Effect of ivabradine, a novel antianginal agent, on driving performance: A randomized, double-blind, placebo-controlled trial in healthy volunteers.

BACKGROUND AND OBJECTIVE: Ivabradine is a novel pure heart rate-lowering agent that selectively and specifically inhibits pacemaker I(f) current. Ivabradine has been shown to have antianginal and anti-ischaemic properties in patients with stable angina pectoris. Because f channels are also present in the retina, visual symptoms represent a potential adverse effect of ivabradine that may affect driving performance. The aim of the study was to investigate whether visual symptoms reported after repeated administration of ivabradine at high doses could affect driving performance. METHODS: This randomized, double-blind, placebo-controlled study was conducted in healthy volunteers. Seventy-five subjects were randomized to ivabradine 10 mg twice daily and 15 subjects to placebo for 7 days, followed by ivabradine 15 mg twice daily or placebo, respectively, for a second week if no visual symptoms were reported. As soon as a subject reported visual symptoms between day 1 and day 14, he or she was assigned to perform driving simulator sessions. If no visual symptoms were reported, driving simulator sessions were performed after 14 days' treatment. Driving parameters included absolute speed, deviation from the speed limit, deviation from the ideal route and number of collisions in different light conditions. RESULTS: In the daylight and evening driving sessions, there was no significant difference in all measured parameters (as indicated by absolute speed, deviation from the speed limit and deviation from the ideal route results) between the ivabradine and the placebo groups, independently of visual symptoms. No collisions were observed in the entire study irrespective of the testing conditions and the treatment groups assessed. No relevant differences were seen in the ivabradine subsets of subjects reporting visual symptoms or not. CONCLUSION: This study suggests that ivabradine administered at dosages higher than those recommended in the clinic did not affect driving performance regardless of whether or not visual symptoms were present.

Suicidality in opioid-dependent subjects.

We determined suicide attempt characteristics in 160 opioid-dependent subjects. Three aspects of suicide vulnerability were also examined: familial aggregation of suicidal behaviors, degree of aggression/impulsivity, and smoking. Forty-eight percent of subjects had a personal history of suicide attempt. A personal history of suicide attempt was associated with an early onset of heroin use, but not with gender differences. A family history of suicide was a progressive risk factor for suicide attempt. Subjects with a personal history of suicide attempt had a higher degree of aggression/impulsivity and smoked more cigarettes. In conclusion, opioid-dependent subjects who attempt suicide show familial aggregation and clinical expressions of suicidal liability similar to those described in other psychiatric groups.

Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, placebo-controlled study.

PURPOSE: Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS: Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS: Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION: This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.

Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates.

Evidence supports that hyperactivity of the hypothalamic-pituitary-adrenal axis has a pivotal role in the psychobiology of severe depression. The present study aimed at assessing hypothalamic-pituitary dopaminergic, noradrenergic, and thyroid activity in unipolar depressed patients with melancholic and psychotic features and with concomitant hypercortisolemia. Hormonal responses to dexamethasone, apomorphine (a dopamine receptor agonist), clonidine (an alpha 2-adrenoreceptor agonist) and 0800 and 2300 h protirelin (TRH) were measured in 18 drug-free inpatients with a DSM-IV diagnosis of severe major depressive disorder with melancholic and psychotic features showing cortisol nonsuppression following dexamethasone and 23 matched hospitalized healthy controls. Compared with controls, patients showed (1) lower adrenocorticotropin and cortisol response to apomorphine (p<0.015 and <0.004, respectively), (2) lower growth hormone response to clonidine (p=0.001), and (3) lower responses to TRH: 2300 h maximum increment in serum thyrotropin (TSH) level (p=0.006) and the difference between 2300 and 0800 h maximum increment in serum TSH values (p=0.0001). Our findings, in a subgroup of unipolar depressed inpatients with psychotic and melancholic features, are compatible with the hypothesis that chronic elevation of cortisol may lead to dopaminergic, noradrenergic and thyroid dysfunction.

Treatments in depression.

