Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Dear Doctor Letters regarding citalopram and escitalopram: guidelines vs real-world data.

Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs' effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14-5% and 47-31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging psychotropic drugs reduced only insignificantly (from 35.9 to 30.9%). However, the proportion of patients with doses of quetiapine > 150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%). After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs' recommendations were not entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic requirements of the included population. Official warnings should consider clinical needs.

Sex differences in pharmacological treatment of major depressive disorder: results from the AMSP pharmacovigilance program from 2001 to 2017.

Data on drug prescription for outpatients with major depressive disorder (MDD) suggest women are more likely to be treated with psychotropic drugs, while data on sex differences regarding pharmacological treatment of psychiatric inpatients are currently not available. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) of 44,418 psychiatric inpatients with MDD were analyzed for sex differences between 2001 and 2017. Sex differences were analyzed using relative risks (RR) and 95% confidence intervals (95% CI). Time trends were analyzed by comparing the first (2001-2003) with the last time period (2015-2017). In general, men and women were equally likely to use psychotropic drugs. Monotherapy was more common in men. Women were more likely to utilize ≥ 4 psychotropic drugs. Antidepressant drugs (ADDs) were the most prescribed drug class. Men had a higher utilization of noradrenergic and specific serotonergic antidepressants (RR 1.15; 95% CI 1.12-1.19), especially mirtazapine (RR 1.16; 95% CI 1.12-1.19), but also of other ADDs such as bupropion (RR 1.50; 95% CI 1.35-1.68). Males had a slightly higher utilization of second-generation antipsychotic drugs (RR 1.06; 95% CI 1.03-1.09) and were less often treated with low-potency first-generation antipsychotic drugs (RR 0.86; 95% CI 0.83-0.90). Tranquilizing (e.g., benzodiazepines; RR 0.89; 95% CI 0.86-0.92) and hypnotic drugs (e.g., Z-drugs; RR 0.85; 95% CI 0.81-0.89) were less utilized in the treatment of male patients. Not all sex differences were stable over time. More sex differences were detectable in 2015-2017 than in 2001-2003. Findings suggest that certain psychotropic drugs are preferred in the treatment of men vs. women, however, sex differences found in this study are not as large as in ambulatory settings. To make evidence-based sex-specific recommendations in the treatment of MDD, differences in drug response and tolerability need to be further researched.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

What happens with schizophrenia patients after their discharge from hospital? Results on outcome and treatment from a "real-world" 2-year follow-up trial.

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

BACKGROUND: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). METHODS: An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. RESULTS: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. CONCLUSIONS: Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project.

Background: Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods: First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results: Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions: The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Correction to: Cerebrospinal fluid amyloid-ß 2-42 is decreased in Alzheimer's, but not in frontotemporal dementia.

The respective first and last authors of this article, Mirko Bibl and Jens Wiltfang, would like to clarify the issue of the seeming duplicate publication of a figure in two articles.

Validity of remission and recovery criteria for schizophrenia and major depression: comparison of the results of two one-year follow-up naturalistic studies.

The objective of the present study was the application and comparison of common remission and recovery criteria between patients with the diagnosis of schizophrenia and major depressive disorder (MDD) under inclusion of other outcome parameters. Patients with schizophrenia and MDD who were treated as inpatients at the beginning of the study were examined within two naturalistic follow-up trials from admission to discharge of an inpatient treatment period and the one-year follow-up assessment. PANSS criteria of the Remission in Schizophrenia Working Group (RSWG) for schizophrenia and HAMD criteria of the ACNP Task Force in MDD for depressive patients as well as the Clinical Global Impression-Severity Scale (CGI-S) were applied as symptomatic outcome measures additionally to functional outcome parameters. Data of 153 schizophrenia patients and 231 patients with a MDD episode have been included in the analysis. More depressive than schizophrenia patients reached a threshold score of ≤3 on the CGI-S, indicating symptomatic remission at discharge and at the one-year follow-up. In contrast similar proportions of patients reaching symptomatic remission at discharge from inpatient treatment and at the one-year follow-up in the schizophrenia and in the MDD group were found when disease-related consensus criteria (RSWG vs. ACNP Task Force) were used. Functional remission and recovery rates were significantly lower in schizophrenia than in depressive patients at the one-year follow-up visit. Common outcome criteria for remission and recovery in schizophrenia and major depression were not directly comparable. However, our results indicated a significantly poorer outcome in schizophrenia than in depressive patients according to terms of remission and recovery.

