Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.

Low-grade inflammation is considered as a pathophysiological mechanism in a subtype of patients with major depressive disorder (MDD). Anti-inflammatory drugs have shown efficacy in treating MDD. However, it remains unclear how to identify suitable patients for anti-inflammatory treatment of depression. This study investigates the predictive value of pre-treatment high-sensitivity C-Reactive Protein (hsCRP) stratification on the outcome of celecoxib augmentation of vortioxetine. The PREDDICT study was conducted as a randomized, double-blind, placebo-controlled 6-week trial on augmentation of vortioxetine with celecoxib between December 2017 and April 2020 at the University of Adelaide (Australia). The present analysis focusses on the question of whether the pre-treatment hsCRP measurement and stratification of patients to depression with inflammation (hsCRP >3 mg/L) or without inflammation (hsCRP ≤3 mg/L) has an impact on the outcome of anti-inflammatory treatment with celecoxib. A total of n = 119 mostly treatment-resistant MDD patients with moderate to severe symptomatology were recruited in the trial. There was no effect of treatment group (celecoxib or placebo), pre-treatment hsCRP strata (with/without inflammation), or interaction between the two terms on treatment outcome. The results of the current analysis do not support the hypothesis that pre-treatment hsCRP level is predictive for response to anti-inflammatory treatment with celecoxib in MDD patients. Further research is needed to identify appropriate biomarkers for the prediction of anti-inflammatory treatment outcome in depression. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

The Effects of Dose, Practice Habits, and Objects of Focus on Digital Meditation Effectiveness and Adherence: Longitudinal Study of 280,000 Digital Meditation Sessions Across 103 Countries.

BACKGROUND: The efficacy of digital meditation is well established. However, the extent to which the benefits remain after 12 weeks in real-world settings remains unknown. Additionally, findings related to dosage and practice habits have been mixed, and the studies were conducted on small and homogeneous samples and used a limited range of analytical procedures and meditation techniques. Findings related to the predictors of adherence are also lacking and may help inform future meditators and meditation programs on how to best structure healthy sustainable practices. OBJECTIVE: This study aimed to measure outcome change across a large and globally diverse population of meditators and meditations in their naturalistic practice environments, assess the dose-response relationships between practice habits and outcome change, and identify predictors of adherence. METHODS: We used ecological momentary assessment to assess participants' well-being over a 14-month period. We engineered outcomes related to the variability of change over time (equanimity) and recovery following a drop in mood (resilience) and established the convergent and divergent validity of these outcomes using a validated scale. Using linear mixed-effects and generalized additive mixed-effects models, we modeled outcome changes and patterns of dose-response across outcomes. We then used logistic regression to study the practice habits of participants in their first 30 sessions to derive odds ratios of long-term adherence. RESULTS: Significant improvements were observed in all outcomes (P<.001). Generalized additive mixed models revealed rapid improvements over the first 50-100 sessions, with further improvements observed until the end of the study period. Outcome change corresponded to 1 extra day of improved mood for every 5 days meditated and half-a-day-faster mood recovery compared with baseline. Overall, consistency of practice was associated with the largest outcome change (4-7 d/wk). No significant differences were observed across session lengths in linear models (mood: P=.19; equanimity: P=.10; resilience: P=.29); however, generalized additive models revealed significant differences over time (P<.001). Longer sessions (21-30 min) were associated with the largest magnitude of change in mood from the 20th session onward and fewer sessions to recovery (increased resilience); midlength sessions (11-20 min) were associated with the largest decreases in recovery; and mood stability was similar across session lengths (equanimity). Completing a greater variety of practice types was associated with significantly greater improvements across all outcomes. Adhering to a long-term practice was best predicted by practice consistency (4-7 d/wk), a morning routine, and maintaining an equal balance between interoceptive and exteroceptive meditations. CONCLUSIONS: Long-term real-world digital meditation practice is effective and associated with improvements in mood, equanimity, and resilience. Practice consistency and variety rather than length best predict improvement. Long-term sustainable practices are best predicted by consistency, a morning routine, and a practice balanced across objects of focus that are internal and external to the body.

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Characterisation of age and polarity at onset in bipolar disorder.

BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ß = -0.34 years, s.e. = 0.08), major depression (ß = -0.34 years, s.e. = 0.08), schizophrenia (ß = -0.39 years, s.e. = 0.08), and educational attainment (ß = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Exploratory study of association between blood immune markers and cognitive symptom severity in major depressive disorder: Stratification by body mass index status.

