GAMIAN-Europe/BEAM survey II: cross-national analysis of unemployment, family history, treatment satisfaction and impact of the bipolar disorder on life style.

OBJECTIVES: In a previous report, we described the global analysis of the 'GAMIAN-Europe/BEAM survey' carried out in order to gain a better understanding of what is like to live with a bipolar disorder (BD). We report here on a cross-national analysis of unemployment, family history, side effects, treatment satisfaction and the impact the disorder had and has on patients' perception of life style and quality of life. METHODS: The methodology has been described in the previous report [Morselli PL and Elgie R, J Bipolar Disord (2003) 5, 265]. The analysis was carried out on the data derived from eight countries (France, Italy, Holland, Portugal, Russia, Scotland, Spain and Sweden) on a total of 968 respondents. Data from three other countries were not evaluated because of the low number of respondents. RESULTS: The data suggest that the problems and difficulties encountered by bipolar patients are similar throughout the various European countries, regardless of the political, social or cultural settings. The disease leads to a very high rate of unemployment and has a significant negative impact on the perception of the quality of life, both within and outside the family. Data also indicate a high level of family history. Considering the many variables analysed in the different nations, trans-national differences are often present for a given specific issue. However, with regard to the core issues, no significantly different patterns appear to emerge for any given nation. The current attitude towards the disorder displays an increased insight about the condition on the part of patients. There is also a definite trend towards an improvement in their perception of the disease with an evident minor or reduced impact of the disorder on the life-style of patients. CONCLUSIONS: Globally, the data indicate that in all participating countries there has been, in recent years, a consistent improvement in the 'perceived quality of life' of the 'informed patient' with an increased insight into the condition and an enhanced rate of compliance. Nevertheless, a lot still needs to be done to markedly improve the 'social functioning' and the 'social integration' of those who suffer from BD. The data reported underline some of the issues that still represent a truly onerous burden for BD patients in whichever European country they may live.

Initiation of and adherence to treatment for mental disorders: examination of patient advocate group members in 11 countries.

OBJECTIVE: Greater understanding of the help-seeking process is needed to reduce the level of unmet need for mental health treatment. DESIGN: Cross-sectional mail survey. STUDY POPULATION: The study population consisted of 3,516 respondents to a survey of members of 14 patient advocacy groups in 11 countries. Respondents reported whether they initiated and adhered to the treatment most recently recommended to them. OUTCOMES: Crude and adjusted likelihoods of initiating and adhering to recommended treatment were studied. RESULTS: The vast majority of respondents reported initiating the most recent treatment recommended to them (94%), and most of those who initiated treatment also adhered to such treatment (83%). Predictors of initiation by the respondents included higher levels of education, having pharmacotherapy recommended to the respondent, and having received explanations about the diagnosis and treatment. Predictors of adherence to therapy included male gender, receipt of pharmacotherapy, and presence of insurance coverage. Side effects were an important reported reason for treatment dropout, with 44% of respondents reporting lifetime treatment dropout due to side effects. CONCLUSIONS: Successful initiation and adherence to mental health treatments depend critically on patients' knowledge and awareness, clinicians' communication skills, treatment side effects, and barriers such as lack of insurance. Further study and intervention focused on these modifiable factors are needed to improve the adequacy of mental health treatment.

Duration between onset and time of obtaining initial treatment among people with anxiety and mood disorders: an international survey of members of mental health patient advocate groups.

BACKGROUND: Self-report data obtained from members of advocate groups for patients with anxiety or mood disorders in 11 countries were used to study time to initial professional help-seeking after incident episodes. METHOD: Data were taken from 3516 self-administered questionnaires completed by members of GAMIAN, an international consortium of mental health patient advocate groups. Reports about age at onset and age at first seeking treatment were obtained retrospectively. RESULTS: Approximately 40% of respondents reported that they sought treatment in the same year as the first onset of their disorder. The median delay in help-seeking was 8 years for the remainder of respondents. Synthetic cohort analysis suggests that delays have decreased in recent cohorts. However, time to initial help-seeking in all cohorts and all countries was found to be inversely related to age at onset. CONCLUSIONS: Although caution is needed in generalizing the results beyond members of patient advocate groups, the key patterns found here were also found in previous analyses of general population surveys carried out in the US and Canada. The critical and consistent finding in all these studies is that presumably curable adolescents with early-onset disorders are, in effect, ignored by the treatment system in these countries. Aggressive outreach and intervention among early-onset cases might prove to be a cost-effective approach both to prevent the onset of secondary disorders and to improve success in treating primary disorders.

