear cell membranes. Binding studies with [3H]NMS to purified mononuclear cell subpopulations demonstrated that muscarinic binding sites were mainly localized on thymus-derived (T) lymphocytes and large granule lymphocytes. Moreover evidence is presented of an age-dependent increase of the density of muscarinic binding sites on T-lymphocytes. The results are discussed in terms of the usefulness of the binding of [3H]NMS in studying the physiological function of muscarinic receptors on human T-lymphocytes and their possible changes in patients with neurological diseases.

Peripheral-type benzodiazepine receptors on human blood mononuclear cells are not regulated by ovarian steroids.

Peripheral-type benzodiazepine receptors (pBZr) have been shown to be sensitive to hormonal perturbations, including changes in ovarian steroids. This study examines whether estradiol and progesterone modulate pBZr binding in membranes of human blood mononuclear cells, as measured by binding of both 3H-PK 11195 and 3H-Ro 5-4864. Our findings were negative. There was no steroidal modulation of pBZr binding to these membrane preparations in vivo in normal women studied at different sex-steroid phases of the menstrual cycle, or during 8-30 weeks of pregnancy. There was also no effect of hormones on the binding sites in cultures of mononuclear cells treated with estradiol or progesterone (up to 10(-5) M) over a period between 2 and 72 h. Further, we performed in vitro competition experiments, which showed that both steroids are not active at the pBZr. Our data suggest that pBZr located in human blood mononuclear cells are insensitive to the physiological variations of circulating female hormones.

Hypothalamic-pituitary-adrenal axis function, psychopathological traits, and natural killer (NK) cell activity in anorexia nervosa.

To evaluate the role of Hypothalamic-Pituitary-Adrenal (HPA) hormones and psychoneuroendocrine modulation on NK cell activity in Anorexia Nervosa (AN) we studied in 24 patients and 20 sex- and age-matched healthy controls, the spontaneous NK activity of peripheral blood mononuclear (PBM) cells and the susceptibility in vitro to cortisol or immune interferon or interleukin-2. NK cytotoxicity of PBM cells was measured in a direct non-radiometric 4h cytolytic assay using K562 cells as targets. HPA axis function was evaluated by IV ovine Corticotropin Releasing Hormone (o-CRH) administration. We did not find clear-cut abnormalities of NK cytotoxicities either in basal conditions or after exposure to challengers. The extent of cortisol-dependent inhibition was comparable in patients and controls. Significant inverse and direct correlations were found respectively between the spontaneous NK cell activity and baseline serum cortisol at 0800 h (r = -0.5; p < .02), and between IL-2 dependent boosting of NK cell cytotoxicity and ACTH, beta-endorphin or cortisol responses after o-CRH, expressed as areas under the curve (AUC) (r = 0.46, p < .05; r = 0.46, p < .05; and r = -0.48, p < .05, respectively). Correlations observed with AUC ratios yielded more significant results (r = 0.62; p < .01 and r = 0.51; p < .05 respectively). These data suggest a role for Proopiomelanocortin (POMC) derived peptides in the regulation of NK cell activity in AN, and multifaceted relationships between this particular immune function, on the one hand, and certain patterns of HPA axis function on the other.

Predictors of drug treatment response in obsessive-compulsive disorder.

BACKGROUND: Although a large body of evidence indicates the efficacy of pharmacotherapy in the treatment of obsessive-compulsive disorder (OCD), a considerable percentage of these patients do not respond. Very few studies focus on factors related to treatment response of OCD. The purpose of this study was to investigate which clinical factors are related to drug treatment response in OCD. METHOD: We examined 53 OCD patients treated with either clomipramine or fluoxetine for a period of 6 months, dividing the sample into "responders" and "nonresponders" to treatment. At admission, patients were evaluated using a semistructured clinical interview, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Hamilton Rating Scale for Depression, and the Hamilton Rating Scale for Anxiety. We then compared acute-phase patient characteristics and response to drug treatment. Response was defined as a decrease of at least 40% in the Y-BOCS total score and a rating of "improved" or "very improved" on the Clinical Global Impressions scale within 16 weeks of treatment and maintained over three consecutive evaluations. RESULTS: By the sixth month of treatment, 31 patients (58.5%) responded to either clomipramine or fluoxetine. Nonresponders had lower age at onset and longer duration of the disorder; in addition, they showed higher frequency of compulsions, washing rituals, chronic course, concomitant schizotypal personality disorder, and previous hospitalizations. A worse response to drug treatment was predicted in a stepwise multiple regression by (1) concomitant schizotypal personality disorder, (2) presence of compulsions, and (3) longer illness length. CONCLUSION: Our findings suggest that there are distinct types of OCD with respect to drug treatment response. They provide indirect evidence of treatment specificity by identifying characteristics responsive to different modalities, which may be of value in the selection of patients for alternative treatments.