BACKGROUND: A subset of patients with Major Depressive Disorder (MDD) have shown differences relative to healthy controls in blood inflammatory and immune markers. Meanwhile, MDD and comorbid obesity appear to present with distinct biological and symptom characteristics, categorised as "atypical" or "immunometabolic" depression, although the relevant underlying biological mechanisms are still uncertain. Therefore, this exploratory study aimed to better characterise the relationship between peripheral blood immune markers and symptoms of MDD, as well as the extent to which body mass index (BMI) may alter this relationship. METHODS: Linear regression analyses were performed between selected baseline characteristics including clinical scales and blood inflammatory markers in participants with MDD (n = 119) enrolled in the PREDDICT randomised controlled trial (RCT), using age, sex and BMI as covariates, and then stratified by BMI status. Specifically, the Montgomery-Åsberg Depression Rating Scale (MADRS) for symptom severity, Clinical Global Impression scale (CGI) for functional impairment, Oxford Depression Questionnaire (ODQ) for emotional blunting, and THINC integrated tool (THINC-it) for cognitive function were considered as clinical measures. RESULTS: There was a significant association between basophil count and THINC-it Codebreaker mean response time (associated with complex attention, perceptual motor, executive function, and learning and memory abilities) in overweight individuals and with THINC-it Trails total response time (associated with executive function ability) in moderately obese individuals, when controlling for age, sex, and years of education. No correlation was found between any tested blood markers and MADRS, CGI or ODQ clinical measures, regardless of BMI. DISCUSSION: Although the present study is exploratory, the results suggest that targeting of the immune system and of metabolic parameters might confer benefits, specifically in patients with high BMI and experiencing cognitive impairment associated with MDD. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017.

Implementation and Outcomes of a Clozapine-Associated Myocarditis Screening Program in a Region of South Australia-Lessons Learned.

PURPOSE: Clozapine-associated myocarditis (CAM) is a serious complication, mostly occurring in the first month of treatment. Public mental health in South Australia introduced a screening protocol in 2011 using baseline and weekly C-reactive protein and troponin. The aim of this study was to assess protocol adherence and management of cases with positive screening results. METHODS: We identified all patients commenced on clozapine in our area between 2012 and 2015. Those with abnormal C-reactive protein and/or troponin in the first 4 weeks of treatment were identified (potential cases). For those, we collected clinical characteristics and test results and reviewed their management. FINDINGS: Protocol compliance increased to 80%. We identified 24 potential CAM cases, 8 at high risk based on established definition (7.6% of new commencements) and 9 formally diagnosed from 143 commenced on clozapine. Potential cases not meeting CAM definition were significantly more likely commenced on clozapine for the first time and have preexisting respiratory disease. Likely CAM cases were younger, and more often prescribed additional antipsychotics, specifically quetiapine. Seven (78%) of 9 patients diagnosed with CAM met published CAM definition. In 14 undiagnosed potential cases, 10 (71%) did not have timely testing to exclude CAM. CONCLUSIONS: Maintaining a high index of suspicion, clinical monitoring and timely testing is important to supplement CAM screening protocols. More research is needed to identify those that can be safely rechallenged or even continue clozapine treatment with monitoring.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Large-scale evidence for an association between low-grade peripheral inflammation and brain structural alterations in major depression in the BiDirect study

Background: Preliminary research suggests that major depressive disorder (MDD) is associated with structural alterations in the brain; as well as with low-grade peripheral inflammation. However, even though a link between inflammatory processes and altered brain structural integrity has been purported by experimental research, well-powered studies to confirm this hypothesis in patients with MDD have been lacking. We aimed to investigate the potential association between structural brain alterations and low-grade inflammation as interrelated biological correlates of MDD. Methods: In this cross-sectional study, 514 patients with MDD and 359 healthy controls underwent structural MRI. We used voxel-based morphometry to study local differences in grey matter volume. We also assessed serum levels of high-sensitivity C-reactive protein (hsCRP) in each participant. Results: Compared with healthy controls (age [mean ± standard deviation] 52.57 ± 7.94 yr; 50% male), patients with MDD (49.14 ± 7.28 yr, 39% male) exhibited significantly increased hsCRP levels (Z = −5.562, p < 0.001) and significantly decreased grey matter volume in the prefrontal cortex and the insula. Prefrontal grey matter volume reductions were significantly associated with higher hsCRP levels in patients with MDD (x = 50, y = 50, z = 8; t1,501 = 5.15; k = 92; pFWE < 0.001). In the MDD sample, the significant negative association between hsCRP and grey matter appeared independent of age, sex, body mass index, current smoking status, antidepressant load, hospitalization and medical comorbidities. Limitations: This study had a cross-sectional design. Conclusion: The present study highlights the role of reduced grey matter volume and low-grade peripheral inflammation as interrelated biological correlates of MDD. The reported inverse association between peripheral low-grade inflammation and brain structural integrity in patients with MDD translates current knowledge from experimental studies to the bedside.

