Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies.

AIMS: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. METHODS: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. RESULTS: In rats, BI 474121 was associated with a dose-dependent increase (71% at the highest dose tested [3.0 mg kg-1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum-measured concentration CSF-to-plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose-adjusted geometric mean: 8.96% overall). BI 474121 2.5-40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure-related change from baseline ratio, BI 474121: 1.44-2.20 vs. placebo: 1.26). The most common treatment-emergent adverse event (AE) was mild-to-moderate post-lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. CONCLUSIONS: BI 474121 crosses the blood-brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. CLINICALTRIALS: gov number (NCT04672954).

A double-blind, randomized, placebo-controlled proof of concept study of the efficacy and safety of Lu AF11167 for persistent negative symptoms in people with schizophrenia.

Lu AF11167 is a selective, high-affinity inhibitor of PDE10A that modulates dopamine D1 and D2 receptor-mediated intraneuronal signalling without binding to these receptors. This randomized, double-blind, parallel-group, placebo-controlled study (NCT03793712) with open-label extension (NCT03929497) evaluated the efficacy of two fixed-flexible doses (1-2mg/day and 3-4mg/day) of Lu AF11167 in stable, non-acute patients with schizophrenia and persistent prominent negative symptoms. The studies were discontinued following a futility analysis of the double-blind study, and we report data collected up to study termination. Of the 210 patients screened, 162 were randomized, 111 completed the double-blind study and 96 entered the open-label study before early termination. The withdrawal rate due to impending relapse was low and comparable across treatment groups (n = 2-4 per group in the double-blind study and n = 1 in the open-label extension). Double-blind treatment with Lu AF11167 3-4mg was not superior to placebo in the reduction of Brief Negative Symptom Scale (BNSS) total scores from Baseline to Week 12 (primary endpoint); adjusted mean changes were -6.8 with placebo, -5.7 with Lu AF11167 1-2 mg group and -6.0 with Lu AF11167 3-4mg. Treatment with Lu AF11167 1-2mg also failed to separate from placebo on the primary endpoint. Neither dose group showed significant improvements versus placebo on any of the secondary efficacy measures exploring effect of treatment on overall symptomology, negative symptoms, positive symptoms, or functioning. Administration of Lu AF11167 was safe and well tolerated and adverse events were not a major reason for withdrawal from the study.

Intravenous vortioxetine to accelerate onset of effect in major depressive disorder: a 7-day randomized, double-blind, placebo-controlled exploratory study.

This 7-day randomized, double-blind, placebo-controlled fixed-dose study (NCT03766867) explored the potential for accelerating the onset of antidepressant efficacy of single-dose intravenous (IV) vortioxetine at oral vortioxetine treatment initiation. Patients (ages 18-65 years) hospitalized per standard-of-care with major depressive disorder, who were currently treated with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor for a major depressive episode [Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 30], received one dose of single-blind IV placebo (1-day placebo lead-in period) before being randomly switched to either single-dose IV vortioxetine 25 mg plus daily oral vortioxetine 10 mg (n = 39), or IV placebo plus daily oral placebo (n = 41). In the placebo lead-in period, patients improved slightly by 0.6 MADRS-6 point; however, at day 1 after randomization, both treatment groups had improved by approximately 3 MADRS-6 points (mean difference = -0.8; P = 0.263), the study thus not meeting its primary endpoint. Similar results were seen for other outcomes except a numerically larger improvement in anxiety symptoms with vortioxetine vs placebo. Pharmacokinetic data confirmed that IV vortioxetine facilitated reaching steady-state plasma concentration within 24 h. IV plus oral vortioxetine was well tolerated, with low levels of nausea as the most common adverse event.

Double-blind placebo controlled trial of the anxiolytic effects of a standardized Echinacea extract.

Earlier studies suggested that specific Echinacea preparations might decrease anxiety. To further study the issue, we performed a double blind, placebo controlled trial with a standardized Echinacea angustifolia root extract. Participants were volunteers scoring above 45 points on the state or on the trait subscale of the State Trait Anxiety Inventory (STAI). They were treated with 40 mg Echinacea or with placebo tablets twice daily for 7 days followed by a 3 week-long washout period. Participants were also administered the Beck Depression Inventory (BDI) and the Perceived Stress Scale (PSS). In the Echinacea group, state anxiety scores decreased by approximately 11 points by the end of the treatment period, whereas the decrease was around 3-points in the placebo group (p< 0.01). The effect maintained over the washout period. The difference from placebo was significant from the 7th day of treatment throughout. Changes were less robust with trait anxiety scores, but the preparation performed better than placebo in patients with high baseline anxiety. Neither BDI nor PSS scores were affected by the treatments. Adverse effects were rare and mild, and all were observed in the placebo group. These findings suggest that particular Echinacea preparations have significant beneficial effects on anxiety in humans.