Major depression is believed to be a multifactorial disorder involving predisposing temperament and personality traits, exposure to traumatic and stressful life events, and biological susceptibility. Depression, both unipolar and bipolar, is a "phasic" disease. Stressful life events are known to trigger depressive episodes, while their influence seems to decrease over the course of the illness. This suggests that depression is associated with progressive stress response abnormalities, possibly linked to impairments of structural plasticity and cellular resilience. It therefore appears crucial to adequately treat depression in the early stages of the illness, in order to prevent morphological and functional abnormalities. While evidence suggests that a severely depressed patient needs antidepressant drug therapy and that a non-severely depressed patient may benefit from other approaches (ie, "nonbiological"), little research has been done on the effectiveness of different treatments for depression. The assertion that the clinical efficacy of antidepressants is comparable between the classes and within the classes of those medications may be true from a statistical viewpoint, but is of limited value in practice. The antidepressant drugs may produce differences in therapeutic response and tolerability. Among the possible predictors of outcome in depression treatment, those derived from clinical assessment, neuroendocrine investigations, polysomnographic sleep parameters, genetic variables, and brain imaging techniques have been extensively studied. This article also reviews therapeutic strategies used when initial treatment fails, and describes briefly new concepts in antidepressant therapies such as the regulation of disturbances in circadian rhythms. The treatment of depressive illness does not stop with treatment of acute episodes, and has to be envisaged as a continuous therapeutic intervention, of which we are still not able to determine the optimal duration of treatment and the moment that it should be ceased.

Facial expressiveness in patients with schizophrenia compared to depressed patients and nonpatient comparison subjects.

OBJECTIVE: Blunted affect is a major symptom in schizophrenia, and affective deficits clinically encompass deficits in expressiveness. Emotion research and ethological studies have shown that patients with schizophrenia are impaired in various modalities of expressiveness (posed and spontaneous emotion expressions, coverbal gestures, and smiles). Similar deficits have been described in depression, but comparative studies have brought mixed results. Our aim was to study and compare facial expressive behaviors related to affective deficits in patients with schizophrenia, depressed patients, and nonpatient comparison subjects. METHOD: Fifty-eight nondepressed inpatients with schizophrenia, 25 nonpsychotic inpatients with unipolar depression, and 25 nonpatient comparison subjects were asked to reproduce facial emotional expressions. Then the subjects were asked to speak about a specific emotion for 2 minutes. Each time, six cross-cultural emotions were tested. Facial emotional expressions were rated with the Facial Action Coding System. The number of facial coverbal gestures (facial expressions that are tied to speech) and the number of words were calculated. RESULTS: In relation to nonpatient comparison subjects, both patient groups were impaired for all expressive variables. Few differences were found between schizophrenia and depression: depressed subjects had less spontaneous expressions of other-than-happiness emotions, but overall, they appeared more expressive. Fifteen patients with schizophrenia were tested without and with typical or atypical antipsychotic medications: no differences could be found in study performance. CONCLUSIONS: The patients with schizophrenia and the patients with depression presented similar deficits in various expressive modalities: posed and spontaneous emotional expression, smiling, coverbal gestures, and verbal output.

Suicide attempts and family history of suicide in three psychiatric populations.

The influence of a family history of suicide on suicide attempt rate and characteristics in depression, schizophrenia, and opioid dependence was examined. One hundred sixty inpatients with unipolar depression, 160 inpatients with schizophrenia, and 160 opioid-dependent patients were interviewed. Overall, a family history of suicide was associated with a higher risk for suicide attempt, with high-lethality method, with repeated attempts, and with number of attempts, while the interaction between family history and diagnostic group was not significant. Thus, a positive family history of suicide was a risk factor for several suicide attempt characteristics independent of psychiatric diagnosis.

Neuroendocrine predictors of the evolution of depression.

Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.

A dimensional impulsive-aggressive phenotype is associated with the A218C polymorphism of the tryptophan hydroxylase gene: a pilot study in well-characterized impulsive inpatients.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, and association and linkage studies of its variants in suicidal and impulsive-aggressive behavior have brought conflicting results. This pilot study was designed to investigate whether TPH A218C genotypes could be associated with impulsive behavioral tendencies (IBTs) in consecutively admitted nonpsychotic nonorganic inpatients. Patients (20 females and 34 males; age, 38.8 +/- 11.8) did not differ from healthy nonimpulsive controls (16 females and 11 males; age, 35.2 +/- 10.2) regarding TPH genotypes, but in the patients, the number of IBT was related to the presence of the 218C allele. It was concluded that impulsive-aggressive behavior may be associated with the TPH genotype in well-characterized impulsive patients and that the present results stress the importance of considering impulsiveness-aggressiveness in studies investigating the relationship between suicidal behavior and TPH genotypes.

