The relationship between cognition and functioning in schizophrenia: A semi-systematic review.

In schizophrenia, impairments in neurocognition (NC) and social cognition (SC) are associated with reduced functional capacity (FC) and poor real-world functioning (RWF). In this semi-systematic review, we examined this association across a range of research questions. We conducted a systematic search in Embase and MEDLINE from 2005 to 2019, and conducted additional pragmatic searches. After screening of titles, abstracts and full-texts, we included 564 citations, of which 44 (26 primary studies, 15 systematic reviews and 3 narrative reviews) were prioritized for reporting. Both NC and SC were significantly associated with functioning, with slightly stronger association for SC. Effect sizes were generally larger for FC than for RWF. NC showed stronger associations with occupational functioning and independent living, and SC with social functioning. Baseline cognition predicted long-term RWF up to 20 years of follow-up, though long-term data were limited for SC. Cognitive remediation improved RWF functioning, especially when it was combined with psychosocial rehabilitation. SC mediated the relationship of NC with functioning. Negative symptoms appeared to mediate and moderate the association of cognition with functioning. Other factors involved included severity of cognitive dysfunction, metacognition, depression and choice of RWF instrument. We discuss potential implications for studies of pharmacological cognitive interventions in schizophrenia - the relevance of both NC and SC, the advantage of adjunctive psychosocial rehabilitation, the role of relevant moderating and mediating variables, and the challenges with RWF instrument selection. Successful cognitive interventions could allow patients with schizophrenia to improve their potential for community functioning.

Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study.

BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no approved pharmacotherapy is available. This study investigated whether the glycine transporter-1 inhibitor BI 425809 improves cognition in patients with schizophrenia. METHODS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group trial (81 centres, 11 countries), randomly assigned outpatients (aged 18-50 years) with schizophrenia on stable treatment to add-on once-daily oral BI 425809 2 mg, 5 mg, 10 mg, or 25 mg or placebo (1:1:1:1:2) for 12 weeks. Treatment was assigned in blocks using interactive response technology; patients, investigators, and all trial personnel were masked to group assignment. The primary endpoint was change from baseline in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score at week 12. Six predefined dose-response models were evaluated using a multiple comparison procedure and modelling approach with mixed model repeated measures to assess evidence for a non-flat dose-response relationship for cognitive improvements with BI 425809. Adverse events were monitored. Safety analyses included all randomly allocated patients who received one or more doses of trial medication; efficacy analyses included patients from this set who also had available baseline data and at least one post-baseline on-treatment measurement for the primary or secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02832037. FINDINGS: 509 patients were randomly assigned between April 25, 2018, and Oct 4, 2019 (BI 425809 2 mg, n=85; 5 mg, n=84; 10 mg, n=85; 25 mg, n=85; placebo, n=170 444 (87%) completed the 12-week treatment. Five of six dose-response models showed a statistically significant benefit of BI 425809 over placebo (linear [t=2·55, p=0·015], linear in log [t=2·56, p=0·015]; Emax [t=2·75, p=0·0089], sigmoid Emax [t=2·98, p=0·0038], logistic [t=2·77, p=0·0085]). Pairwise comparisons showed greater mean improvement from baseline in MCCB overall composite T-score at week 12 with BI 425809 10 mg and 25 mg versus placebo (adjusted mean difference 1·98 [95% CI 0·43-3·53] for 10 mg and 1·73 [0·18-3·28] for 25 mg; standardised effect size 0·34 for 10 mg and 0·30 for 25 mg). Adverse events were balanced across groups, reported in 50 (59%) of 85 patients on BI 425809 2 mg, 44 (52%) of 84 on 5 mg, 35 (41%) of 85 on 10 mg, 36 (42%) of 85 on 25 mg, and 74 (44%) of 170 on placebo. INTERPRETATION: BI 425809 improved cognition after 12 weeks in patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo. If these encouraging results are confirmed in phase 3 trials, BI 425809 could provide an effective treatment for cognitive impairment associated with schizophrenia. FUNDING: Boehringer Ingelheim.

Treatment pathway analysis of newly diagnosed dementia patients in four electronic health record databases in Europe.