Add-on Antidepressants in the Naturalistic Treatment of Schizophrenia Spectrum Disorder - When, Who, and How?

The aim of this study was to evaluate antidepressant add-on treatment within the acute treatment of schizophrenia spectrum disorder patients. Antidepressant add-on was evaluated in 365 patients within a naturalistic multicenter study. Patients with/without antidepressant add-on were compared regarding clinical and treatment-related variables, response and remission, and remission of depressive and negative symptoms. The efficacy of antidepressant add-on treatment was furthermore analyzed applying marginal structure models. Twenty-three percent of the patients received antidepressant add-on for a mean duration of 50.28 (33.42) days. Patients with the diagnosis of a schizoaffective disorder, multiple illness episodes, and a longer duration of their illness as well as those with significantly fewer baseline positive symptoms, more negative and depressive symptoms, more side effects, and less subjective well-being were augmented with antidepressants. At discharge no significant effect of antidepressant add-on treatment was observed in terms of a 25% improvement (p=0.2623), a 50% improvement (p=0.3946), remission (p=0.0552), or remission of depressive (p=0.6336) and negative symptoms (p=0.8756). Also, when analyzing marginal structure models considering the diagnostic subgroups, no significant effect was found. Add-on with antidepressants is common. A final recommendation in terms of this strategy's efficacy cannot be given.

SUCLG2 identified as both a determinator of CSF Aß1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Cerebrospinal fluid amyloid-beta 1-42 (Aß1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aß1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aß1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aß1-42.

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.

Patient-oriented randomisation: A new trial design applied in the Neuroleptic Strategy Study.

BACKGROUND: The 'gold standard' for clinical studies is a randomised controlled trial usually comparing specific treatments. If the scientific study expands to strategy comparison with each strategy including various treatments, the research problems are increasingly complicated. The strategy debate in the psychiatric community is the starting point for the development of our new design. It is widely accepted that second-generation antipsychotics are the therapy of choice in the treatment of schizophrenia. However, their general superiority over first-generation antipsychotics could not be demonstrated in recent randomised controlled trials. Furthermore, we are becoming increasingly aware that the experimental conditions of randomised controlled trials, as in the European First Episode Schizophrenia Trial and Clinical Antipsychotic Trials of Intervention Effectiveness Phase 1 studies, may be inappropriate for psychiatric treatments. The high heterogeneity in the patient population produces discrepancies between daily clinical perception and randomised controlled trials results. The patient-oriented approach in the Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study reflects everyday clinical practice. The results, however, are highly dependent on the physicians' preferences. The goal of the design described here is to take an intermediate path between randomised controlled trials and clinical studies such as Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, combining the advantages of both study types. METHODS: The idea is to randomise two treatment pairs each consisting of one first-generation antipsychotic and one second-generation antipsychotic in a first step and subsequently, to involve the investigators in deciding for a pair most appropriate to the patients' needs and then to randomise the allocation to one drug (first-generation antipsychotic or second-generation antipsychotic) of that chosen pair. This idea was first implemented in the clinical trial, the Neuroleptic Strategy Study, with a randomised design comparing efficacy and safety of two different strategies: either to use first-generation antipsychotics (haloperidol and flupentixol) or second-generation antipsychotics (olanzapine, aripiprazole and quetiapine) in patients suffering from schizophrenia. RESULTS: In the course of the Neuroleptic Strategy Study, feasibility of this design was demonstrated. All aspects of the new design were implemented: randomisation process, documentation of responses from investigators as well as patients and drug logistic experience. In implementing the design, furthermore, we could investigate its theoretical properties. The physicians' preferences for specific drugs used for the respective patients were analysed. CONCLUSION: The idea of patient-oriented randomisation can be generalised. In light of the heterogeneity and complexity of patient-drug interaction, this design should prove particularly useful.

Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment.

INTRODUCTION: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). METHODS: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aß, tau, ptau). RESULTS: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (ß ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)). DISCUSSION: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.