A double-blind comparison of venlafaxine and fluoxetine for treatment of major depression in outpatients.

1. This was a randomized, double-blind comparison of the efficacy and safety of venlafaxine and fluoxetine in outpatients with major depression. 2. Three hundred fourteen patients were randomly assigned to either venlafaxine 37.5 mg twice daily or fluoxetine 20 mg once daily for a maximum of 8 weeks. 3. If the response was inadequate after two weeks of treatment, the dosage of venlafaxine could be increased to 75 mg twice daily. 4. A clinical response, defined as at least a 50% decrease from baseline in the total HAM-D score, was attained at week 6 in 72% of patients on venlafaxine and 60% of patients on fluoxetine (p = 0.023). 5. Among patients who increased their dose at 2 weeks, venlafaxine was significantly (p < 0.05) superior from week 3 onward on the HAM-D. 6. Venlafaxine 75 mg daily is comparable to fluoxetine, but at 150 mg daily, it may be superior to fluoxetine in outpatients with major depression who do not respond early to treatment.

Lymphocyte peripheral benzodiazepine receptor mRNA decreases in obsessive-compulsive disorder.

The relative content of peripheral benzodiazepine receptor (pBR) mRNA was examined by reverse transcriptase-polymerase chain reaction in lymphocytes of obsessive-compulsive disorder (OCD) patients, according to their clinical course of illness. pBR mRNA significantly decreased only in chronic OCD patients (n=8) as compared to controls (n=10), whereas no significant changes were observed in episodic OCD patients (n=7). We suggest that modulation of pBR gene expression might delineate a clinical heterogeneity in OCD.

The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia.

Previous studies have reported that the cAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders. Abnormalities in the cAMP-dependent protein kinase have also been reported in platelets of patients with obsessive compulsive disorder and schizophrenia. However, it remains to be determined whether abnormalities in Rap1 are specifically related to affective disorders or may also be present in schizophrenia and obsessive compulsive disorder. Thus, we investigated Rap1 in platelets from 12 drug-free patients with obsessive compulsive disorder, ten drug-free patients with schizophrenia, and 20 healthy subjects. While no difference was observed in the levels of Rap1 between groups, the phosphorylation state of Rap1 was significantly lower in patients with obsessive compulsive disorder than in schizophrenic patients and controls. These data further support the idea that abnormalities of cAMP signalling pathway could be associated, albeit in a somewhat different way, with several psychiatric disorders.

A study of 3H-PK 11,195 binding to "peripheral-type" benzodiazepine receptors on human lymphocytes. Evidence of decreased binding in hepatic encephalopathy.

In an attempt to assess the involvement of the "peripheral-type" benzodiazepine receptors (pBDZR) in hepatic encephalopathy (HE), we examined the binding of the isoquinoline carboxamide derivative 3H-PK 11,195 to lymphocyte membranes from a group of patients with liver cirrhosis with or without clinical signs of HE and normal controls. Lymphocyte 3H-PK 11,195 binding is saturable, with high affinity and presents the pharmacological specificity corresponding to pBDZR. A significant 40% decrease in the number of 3H-PK 11,195 binding sites, without a concomitant change in the apparent affinity, is observed in the group with HE as compared to the controls, but not in that with liver diseases without HE. The decrease in binding capacity correlates significantly with the clinical grading of HE, but not with age, sex, aetiology of cirrhosis or presence of surgical shunt. In contrast to the reduction of pBDZR, 3H-N-methylscopolamine binding to lymphocyte muscarinic receptors is not affected in HE. These findings are consistent with a role for pBDZR in HE and may stimulate studies of endogenous modulators and pharmacological agents for these receptors in the disease.