PURPOSE: Real-world studies to describe the use of first, second and third line therapies for the management and symptomatic treatment of dementia are lacking. This retrospective cohort study describes the first-, second- and third-line therapies used for the management and symptomatic treatment of dementia, and in particular Alzheimer's Disease. METHODS: Medical records of patients with newly diagnosed dementia between 1997 and 2017 were collected using four databases from the UK, Denmark, Italy and the Netherlands. RESULTS: We identified 191,933 newly diagnosed dementia patients in the four databases between 1997 and 2017 with 39,836 (IPCI (NL): 3281, HSD (IT): 1601, AUH (DK): 4474, THIN (UK): 30,480) fulfilling the inclusion criteria, and of these, 21,131 had received a specific diagnosis of Alzheimer's disease. The most common first line therapy initiated within a year (± 365 days) of diagnosis were Acetylcholinesterase inhibitors, namely rivastigmine in IPCI, donepezil in HSD and the THIN and the N-methyl-D-aspartate blocker memantine in AUH. CONCLUSION: We provide a real-world insight into the heterogeneous management and treatment pathways of newly diagnosed dementia patients and a subset of Alzheimer's Disease patients from across Europe.

Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study.

BACKGROUND: Inflammatory processes have been shown to play a role in dementia. To understand this role, we selected two anti-inflammatory drugs (methotrexate and sulfasalazine) to study their association with dementia risk. METHODS: A retrospective matched case-control study of patients over 50 with rheumatoid arthritis (486 dementia cases and 641 controls) who were identified from electronic health records in the UK, Spain, Denmark and the Netherlands. Conditional logistic regression models were fitted to estimate the risk of dementia. RESULTS: Prior methotrexate use was associated with a lower risk of dementia (OR 0.71, 95% CI 0.52-0.98). Furthermore, methotrexate use with therapy longer than 4 years had the lowest risk of dementia (odds ratio 0.37, 95% CI 0.17-0.79). Sulfasalazine use was not associated with dementia (odds ratio 0.88, 95% CI 0.57-1.37). CONCLUSIONS: Further studies are still required to clarify the relationship between prior methotrexate use and duration as well as biological treatments with dementia risk.

Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients with Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial.

BACKGROUND AND OBJECTIVE: Cognitive impairments associated with schizophrenia (CIAS) predict poor functional outcomes, but there are currently no approved pharmacological treatments for patients with CIAS. Additional cognitive stimulation may be required for pro-cognitive medications to improve efficacy, and computerized cognitive training (CCT) can be used to increase cognitive activity. A trial evaluating the effects of the novel glycine transporter inhibitor BI 425809 compared with placebo, on a background of regularly self-administered CCT in clinically stable patients with schizophrenia has commenced and its methodology is described here. METHODS: This Phase II, multinational, randomized, double-blind, placebo-controlled, parallel-group trial will randomize 200 clinically stable outpatients, aged 18-50 years with established schizophrenia and no other major psychiatric disorder, 1:1 to BI 425809 or placebo once daily for 12 weeks. Following screening, which included a 2-week CCT run-in period, patients sufficiently compliant with CCT (target: ≥ 2 h of CCT per week during CCT run-in) will be randomized. During the 12-week treatment period, all patients should complete a total of approximately 30 h of CCT. The primary endpoint is change from baseline in neurocognitive function as measured by the neurocognitive composite score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), after 12 weeks of treatment. Secondary endpoints include change from baseline in overall MCCB score, Schizophrenia Cognition Rating Scale, Positive and Negative Syndrome Scale, and safety (adverse events [AEs]) and serious AEs. Primary and secondary endpoints will be analyzed using the Restricted Maximum Likelihood-based mixed model for repeated measures. Novel endpoints include the Balloon Effort Task to evaluate patients' motivation and the Virtual Reality Functional Capacity Assessment Tool to assess skills for daily functioning. DISCUSSION: This is one of the largest and longest trials to date to combine pharmacological therapy with CCT in patients with schizophrenia and will determine the benefit of combining BI 425809 pharmacotherapy with cognitive stimulation through self-administered CCT. This trial will further evaluate whether improvements in neurocognition translate into improved everyday functioning, whether self-administered CCT can be effectively implemented in a large multinational trial, and the role of motivation in neurocognitive and functional improvements. TRIAL REGISTRATION: Registered on Clinicaltrials.gov on March 1, 2019 (NCT03859973).