Present and future role of Mental Illness Advocacy Associations in the management of the mentally ill: realities, needs and hopes at the edge of the third millennium.

OBJECTIVE: The purpose of the present review is the analysis of the development and current status of the Mental Illness Advocacy Movement in the USA and in Europe, as well as of the role such a movement is playing in the management of the mentally ill. METHODS: Information on the issue has been collected via literature search and several personal inquiries and contacts with different Mental Illness Advocacy Groups in the USA and in Europe. RESULTS: The findings indicate that the Mental Illness Advocacy Movement is very alive and in full growth. Its role in the management of the mentally ill has become more and more important over the years. In several countries, it makes it possible to overcome some of the deficiencies of the National or Private Health Services. Thanks to the actions of the various Mental Illness Advocacy Groups, today, patients and families are more and better informed of their conditions and their rights. In many cases, this results in earlier diagnosis, better compliance and better outcomes. However, despite significant improvement in the status of the mentally ill patient, much still remains to be done. CONCLUSIONS: We need an improved dialogue with mental heath providers, public administrators, mental health policy makers, mass media and politicians. The dialogue between primary care team and the specialist must also be improved. A global alliance for action is needed to ensure better and more available services to those who suffer from mental disorders.

Prevalence of nightmares and their relationship to psychopathology and daytime functioning in insomnia subjects.

A representative sample of 5,622 subjects between 15 and 96 years of age from the noninstitutionalized general population of France were interviewed by telephone concerning their sleeping habits and sleep disorders. The interviews were conducted using the Sleep-Eval knowledge-based system, a nonmonotonic, level 2 expert system with a causal reasoning mode. Questions investigated nightmares, based on the Diagnostic and Statistical Manual, fourth edition (DSM-IV), definition, psychopathological traits, and included 12 other groups of information, including sociodemographics, sleep-wake schedule, daytime functioning, psychiatric and medical history, and drug intake. The data from 1,049 subjects suffering from insomnia were considered for this analysis. Bivariate analyses, logistic regression analysis using the method of indicator contrasts for the investigation of independent variables, and calculation of significant odds ratios were performed. Nightmares were reported in 18.3% of the surveyed insomniac population and were two times higher in women than in men. The following factors were found to be significantly associated with nightmares 1) sleep with many awakenings, 2) abnormally long sleep onset, 3) daytime memory impairment following poor nocturnal sleep, 4) daytime anxiety following poor nocturnal sleep, and 5) being a woman. There was a strong association between the report of nightmares in women and the presence of either a depressive disorder, anxiety disorder, or both disorders together. When the effects of major psychiatric disorders were controlled for, nightmares were significantly associated with being a woman, feeling depressed after a poor night's sleep, and complaining of a long sleep latency. Nightmares can lead to a negative conditioning toward sleep and to chronic sleep complaints. Considering the frequency of nightmares in an adult insomniac population and the significant relationship between nightmares and certain subgroups, nightmares should receive more attention in patients, especially women complaining of disrupted sleep, as high rates of psychiatric disorders were found in this specific group.

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.

Influence of the rate of intravenous administration of eliprodil (SL 82.0715), a new anti-ischaemic agent, on its distribution in rat plasma and tissues.

This investigation studied the possible effect of different iv administration rates (bolus and infusions) of eliprodil, a new anti-ischemic agent, on the drug distribution in various body compartments. Following bolus administration of a 15-mg kg-1 dose, plasma concentrations were best fitted by a 3-compartment open model of t1/2 alpha = 14 sec, t1/2 beta = 4 min, and t1/2 gamma = 1.8 hr. Plasma and heart Cmax values were lowered by decreasing the infusion rate (the 15-mg dose was administered in 15 or 60 min) whereas brain Cmax values were not modified. In contrast, AUC values did not depend upon the rate of infusion. The present findings may have important implications in relating tissue concentrations with the desired therapeutic effect as well as with the side effects of the drug at its sites of action within brain and heart. The use of a simplified model built with plasma and tissue kinetic parameters following bolus injection allows one to predict the amount of drug present in the organs according to the mode of administration, but not the evolution of tissue to plasma ratio during the infusions.