Delineating psychopathologic clusters within dysthymia: a study of 512 out-patients without major depression.

BACKGROUND: The literature indicates that emotional-cognitive symptoms are much more characteristic of dysthymia than the vegetative and psychomotor symptoms of major depression, yet this is insufficiently emphasized in the official criteria listed in the criteria of the American Psychiatric Association. Furthermore, as previous studies have examined these symptoms more in relation to prevalence than to possible symptom aggregation, in the present analyses we address both aspects. METHODS: In two multicenter collaborative trials, 512 out-patients meeting the symptom criteria of DSM-III-R dysthymia but without major depression were recruited. In this respect they conformed to the conceptual framework of ICD-10 which tends to restrict dysthymia to a subthreshold depression without excursion into severe depressive episodes. The Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms. RESULTS: Symptoms most frequently observed, besides depressed mood (100% by definition), were 'low energy or fatigue' (96%) and 'poor concentration or indecisiveness' (88%), followed by 'low self-esteem' (80%), 'insomnia or hypersomnia' (77%), 'poor appetite or overeating' (69%) and 'feeling of hopelessness' (42%). Interestingly, in the subjects with fewer than five symptoms, the most frequent were low energy or fatigue (93%), poor concentration or indecisiveness (79%) and low self-esteem (77%), the other symptoms being present in no more than half the sample. MADRS factor analysis identified two main factors: the first consisting of apparent and reported sadness, and the second concentration difficulties and lassitude. HAM-A factor analysis identified two factors clearly differentiating somatic and psychic symptoms. LIMITATIONS: Because suicidal patients were excluded on the ground of human subject concerns, our sample is representative of the milder range of symptomatology within the spectrum of dysthymia. This may in part explain the low prevalence of neurovegetative symptoms. CONCLUSION: Despite this, the present study involves the largest sample of pure dysthymia ever studied. Our results indicate that dysthymic disorder appears to primarily involve psychologic symptoms. The psychological symptoms themselves seem to cluster into sadness versus mental fatigue; as for anxiety symptoms, they appear divisible into somatic and psychic clusters, with the latter prevailing in dysthymia. Dysthymia proper, dominated by negative affectivity, might be distinguishable from a 'neurasthenic' subform dominated by low energy or 'deficit' symptoms at mental and physical levels.

Recognition and treatment of dysthymia in elderly patients.

This review focuses on recent literature concerning dysthymia in the elderly population. Epidemiological data and clinical picture, diagnostic and therapeutic issues are evaluated and discussed. Although depressive syndromes are common in older patients, prevalence rates of dysthymia in the elderly are lower than in younger adults. This finding may be the consequence of the diagnostic criteria provided by the Diagnostic and Statistical Manual of Mental Disorders (DSM) which are not specific for older adults. Other factors that complicate making diagnoses of dysthymia in older individuals are comorbid general conditions, cognitive deterioration and disorders, and frequent adverse life events (e.g. bereavement). The effects of these factors should be better defined to clarify whether elderly dysthymia is underestimated and if modified diagnostic criteria should be provided. A few researchers have identified a series of clinical features that are clearly different in the elderly and in young adult patients with dysthymia. These features are particularly related to the late onset and to the peculiar comorbidity of this disorder and suggest that dysthymia is a different disorder in the elderly. Drug treatment of depressive conditions in the elderly is currently based on new antidepressants [selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors, norepinephrine (noradrenaline) reuptake inhibitors, benzamides]. These agents have an improved adverse effect profile compared with some of the older agents. Moreover, very few systematic studies have been performed using these drugs in samples of older patients with dysthymia and available data do not allow conclusions on drug choice and dosage. Besides, no specific data are available concerning the psychotherapy of dysthymia in this age group. All these topics need to be further investigated in studies comparing the elderly with control groups of younger patients with dysthymia.

Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline. AMILONG investigators.