Alzheimer's Diagnosis: Real-World Physician Behavior Across Countries.

INTRODUCTION: Appropriate management of patients with Alzheimer's disease (AD) helps preserve their independence and time at home. We explored physician behavior in the management of AD, focusing on diagnosis. METHODS: Online questionnaires and patient record forms (PRFs) were created by an independent market research agency and completed by participating physicians. Physicians were recruited from France, Germany, Japan, the UK, and the USA. A sample of 1086 physicians was recruited, including general practitioners, geriatricians, neurologists, and psychiatrists. Physicians completed an online interview and 2-3 PRFs based on randomly selected records of their patients with AD. Data on triggers and timing of diagnosis were captured. Data were assessed for all countries combined (global) and within each country and physician specialty. RESULTS: A total of 3346 PRFs were submitted. Approximately half of patients received diagnosis within 6 months. There were large country differences. In France, only 35% of patients were diagnosed within 6 months compared to 65% in Japan. Physicians in France also reported diagnoses taking > 9 months for a substantial number of patients (39%) compared with other countries (16-29%). Caregivers were the main driver toward diagnosis. Physician suspicion of AD was a trigger for diagnosis in only 20% of cases, globally. Overall, referral rates were low (14-23%). CONCLUSION: This study suggests that detection and timely diagnosis of AD remains suboptimal. This highlights the importance of fostering awareness of early symptoms and education on the benefits of timely diagnosis, a critical step in initiating treatment as early as possible.

Alzheimer's Treatment: Real-World Physician Behavior Across Countries.

OBJECTIVE: Timely initiation of Alzheimer's disease (AD)-specific treatment may postpone cognitive deterioration and preserve patient independence. We explored real-world physician behavior in the treatment of AD. METHODS: Online questionnaires and patient record forms (PRFs) were completed by participating physicians. The physicians included general practitioners, neurologists, geriatricians and psychiatrists, recruited from France, Germany, Japan, the UK and the USA. Physicians completed an online interview and two to three PRFs based on selected records of their patients with AD. Data on treatment algorithms and key drivers for therapy were captured. RESULTS: A total of 3346 PRFs were submitted and 1086 physicians interviewed. Overall, 44% of patients with mild cognitive impairment/prodromal AD, 71% of patients with mild disease and 76% of patients with moderate disease had already received therapy. The most common reasons for not prescribing therapy were patient refusal (35%) and early disease stage (26%). Except in the USA, the majority of physicians preferred to prescribe monotherapy. Almost 30% of patients at any stage of the disease did not receive AD-specific pharmacotherapy immediately after diagnosis. CONCLUSIONS: Physicians' attitudes toward AD treatment could be driven by limited awareness regarding the benefits of early intervention and the modest efficacy of currently available therapies. Efficacious therapies for AD, especially early AD, which could be used alone or in combination with current medications to maximize treatment benefit, are still needed. The availability of more efficacious therapies may improve time to treatment initiation, treatment rates and acceptance of treatment by patients, caregivers and physicians.

DNA Barcoding in Forensic Entomology - Establishing a DNA Reference Library of Potentially Forensic Relevant Arthropod Species.

Throughout the years, DNA barcoding has gained in importance in forensic entomology as it leads to fast and reliable species determination. High-quality results, however, can only be achieved with a comprehensive DNA barcode reference database at hand. In collaboration with the Bavarian State Criminal Police Office, we have initiated at the Bavarian State Collection of Zoology the establishment of a reference library containing arthropods of potential forensic relevance to be used for DNA barcoding applications. CO1-5P' DNA barcode sequences of hundreds of arthropods were obtained via DNA extraction, PCR and Sanger Sequencing, leading to the establishment of a database containing 502 high-quality sequences which provide coverage for 88 arthropod species. Furthermore, we demonstrate an application example of this library using it as a backbone to a high throughput sequencing analysis of arthropod bulk samples collected from human corpses, which enabled the identification of 31 different arthropod Barcode Index Numbers.

Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study.

BACKGROUND: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. METHODS: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid ß and tau in cerebrospinal fluid/blood and neurophysiological measures. DISCUSSION: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. TRIAL REGISTRATION: Nederlands Trial Register NTR5867 . Registered 20 May 2016.

Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease.

BACKGROUND: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). METHODS: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid ß (Aß)1-42, Aß42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. RESULTS: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. CONCLUSIONS: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.

To eat or get heat: Behavioral trade-offs between thermoregulation and feeding in gregarious necrophagous larvae.

The thermoregulation behavior of Lucilia sericata larvae (Diptera: Calliphoridae), a necrophagous species that feeds on vertebrate cadavers, was investigated. These larvae require high heat incomes to develop, and can elevate temperatures by forming large aggregates. We hypothesized that L. sericata larvae should continue to feed at temperatures up to 38 °C, which can be reached inside larval masses. Thermal regulation behavior such as movement between a hot food spot and colder areas was also postulated. The hypotheses were tested by tracking for 1 h the activity of single, starved third instar larvae in a Petri dish containing 1 food spot (FS) that was heated to a constant temperature of 25 °C, 34 °C or 38 °C with an ambient temperature of 25 °C. The influence of previous conspecific activity in the food on larval behavior was also tested. The crops of larvae were dissected to monitor food content in the digestive systems. Based on relative crop measurements, larvae fed at all food temperatures, but temperature strongly affected larval behavior and kinematics. The total time spent by larvae in FS and the duration of each stay decreased at high FS temperature. Previous activity of conspecifics in the food slightly increased the time spent by larvae in FS and also decreased the average distance to FS. Therefore, necrophagous L. sericata larvae likely thermoregulate during normal feeding activities by adjusting to local fluctuations in temperature, particularly inside maggot masses. By maintaining a steady internal body temperature, larvae likely reduce their development time.

Alzheimer's Disease Assessment Scale-Cognitive subscale variants in mild cognitive impairment and mild Alzheimer's disease: change over time and the effect of enrichment strategies.

BACKGROUND: Development of new treatments for Alzheimer's disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer's Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers. METHODS: Subjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time. RESULTS: The decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large. CONCLUSIONS: The possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which subjects score close to ceiling.

BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study.

METHODS: Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication. RESULTS: The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73 = 27.4%) and eletriptan 40 mg (24/69 = 34.8%) groups compared to placebo (6/70 = 8.6%, p = .0016), but not by subjects in the BI 44370 TA 200 mg group (14/65 = 21.5%). The effect of 50 mg BI 44370 TA (5/64 = 7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups. CONCLUSION: Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks.

Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for severe depression: a double-blind randomized trial.

OBJECTIVE: To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily. METHOD: Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥ 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores ≥ 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) ≥ 4 and hospitalized ≥ 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008. RESULTS: There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea. CONCLUSIONS: Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00422162.

Wide spectrum modulation by KP-544 in models relevant for neuronal survival.

Reduced neurotrophic signalling has been proposed as a part of the pathophysiology behind neuronal death and dysfunction. The small molecule KP-544 was developed with the intention to enhance nerve growth factor signalling. To characterize the actions of KP-544 pharmacologically, we used four diverse models with relevance for neuronal function and survival. We found that 300-1000 nM KP-544 enhanced the neurite outgrowth in PC12 cells in response to a suboptimal concentration of nerve growth factor. KP-544 also protected the cerebellar granule cells from excitotoxicity apoptosis induced by the mitochondrial toxin methyl-phenyl-pyridinium, and modulated inflammation by inhibiting interleukin-6 production in primary astrocytes. Chronic treatment of rats with KP-544 prevented the hyper-responsiveness to amphetamine of animals treated with methylazoxymethanol acetate, a recently described neurodevelopmental model of schizophrenia.

Effect of chronic intermittent restraint stress on hippocampal expression of marker proteins for synaptic plasticity and progenitor cell proliferation in rats.