Dopamine and serotonin function in untreated schizophrenia: clinical correlates of the apomorphine and d-fenfluramine tests.

This study examined the prolactin (PRL), adrenocorticotropin (ACTH) and cortisol responses to the direct DA receptor agonist apomorphine (APO) and the selective 5HT-releasing agent d-fenfluramine (d-FEN) in 20 untreated inpatients with DSM-IV schizophrenia and without a history of suicide attempt, compared to 23 hospitalized healthy controls. We hypothesized that different patterns of responsiveness of the DA and 5-HT systems might be associated with specific schizophrenic symptom clusters. A positive correlation was observed between pituitary-adrenal response to APO and d-FEN tests (i.e. deltaACTH and deltacortisol) in the overall population and in schizophrenic patients. Pituitary-adrenal response to APO was lower in patients than in normal controls. Moreover, lower pituitary-adrenal response to APO and d-FEN was associated with increased severity of BPRS thought disturbance score. Lower pituitary-adrenal responses to APO (and to a lesser degree to d-FEN) differentiated paranoid from disorganized schizophrenic patients. Neither PRL suppression to APO, nor PRL stimulation to d-FEN were altered in schizophrenic patients. Our results suggest that decreased hypothalamic DA receptor activity (possibly secondary to increased presynaptic DA release) together with relatively decreased 5-HT tone characterize paranoid SCH, while normal hypothalamic DA receptor activity together with relatively increased 5-HT tone characterize the disorganized SCH subtype.

Increased adrenocorticotropin suppression following dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder.

Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have an enhanced sensitization of the hypothalamic--pituitary--adrenocortical (HPA) axis. However, few studies in adolescents have been performed. Fourteen sexually abused adolescent inpatients with DSM-IV PTSD (12 female, two male; mean +/- SD age, 16.2 +/- 1.9 years) were compared with 14 adolescent hospitalized controls (11 female, three male; mean age, 15.7 +/- 2.0 years). All subjects underwent a standard dexamethasone suppression test (DST, 1 mg given orally at 2300 h) five days after admission. Baseline blood samples were obtained at 0800 h, and the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 0800, 1600, and 2300 h. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post-DST ACTH levels were significantly lower in PTSD than in control adolescents (at 0800 h: P < 0.005; at 1600 h: P < 0.001; at 2300 h: P < 0.05). In patients, post-DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.

Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study.

BACKGROUND: The prevalence of generalized anxiety disorder (GAD) represents an important public health issue. Hydroxyzine, an antagonist of histamine receptors, showed both efficacy and safety in previous short-term double-blind studies over placebo in this pathology. The aim of the current study was to confirm those positive results over a 3-month period in adult outpatients. METHOD: This multicenter, parallel (hydroxyzine [50 mg/day]; bromazepam [6 mg/day]), randomized, double-blind, placebo-controlled trial included 2 weeks of single-blind run-in placebo, 12 weeks of double-blind randomized treatment, and 4 weeks of single-blind run-out placebo. Three hundred thirty-four of 369 selected outpatients with a diagnosis of GAD according to DSM-IV criteria and a Hamilton Rating Scale for Anxiety (HAM-A) total score >/= 20 were randomized before entering the double-blind period. The primary outcome criterion was the change in the HAM-A score from baseline to 12 weeks of double-blind treatment with hydroxyzine compared with placebo. RESULTS: In the intent-to-treat analysis, the mean +/- SD change in HAM-A scores from baseline to endpoint was -12.16 +/- 7.74 for hydroxyzine and -9.64 +/- 7.74 for placebo (p =.019). Results at endpoint for percentage of responders (p =.003) and remission rates (p =.028), Clinical Global Impressions-Severity scale score (p =.001), maintenance of efficacy (p =.022), and Hospital Anxiety and Depression scale score on day 84 (p =.008) also confirmed the efficacy of hydroxyzine over placebo. The study showed no statistically significant difference between hydroxyzine and bromazepam. Except for drowsiness, which was more frequent with bromazepam, safety results were comparable in the 3 groups. CONCLUSION: Hydroxyzine showed both efficacy and safety in the treatment of GAD and appears to be an effective alternative treatment to benzodiazepine prescription.

Serotonergic function and suicidal behavior in schizophrenia.