Comparative effectiveness of depot and oral second generation antipsychotic drugs in schizophrenia: a nationwide study in Hungary.

We conducted a nationwide, full-population based investigation to evaluate the comparative effectiveness of all marketed second generation antipsychotic drugs (SGA) prescribed for outpatients with the diagnosis of schizophrenia in Hungary. Using the national central register, our observational follow-up study included all patients with schizophrenia or related disorder between 01/01/2006 and 30/06/2008. The study cohort comprised 9567 patients who started new SGA during the inclusion period (01/07/2007-30/06/2008). All-cause medication discontinuation of 8 SGAs (1 depot and 7 oral formulations) marketed during the inclusion period, and the time to all-cause discontinuation were the main outcomes. Statistical models included the Kaplan-Meier and the Cox proportional hazards models with propensity score adjustment. Patients treated with a depot formulation risperidone had the longest time to discontinuation with a median of 215 days (95%CI:181-242 days), which was statistically significantly different compared to patients treated with the rest of the medications: olanzapine (136 days, 95%CI:121-153 days), aripiprazole (102 days, 95%CI:81-126 days), ziprasidone (93 days, 95%CI:82-119 days), quetiapine (89 days, 95%CI:81-100 days), clozapine (76 days, 95%CI:54-92 days), amisulpride (73 days, 95%CI:62-85 days), and risperidone (55 days, 95%CI: 41-63 days). Our results in Hungary are partly similar to those of a recent register-based study in Finland with patients who were discharged from their first hospitalization for schizophrenia (Tiihonen et al., 2006, 2011); namely the median times to all-cause medication discontinuation were <120 days for the majority of the oral SGA. In terms of medication differences, our data support the superior effectiveness of the depot formulation regarding all-cause discontinuation, followed by olanzapine at the efficacy rank order.

The anxiolytic potential and psychotropic side effects of an echinacea preparation in laboratory animals and healthy volunteers.

We investigated the toxicity, psychotropic side effects and anxiolytic potential of an Echinacea angustifolia extract that produced promising effects in laboratory tests performed earlier. Rats were studied in the elevated plus-maze, conditioned fear, open-field, object recognition and conditioned place preference tests. Toxicity was studied in rats after intragastric administration. The preparation decreased anxiety in the elevated plus-maze and ameliorated contextual conditioned fear. No lethality or behavioural signs of discomfort were noticed in rats treated with 1000 and 3000 mg/kg Echinacea angustifolia. The extract was without effect in tests of locomotion (open-field), memory (object recognition) and rewarding potential (conditioned place preference) within a wide dose range. A pharmacological formulation based on the same E. angustifolia extract was tested in human subjects. One or two tablets per day were administered for 1 week to healthy volunteers scoring high on the State-Trait Anxiety Inventory (STAI). The tablets contained 20 mg of the plant extract. Data were collected using a structured self-assessment diary technique. The high dose (2 tablets per day) decreased STAI scores within 3 days in human subjects, an effect that remained stable for the duration of the treatment (7 days) and for the 2 weeks that followed treatment. The lower dose (1 tablet per day) did not affect anxiety significantly.

[Suicide and lithium prophylaxis. Case reports]. / Ongyilkosság és lítium profilaxis. Esetleírások.

The authors sum up the question of suicide and lithium prophylaxis on the basis of their own three cases.

Predictors for 2-year outcome of major depressive episode.

In this 2-year prospective study, we searched for predictive factors influencing the 2-year outcome of major depressive episodes. Demographic characteristics (age, gender, education, employment), illness-related variables (severity, age at onset, number and duration of previous episodes), personality characteristics (DSM-IV personality disorders, trait anxiety, coping style), life context factors (life events before and during the depressive episode, social support, social adjustment), and biological markers (dexamethasone suppression test, thyroid stimulating hormone levels) of 117 inpatients with major depressive episode were assessed. A structural equation model was used to test the proposed correlational structure of the relevant variables. The non-remission of the depressive symptoms by the end of a 6-week acute treatment phase was found to be the most relevant factor predicting sustained non-remission at the end of a 2-year follow-up period. At the end of the sixth week, the severity of depression depended on the level of social support and on the severity of depression at baseline. Among the baseline variables, anxious personality traits and a lower level of education predicted a high level of depressive symptoms at the end of the 2-year follow-up. Life events before and during the depressive episode, and the biological markers at baseline had no direct effect on the outcome. The rapid remission of the depressive symptoms is the most important predictor for the favorable long-term outcome of a depressive episode. Personality characteristics, social support and level of education,--interacting with each other--also play a significant role.