Zolpidem and rebound insomnia--a double-blind, controlled polysomnographic study in chronic insomniac patients.

In a parallel-group, placebo-controlled, polysomnographic study with randomization, the possible occurrence of rebound insomnia was evaluated in 24 patients suffering from moderate to severe chronic insomnia and receiving either triazolam 0.5 mg, zolpidem 10 mg, or placebo. Treatment duration was 27 nights, followed by three placebo-controlled withdrawal nights. Both drugs showed significant efficacy compared to placebo during the active treatment period. A trend toward tolerance was noted in the triazolam group but not in the zolpidem one. The increase in total sleep time in the zolpidem group was accompanied by an increase in the number of sleep cycles. When active treatment was discontinued, clear rebound insomnia was present in the triazolam group while it was not possible to observe any rebound in the placebo and zolpidem groups. Subjective feelings of the patients, which were assessed by means of visual analog scales, correlated well with polysomnographic data. Our findings tend to indicate that, even after long-term treatment, zolpidem does not induce rebound insomnia or daytime anxiety.

Comparison of the efficacy, safety and withdrawal of alpidem and alprazolam in anxious patients.

BACKGROUND: We investigated whether a new non-benzodiazepine anti-anxiety drug, alpidem, produces weaker withdrawal symptoms than alprazolam. METHOD: Under a double-blind procedure, 122 patients suffering from general anxiety disorders were randomly allocated to either alpidem (50 mg, three times a day) or alprazolam (0.5 mg, three times a day) for six weeks, followed by a two-week placebo withdrawal phase. The diagnosis of withdrawal syndrome (WS) was made, in blind conditions, on the basis of the Withdrawal Symptom Check List (WSCL), after one or two weeks of discontinuation of active treatment. RESULTS: The WS occurred significantly less frequently in the alpidem group (n = 10, 18%) than in the alprazolam group (n = 26, 48%). Typical withdrawal symptoms on the WSCL were also significantly less severe (P = 0.044) in the alpidem group compared with the alprazolam group. CONCLUSIONS: Alpidem may be a valid alternative to current benzodiazepine anxiolytic therapy because it produces fewer and weaker withdrawal symptoms than alprazolam and is better tolerated.

EEG profile of intravenous zolpidem in healthy volunteers.

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

EEG profile of litoxetine after single and repeated administration in healthy volunteers.

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double-blind, cross-over, placebo-controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4-T4, F3-T3, T4-02 and T3-01) was done up to 12 h post-dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose-related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml-1. With repeated administrations, the pharmacodynamic steady-state was achieved as the increase in beta 2 energies was the same before and 12 h post-dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml-1 with the 10 mg dosage and from 8 to 18 ng ml-1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Population approaches in drug development. Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software.

An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.

Effects of alpidem in anxious elderly outpatients: a double-blind, placebo-controlled trial.

The efficacy and safety of alpidem, a new anxiolytic imidazopyridine, were compared with those of placebo in anxious elderly patients (65-80 years) by means of a randomized, double-blind, parallel group study. Following a 7-day "placebo run-in," 40 anxious patients were randomized to receive either alpidem or placebo. Daily doses ranging from 75 to 150 mg (25-50 mg t.i.d.) were administered for 3 weeks. Hamilton Rating Scale for Anxiety (HRSA), State Trait Anxiety Inventory (STAI-X1), Visual Analogue Scale (VAS), and Clinical Global Impression (CGI) were used on days 0, 3, 7, 14, and 21 for assessing efficacy. Psychomotor and mnesic performances were evaluated at the same time by means of the Digit Symbol Substitution Test (DSST), the Grünberger's test for fine motor coordination, and the Hawie's test for immediate memory. Possible adverse events were also recorded during the five visits. The anxiolytic efficacy of alpidem was significantly (p < 0.01) superior to that of placebo in all the rating scales adopted. The anxiolytic action was clearly evident from day 7. For most of the patients the active dose was 25 mg t.i.d. No relevant adverse effects were observed in both groups. No impairment of psychomotor and mnesic performances could be observed in the alpidem group. Alpidem is a new interesting anxiolytic drug for anxious elderly patients because it appears remarkably safe and, at effective doses, it does not impair psychomotor performances and cognitive functions.