Two hundred and fifty patients participated in a 6-month, double-blind study to evaluate safety and efficacy of a medium-term treatment with amisulpride 50 mg/day versus amitriptyline 25-75 mg/day in dysthymia. Patients in treatment groups (165 amisulpride; 85 amitriptyline) were well balanced for demographic and baseline characteristics. A total of 139 patients (93 amisulpride, 46 amitriptyline) completed the study with no statistically significant differences in reasons for premature termination between the two groups. A tendency towards a higher incidence of treatment-emergent adverse events with amitriptyline was observed (73% versus 64% amisulpride). In the amitriptyline group, a statistically significantly higher incidence of central nervous system (41% versus 24%, p=0.004) and autonomic nervous system disorders (45% versus 16%, p < 0.0001) was reported. Conversely, endocrine disorders were more frequent with amisulpride (18% versus 7%, p=0.023). Efficacy was a secondary end-point. Results of the symptom rating scales indicate that both drugs were equally effective: 60% and 62% of patients under amisulpride and amitriptyline, respectively, achieved a reduction > or = 50% of the Montgomery and Asberg Rating Scale total score at end-point. On the item 'global improvement' of the Clinical Global Impression, 67% of amisulpride and 68% of amitriptyline patients were rated as 'very much' or 'much' improved. Results of the present study in a large patient population further confirm the safe use of amisulpride in dysthymia and support its administration upon a medium-term treatment period.

Double-blind study of the efficacy and safety of sertraline versus fluoxetine in major depression.

An eight-week double-blind, multicentre study was performed to evaluate the efficacy and safety of sertraline vs. fluoxetine in the treatment of major depression (DSM-III-R). There were 108 out-patients, from nine Italian centres, entered into the study, of whom 88 were evaluable (48 sertraline, 40 fluoxetine). The final mean daily dose of sertraline was 72 mg and for fluoxetine it was 28 mg. Both treatment groups showed a statistically significant improvement from baseline at one week, and this was maintained until the end of treatment for all of the following measures: Hamilton Rating Scales for Depression and Anxiety, the Montgomery Asberg Depression Rating Scale, Clinical Global Impressions Scale, Zung Self-Rating Scale for Anxiety and the Leeds Sleep Evaluation Questionnaire. Although there was a numerical advantage for sertraline on several efficacy measures, there was no statistically significant difference found between the treatment groups. The incidence of adverse events was similar for both treatments; 40.4% for sertraline and 39.3% for fluoxetine. However, adverse events were generally rated by patients as of lower severity in the sertraline group. In addition, for the fluoxetine group, there was a higher incidence of agitation, anxiety and insomnia than for sertraline. Sertraline was considered to be better tolerated than fluoxetine overall, since only 9.6% of sertraline-treated patients discontinued treatment due to therapy failure whereas in the fluoxetine-treated group this figure was 19.6%. By contrast, 13.5% of sertraline-treated patients discontinued prematurely because of clinical improvement, compared with 10.7% of fluoxetine-treated patients.

Recent life events and obsessive-compulsive disorder (OCD): the role of pregnancy/delivery.

Conflicting results have been reported on the possible role of life events in triggering OCD onset. Moreover, pregnancy and/or delivery, among life events, appear to influence the OCD course and, in some cases, appear related to its onset. Our purpose was to assess the occurrence of potentially traumatizing events among patients with OCD. The study also provides an initial exploration of the association between OCD and pregnancy or delivery. The number and type of stressful life events which occurred in the 12 months before the onset of OCD were determined for both OCD patients (N = 68, 33 women and 35 men) and a group of comparison subjects (N = 68, 33 women and 35 men) by using a semistructured interview in accordance with Paykel's list. The results did not show a significant excess of life events in patients compared with healthy subjects. No differences were detected between OCD patients according to gender. When examining the type of events, OCD female individuals were found to be more likely than normal female subjects to report exposure to postpartum events, and high rates of obstetric complications were observed in these patients. Subjects with postpartum OCD had significantly higher rates of aggressive obsessions to harm the newborn. OCD male subjects did not show an association between a specific event and onset of the disorder. The findings confirm that the postpartum period represents a risk factor for OCD in some individuals, and suggest that obstetric complications may be relevant to the development of the disorder.

Type I and type II schizophrenia: relations between tonic electrodermal activity and clinical ratings before and after haloperidol treatment.