Chronic restraint stress may change hippocampal mRNA levels of markers for synaptic plasticity such as synaptophysin, growth-associated protein 43 (GAP-43), and brain-derived neurotrophic factor (BDNF). In order to examine the relation between that stressor and those biochemical markers on protein level as well as the Ki-67 protein, a marker of progenitor cell proliferation, we subjected rats to chronic intermittent restraint stress for 6 h per day for 14 days excluding the weekends. This stress intensity caused a significant increase in adrenal gland weight and decrease in body weight gain. However, we did not find significant alteration of protein expression levels for synaptophysin, GAP-43, and BDNF by using Western blot analysis. Unlike these findings, the hippocampal protein expression of Ki-67 was significantly reduced by using both Western blot and immunohistochemical analyses. This reduction of Ki-67 expression in chronically stressed rats was correlated with increased adrenal gland weight and decreased body weight gain. All marker proteins used did not show any changes of hippocampal expression level after a single restraint stress session of 3 h. In conclusion, chronic intermittent restraint stress caused changes in the physiological stress response in rats, and a decrease of hippocampal progenitor cells using the Ki-67 protein as marker which indicates a suppression of adult neurogenesis. The results might contribute to understand the relationship between stress and cellular neurobiology of depression, since chronic antidepressant treatment have been shown to increase adult neurogenesis in the rat hippocampus.

The heterozygous reeler mouse: behavioural phenotype.

The aim of this study was to investigate whether heterozygous reeler mice (+/rl) could be used as a genetic mouse model of schizophrenia, as previously suggested [J. Med. Chem. 44 (2001) 477]. The behavioural phenotype of male and female +/rl mice (young adult: 50-70 days old, and fully adult: >75 days old) was compared to their wild type (+/+) littermates. A complex behavioural test battery was employed: Irwin test, rotarod, spontaneous locomotor activity, social behaviour, light-dark transition test, startle response and prepulse inhibition, and hot-plate test. Overall, +/rl mice did not differ from their +/+ littermates at either age, although fully adult +/rl male mice spent more time engaged in social investigation. Some of the behavioural measures investigated were influenced by gender. Young female mice were more active in the light/dark transition test than males, while males were more aggressive than females during social interaction. In addition, performance on the rotarod was shown to deteriorate with age. Our data are in agreement with previous findings [Soc. Neurosci. Abst. 27 (2001) 238; J. Psychopharmacol. 17 (2003) A43], but contrary to those of Costa et al. [Curr. Opin. Pharmacol. 2 (2002) 56], although mice used in the present and previous studies were derived from the same genetic stock at Jackson Laboratories, USA. The present study clearly shows that, compared to its +/+ littermates, the +/rl mouse (young/fully adult) exhibits normal behaviour in a wide range of behavioural measures and suggest that these mice may not be suitable for use as a genetic animal model of schizophrenia.

Do animal models of anxiety predict anxiolytic-like effects of antidepressants?

Chronically administered antidepressant drugs, particularly selective serotonin (5-HT) reuptake inhibitors (SSRIs), are clinically effective in the treatment of all anxiety disorders, while the clinical effectiveness of "traditional" anxiolytics, such as benzodiazepines (BDZs), is limited to generalised anxiety disorder or acute panic attacks. This implies that animal models of anxiety should be sensitive to SSRIs and other antidepressants in order to have predictive validity. We reviewed the literature on the effects of antidepressants in the so-called animal models of anxiety and found that only the isolation-induced calls in guinea-pig pups may reveal anxiolytic-like action of all antidepressant classes after acute administration. Some other models, such as marble-burying or conditioned-freezing behaviours, and isolation- or shock-induced ultrasonic vocalisation models, may detect anxiolytic-like activity of acutely administered antidepressants, although the sensitivity of these models is usually limited to SSRIs and other drugs affecting 5-HT uptake. The predictive validity of models of "anxiety", such as the plus-maze and light-dark transition tests or stress-induced hyperthermia, appears to be limited to BDZ-related drugs. Far less work has been done on chronic administration of antidepressants in animal anxiety models. Unless and until such studies have been undertaken, the true predictive value of the anxiety models will remain unknown.