Recent studies suggest that altered serotonergic (5-HT) function, as assessed by lower prolactin (PRL) response to fenfluramine (FEN), a specific 5-HT releaser and uptake inhibitor, is associated with suicidal behavior in either depressed and personality disordered patients. The purpose of this study was to investigate, in schizophrenic patients, the relationship between suicidal behavior and PRL response to D-fenfluramine (D-FEN). A D-FEN test was performed in 18 healthy controls and 33 drug-free DSM-IV schizophrenic patients (12 with a history of suicide attempts, 21 without it). Schizophrenic patients with a history of suicide attempts showed a lower PRL response to D-FEN (Delta PRL) compared to schizophrenic patients without such history (P<0.04) and also compared to healthy controls (P<0.0003). Delta PRL did not differentiate schizophrenic patients without suicide attempts and controls. These findings could not be explained by PRL basal hormonal levels, age, sex, menstrual status, demographic or clinical characteristics. These results suggest that PRL response to D-FEN is a marker of suicidal tendencies also in schizophrenia, supporting the hypothesis that a dysfunction in serotonergic function is associated with suicidal behavior regardless of the psychiatric diagnosis.

Increased adrenocorticotropin suppression after dexamethasone administration in sexually abused adolescents with posttraumatic stress disorder.

Evidence suggests that individuals with posttraumatic stress disorder (PTSD) have enhanced sensitization of the hypothalamic-pituitary-adrenocortical (HPA) axis. Fourteen adolescent inpatients with DSM-IV PTSD were compared with 14 adolescent hospitalized controls without current axis I diagnoses. All patients were drug-naive. The causative trauma had been sexual abuse in all cases. Dexamethasone, 1 mg orally, was given at 11 PM, 5 days after admission. Baseline blood samples were obtained at 8 AM, and on the following day, adrenocorticotropin (ACTH) and cortisol levels were measured at 8 AM, 4 PM, and 11 PM. Clinical assessment included the Impact of Event Scale, Stanford Acute Stress Reaction Questionnaire, Beck Depression Inventory, and Coping Inventory for Stressful Situations. Post-DST ACTH levels were significantly lower in PTSD than in control adolescents (at 8 AM, P <0.005; at 4 PM, P <0.001; and at 11 PM, P <0.05). In patients, post-DST cortisol levels were reduced but not significantly. No correlations were found between ACTH and cortisol levels and time elapsed since trauma. These results demonstrate that sexually abused adolescents with PTSD show ACTH hypersuppression to DST, suggesting enhanced glucocorticoid receptor sensitivity in the pituitary.

Periodic arousals or periodic limb movements during sleep?

Periodic limb movements during sleep (PLMS), frequently found in polysomnograms, are often accompanied by arousals. The relationship is not clear, however, because PLMS can occur before, after or simultaneous to the electromyographic (EMG) activation. We describe the case of a patient who presents PLMS during two of three consecutive recording nights, and periodic arousals without motor activation on the other night. We conclude that, at least in some patients with a periodic limb movement disorder, there exists an underlying arousal disorder that produces periodic activation and deactivation of the cerebral cortex.

What is the clinical significance of periodic limb movements during sleep?

UNLABELLED: To understand better the clinical impact of periodic limb movements during sleep (PLMS) we analysed data from 51 patients who, following an adaptation night, presented a PLMS index > 5 during two consecutive nocturnal polysomnographic recordings. In the morning following each recording patients completed a questionnaire including five visual analogic scales (VAS): (1) I did not sleep well/I slept very well. (2) I feel very sleepy/I do not feel sleepy at all. (3) I feel very tired/I feel very dynamic. (4) Physically, I do not feel fit/physically, I feel fit. (5) Psychologically, I do not feel fit/psychologically, I feel fit. We compared the responses to these questions with the PLMS index, first inter-individually, then intra-individually between nights. RESULTS: The inter-individual analysis did not show correlations between the PLMS index and the questions (1) and (2). We found a significant correlation between the PLMS index and the questions (3) (r = -0.29; P < 0.05), (4) (r = -0.30; P < 0.05) and (5) (r = -0.39; P < 0.01). For the intra-individual analysis, we did not find correlations between the PLMS index and questions (1)-(3), but found a significant correlation with questions (4) (r = -0.28; P < 0.05) and (5) (r = -0.36; P < 0.01). CONCLUSION: PLMS per se, or the sleep changes induced by them, seem to be associated with decreased physical and psychological fitness on awakening.