Anxiety and mood disorders in primary care practice.

Anxiety and mood disorders are common conditions in primary health care service. Primary care physicians (PCPs) have a privileged role in the early recognition of these conditions. In this study, the prevalence rates of threshold and subthreshold mood and anxiety disorders were surveyed among 1815 primary care attendees in 12 PCPs' offices in Budapest, using the Diagnostic Interview Schedule (DIS). The 1-year prevalence of DIS/DSM-III-R anxiety and/or mood disorders was 16.8%, and the 1-month prevalence was 12.5%. The occurrence rates of subthreshold anxiety and/or depression were 25.7 and 13.1%, respectively. The impact of threshold anxiety and mood disorders on work performance was considerably higher than the impact of subthreshold symptoms. At the time of the interview, 6.7% of the patients received mood and/or anxiety disorder diagnoses by their PCPs. The measure of agreement between the diagnoses generated by the DIS and the ones given by the PCPs was low. The presence of an acute or chronic physical illness made it more difficult for the PCPs to recognize a psychiatric disorder. Conversely, patients' psychological complaints significantly improved the recognition of anxiety and/or mood disorders. The use of the Beck Depression Inventory (BDI) brief version would help the patients to reveal their psychological symptoms, and the physicians to recognize an underlying psychiatric disorder.

The role of symptoms in the recognition of mental health disorders in primary care.

This study investigates the role of patients' complaints and symptoms in the diagnostic process of mood and anxiety disorders in general practice. In 12 primary care practices, 1,211 patients were diagnosed with the aid of the National Institute of Mental Health Diagnostic Interview Schedule, then the diagnoses were compared with those established by the general practitioners. A low rate of concordance was found between these diagnoses. The absence of somatic illnesses and the presence of psychological complaints were the most important factors in the recognition of a mental illness by the general practitioners. The concordance between the general practitioners and the DIS diagnoses was higher if the patients had neither an acute nor a chronic somatic illness.

Cost-outcome of anxiety treatment intervention in primary care in Hungary.

AIM OF THE STUDY: The purpose of this paper is to estimate the changes in health utilization and indirect costs of anxiety and affective disorders in primary care patients after initiation of mental health treatment. METHOD: This study was conducted in 12 general practices for the primary care of adult populations in Budapest, Hungary. Among 2,000 eligible patients aged 18 to 64 years, 1,815 gave written informed consent to participate in the study. The Hungarian version of the Diagnostic Interview Schedule (DIS) for anxiety and mood disorders was used to generate psychiatric diagnoses. For all patients, health care utilization data for the previous 12 months was collected including number of visits, specialist consultations, days spent in hospital, sick days in the last year and prescribed medication. Among the first 1,000 attenders, 151 patients were given DIS/DSM-III-R diagnoses of current anxiety and/or mood disorder or uncomplicated bereavement. Fifty-one patients who agreed to psychiatric treatment were assigned to the treatment group. After the first 1,000 participants, 75 patients were given DIS diagnoses and were considered as controls. In the treatment group, five psychiatrists administered treatment on an outpatient basis for one year. Patients in the control group received as-usual treatment from their primary care physicians. After one year, health care utilization data for the study period was collected. For the purposes of this study, the direct costs considered were limited to health care expenses and the indirect costs were limited to lost workdays. Statistical significance was calculated using a paired-samples T-test procedure comparing the means of two variables for a simple group. RESULTS: In the treatment group, the total cost of prescription drugs increased sharply due to psychiatric drug treatment, thus increasing the direct overall costs of care. In this same group the cost of non-psychiatric drugs showed a 37% decrease, suggesting that a reduction in general medical treatment partially offset the costs of anxiety and depression treatment. The number of hospital days showed marked decrease in the treatment group and a slight, insignificant increase in the control group. Absenteeism fell sharply in the treatment group (-56%) and in the group of patients who received psychiatric treatment elsewhere (-62%). In the control group, there was a large upturn (+182%) in the number of days spent on sick leave. DISCUSSION: Among primary care patients diagnosed with anxiety or affective disorders, psychiatric treatment led to higher direct costs, but this was offset by a decline in indirect costs due to reduced absenteeism compared with ordinary primary care. LIMITATIONS: Patients were not assigned randomly to the different groups because of ethical concerns. There were also significant differences in the baseline characteristics of the groups. Differences in the severity of illness and reasons not attributable to treatment effects may play a role in the change in the rate of service use. IMPLICATIONS FOR HEALTH POLICY: Limiting anxiety patients access to psychiatric treatment causes an increase in absenteeism, thus resulting in higher indirect costs.