To test the hypothesis that schizophrenic patients with positive vs. negative symptoms show different tonic electrodermal patterns, 26 patients with Type I schizophrenia and 19 patients with Type II schizophrenia were evaluated before and after 2 weeks of haloperidol treatment (standard daily dose = 4.5 mg). Clinical assessments were made with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms. Skin conductance level (SCL) and spontaneous fluctuations (SF) frequency were recorded for each patient. Before treatment, Type I patients showed higher SCL and SF compared with Type II patients; after treatment, a significative decrease of clinical and psychophysiological variables was found only in Type I patients.

Onset of obsessive-compulsive disorder: premorbid conditions and prodromal phase.

This article focuses on the clinical onset of obsessive-compulsive disorder (OCD), specifically addressing the age of onset, gradual and acute onset, and whether there are some types of premorbid conditions or a prodromal phase that predispose individuals to the onset of OCD. Clinical and epidemiological studies have come to different conclusions regarding age at onset as well as regarding differences between the sexes. Data gleaned from research to date have demonstrated a relationship between OCD and obsessive-compulsive personality disorder (OCPD), although OCPD does not appear to be the more prevalent personality disorder among patients with OCD. Preliminary research has suggested that Axis I disorders may predispose individuals to OCD onset; however, the significance of this relationship remains to be clarified. Evidence of the association between OCD and subthreshold obsessive-compulsive syndrome suggests that these disorders lie on a continuum of severity, with some cases developing OCD while others do not.

The role of recent life events in the onset of obsessive-compulsive disorder.

Although many investigations into the onset of obsessive-compulsive disorder (OCD) suggest the occurrence of potential life events as triggering factors, such an association has not been well studied to date. The purpose of the present paper is to review the literature on OCD onset in order to determine whether OCD is triggered by recent life events, what specific events may serve as triggers, and the clinical and research implications of these factors. Overall, the available studies do not consistently support the theory that OCD is triggered by specific antecedent life events. However, there is a body of evidence to support the theory that the specific life events of pregnancy and birth of a child can trigger OCD. This apparent association has led to the investigation of certain neurohormonal factors, including changes in estrogen or oxytocin levels, that may be of etiopathogenetic significance in OCD. Confirming such associations may allow clinicians to provide more targeted preventive and therapeutic interventions.

Gender-related clinical differences in obsessive-compulsive disorder.

The purpose of the present study was to investigate the gender-related differences of clinical features in a sample of obsessive-compulsive (OCD) patients. One hundred and sixty outpatients with a principal diagnosis of obsessive-compulsive disorder (DSM-IV, Y-BOCS = 16) were admitted. Patients were evaluated with a semi-structured interview covering the following areas: socio-demographic data, Axis I diagnoses (DSM-IV), OCD clinical features (age at onset of OC symptoms and disorder, type of onset, life events and type of course). For statistical analysis the sample was subdivided in two groups according to gender. We found an earlier age at onset of OC symptoms and disorder in males; an insidious onset and a chronic course of illness were also observed in that group of patients. Females more frequently showed an acute onset of OCD and an episodic course of illness; they also reported more frequently a stressful event in the year preceding OCD onset. A history of anxiety disorders with onset preceding OCD and hypomanic episodes occurring after OCD onset was significantly more common among males, while females showed more frequently a history of eating disorders. We found three gender-related features of OCD: males show an earlier age at onset with a lower impact of precipitant events in triggering the disorder; OCD seems to occur in a relative high proportion of males who already have phobias and/or tic disorders; and a surfeit of chronic course of the illness in males in comparison with females.

Suicide and depression.

Suicide is difficult to predict, has the potential for catastrophic outcome, and is preventable. Although some persons admit freely to feelings of sadness and wishes for their lives to be over, others offer little, if any, overt forecasting of impending self-harm. Many of these same people seek help under other auspices. Approximately two thirds of those who commit suicide had visited a physician during the preceding month. Recognizing the signs and symptoms with which suicide-prone patients present to emergency departments is central to preventing unnecessary death, injury, and disability caused by failed attempts. The common presentations of patients at risk for suicide and some of the psychiatric conditions that carry a risk for suicide are reviewed.