Assessment of the anticholinergic effect of the new antihistamine mizolastine in healthy subjects.

1. Twelve healthy subjects were enrolled in a double-blind placebo controlled cross-over study in order to assess the possible anticholinergic effects of four doses of a new antihistamine compound, mizolastine, compared with hyoscine butylbromide (HBB) used as a reference anticholinergic drug. 2. Although mizolastine, a potent and selective H1-receptor blocker has no affinity for muscarinic receptors and does not antagonize the effects of carbachol in rodents, a study was initiated to investigate its effects on various effectors possessing muscarinic receptors (eye, heart, sweat gland, salivary gland). 3. HBB (40 mg, s.c.) impaired accommodation, decreased salivary flow and inhibited cardiac sinus arrhythmia. Pupil diameter and maximum constriction speed, carbachol-induced skin sweating and Valsalva ratio were unaffected. 4. Mizolastine (5, 10, 20, 40 mg p.o.) did not affect any parameter at any time point, demonstrating a lack of anticholinergic effect.

Determination of zolpidem, a new sleep-inducing agent, and its metabolites in biological fluids: pharmacokinetics, drug metabolism and overdosing investigations in humans.

For the determination of zolpidem, a new sleep inducer, and its metabolites in human plasma and urine, three methods were developed that are suitable for pharmacokinetics, drug metabolism and overdosing investigations. The methods used for pharmacokinetic and drug metabolism studies are based on column-switching high-performance liquid chromatography; they do not require any sample manipulation because the plasma or diluted urine is injected into a pre-column where clean-up and preconcentration take place. The analytes are transferred by valve-switching to the C18 analytical column for chromatography. To investigate overdose cases, urine samples only are used: the method is simple, because the diluted urine can be injected directly into the analytical column (phenyl type). This allows the identification and quantification of the principal urinary metabolite of zolpidem, the unchanged drug being practically undetectable. All the methods use fluorescence detection, which affords high sensitivity and selectivity. It is necessary to use a method capable of the determination of metabolites even if these are apparently pharmacologically inactive, because in different physiopathological populations the qualitative and quantitative metabolic profiles of zolpidem could be different. The method designed for the investigation of (accidental or deliberate) overdose cases is, as required on such occasions, simple and rapid, with good selectivity with respect to commonly prescribed psychotropic drugs.

Pharmacodynamics and pharmacokinetics of mizolastine (SL 85.0324), a new nonsedative H1 antihistamine.

The antihistaminic activity, clinical safety, and pharmacokinetics of mizolastine (SL 85.0324) were studied in a 5-way, double-blind crossover study of ten healthy volunteers with doses of 1 to 75 mg. Inhibition of the histamine-induced wheal and flare showed clear dose-dependent antihistaminic activity beginning from the 2-mg dose with a maximum attained between 10 and 20 mg. The onset of action was rapid (one hour) and the effect persisted for more than 24 hours after a 10-mg dose or more. Mizolastine was well tolerated at doses up to 75 mg; subjective and objective signs of transient sedative activity were not observed at doses below 30 mg. The pharmacokinetic profile (rapid absorption with Tmax congruent to 1 h and elimination T1/2 of about eight hours) parallels the pharmacodynamic activity. Within the considered dose range, the pharmacokinetics was linear with no saturation phenomena.

The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice.

The safety and efficacy of 10 or 20 mg/day zolpidem, a new hypnotic belonging to the imidazopyridine class, were studied over a 180-day period in 96 patients with sleep disorders. The treatment was continued for a further 180 days by 49 of these patients. Follow-up information from 21 patients who discontinued treatment after 180 days showed no rebound insomnia or withdrawal signs. Efficacy of treatment with respect to reduction of sleep onset latency and number of nocturnal wakenings, and improvement in duration of sleep, quality of sleep and morning wakenings was found in nearly 90% of patients and was maintained in those patients who continued treatment for 360 days. This efficacy was achieved with a stable percentage of patients receiving 10 mg/day and 20 mg/day zolpidem from day 30 to the final visit. Zolpidem, therefore, has been shown to be an effective and safe hypnotic, and to be devoid of rebound and withdrawal effects.