[Dementia Competence Network. Results and outlook]. / Das Kompetenznetz Demenzen. Erfolge und Ausblicke.

BACKGROUND: The Dementia Competence Network (DCN) is represented by academic memory clinics and has three major aims: (1) To facilitate the development of diagnostic tools including neuropsychology, biomarkers, imaging and genetics. (2) To implement clinical trials in mild cognitive impairment and dementia and (3) to improve standard care for dementia in Germany. AIMS: This article summarizes the achievements of the DCN so far and highlights future perspectives. METHODS: The DCN has built up two multicentre cohorts. Within the first cohort, patients with mild cognitive impairment or mild dementia were examined longitudinally using multiple neuropsychological assessments and numerous different biomarkers. In a subgroup of the first cohort, patients were treated with antidementive drugs in two placebo-controlled clinical trials. The second cohort included cognitively healthy older people and examined repetitively clinical, neuropsychological and psychosocial parameters for ten years. RESULTS AND DISCUSSION: The DCN has generated a large data and biomaterial bank. Numerous publications have helped to develop further diagnostic procedures and treatment of cognitive disorders and dementia. The DCN has contributed to end stigmatisation of dementia.

Association between autoimmune thyroiditis and depressive disorder in psychiatric outpatients.

Thyroid diseases are often associated with psychiatric disorders. The prevalence of autoimmune thyroiditis in the general population is estimated to be at about 5-14 %. A clinical study was conducted to evaluate the association between autoimmune thyroiditis and depression in psychiatric outpatients. Fifty-two patients with depression and nineteen patients with schizophrenia (serving as control group), attending a psychiatric outpatient unit, were included. In addition to the measurement of thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, antithyroid peroxidase (anti-TPO) antibodies, and anti-thyroglobulin antibodies, ultrasound examination of the thyroid gland was performed. The proportion of pathologically increased anti-TPO levels in patients with depression was high. Furthermore, the distribution of pathologically increased anti-TPO levels was significantly (χ (2) = 5.5; p = 0.019) different between patients with depression (32.7 %) and patients with schizophrenia (5.3 %). In a gender- and age-adjusted logistic regression, the odds ratio of uni- or bipolar patients with depression for an autoimmune thyroiditis was ten times higher (95 % CI = 1.2-85.3) when compared with schizophrenia patients. TSH basal level did not differ between patients with depression and patients with schizophrenia. Our study demonstrates a strong association between anti-TPO levels, which are considered to be of diagnostic value for autoimmune thyroiditis (in combination with a hypoechoic thyroid in ultrasonography) with uni- or bipolar depression. It should be noted that the routinely measured TSH level is not sufficient in itself to diagnose this relevant autoimmune comorbidity.

What are residual symptoms in schizophrenia spectrum disorder? Clinical description and 1-year persistence within a naturalistic trial.

The aim of this study was to evaluate residual symptoms in patients achieving remission according to the consensus criteria and to analyze their potential influence on the patient's outcome one year after discharge. In total, 399 patients suffering from a schizophrenia spectrum disorder were evaluated within a naturalistic study. Remission status was examined using the consensus criteria. Residual symptoms were defined as any symptom present at the time-point of remission following analogous analyses performed in depressed patients. Therefore, a PANSS item with a symptom severity of >1 (= at least borderline mentally ill) was defined to be a residual symptom. Remitters with and without residual symptoms were compared regarding psychopathology, functioning and side effects. In total, 236 patients (59%) were remitters at discharge with 94% of them suffering from at least one residual symptom. The most common residual symptoms were blunted affect (49%), conceptual disorganization (42%) and social withdrawal (40%). A significant association was found between the presence of residual symptoms and the severity of side effects (p < 0.0001) and functioning (p = 0.0003) at discharge as well as between residual symptoms and the risk of relapse and chance of remission one year after discharge. Residual symptoms were highly prevalent in remitted schizophrenia inpatients following the suggested definition. Most residual symptoms were persistent baseline symptoms suggesting an ongoing illness severity. Also, the necessity to re-evaluate the consensus criteria questioning the status of remission in these patients is also pointed out.

Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease.

BACKGROUND: Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. METHODS: The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. RESULTS: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. CONCLUSIONS: The data suggest a neural mechanism for APOE-PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.

Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.