Long-acting atypical antipsychotics in schizophrenia: A systematic review and meta-analyses of effects on functional outcome.

OBJECTIVE: Impairment in psychosocial function is common in schizophrenia. Long-acting injectable atypical antipsychotics are thought to enhance psychosocial function by boosting adherence. However, no systematic review has examined the effects of long-acting injectable atypical antipsychotics on psychosocial function in clinical trials. METHODS: We searched major databases including Medline/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of Controlled Trials and Clinical Trial Registries for randomised controlled trials that compared long-acting injectable atypical antipsychotics to placebo, oral antipsychotic medications or long-acting injectable atypical antipsychotics for all years till 2018, with no language limits. We performed a systematic review of findings on change in psychosocial function and its predictors in the included reports. Data on change in psychosocial functioning were meta-analysed using a random-effects model. RESULTS: A total of 26 studies were included in systematic review, and 19 studies with 8616 adults, 68.1% males were meta-analysed. Long-acting injectable atypical antipsychotics were superior to placebo (standardised mean difference = 0.39; 95% confidence interval = [0.32, 0.47]; p < 0.001; I2 = 0%; 9 studies) and oral antipsychotic medications (standardised mean difference = 0.16; 95% confidence interval = [0.01, 0.31]; p = 0.04; I2 = 77%; 10 studies) for improved psychosocial function and superiority was maintained in short- and long trials. Poor psychosocial function was predicted by longer treatment duration, severe symptoms, poor cognition and poor insight. Functioning was assessed by either a single or a combination of measures, but was not the primary outcome in most studies. Other sources of bias include poor blinding and reporting of randomisation. CONCLUSION: Long-acting injectable atypical antipsychotics are beneficial for recovery of psychosocial function in comparison with placebo, but the magnitude of superiority over oral antipsychotic treatment was small. Severe psychopathology at baseline predicted poor psychosocial function. Future effectiveness trials in which post-randomisation involvement is kept to a minimum, and psychosocial function is included as primary outcome a priori, are needed to capture the real-world impact of long-acting injectable atypical antipsychotics and to address methodological biases.

Beware bandwagons! The bandwagon phenomenon in medicine, psychiatry and management.

OBJECTIVES: We examined the literature on bandwagons, fashions and fads in the fields of medicine, psychiatry and health management. CONCLUSIONS: The bandwagon effect appears to operate across medicine, psychiatry and health management, often to the detriment of patients and health organisations. The authors provide advice on recognising and managing this phenomenon.

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

BACKGROUND: Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. METHODS: Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. FINDINGS: A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). INTERPRETATION: The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. FUNDING: Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans.

Wnts control a wide range of essential developmental processes, including cell fate specification, axon guidance and anteroposterior neuronal polarization. We identified a conserved transmembrane RING finger protein, PLR-1, that governs the response to Wnts by lowering cell-surface levels of the Frizzled family of Wnt receptors in Caenorhabditis elegans. Loss of PLR-1 activity in the neuron AVG causes its anteroposterior polarity to be symmetric or reversed because signaling by the Wnts CWN-1 and CWN-2 are inappropriately activated, whereas ectopic PLR-1 expression blocks Wnt signaling and target gene expression. Frizzleds are enriched at the cell surface; however, when PLR-1 and Frizzled are co-expressed, Frizzled is not detected at the surface but instead is colocalized with PLR-1 in endosomes. The Frizzled cysteine-rich domain (CRD) and invariant second intracellular loop lysine are crucial for PLR-1 downregulation. The PLR-1 RING finger and protease-associated (PA) domain are essential for activity. In a Frizzled-dependent manner, PLR-1 reduces surface levels of the Wnt receptors CAM-1/Ror and LIN-18/Ryk. PLR-1 is a homolog of the mammalian transmembrane E3 ubiquitin ligases RNF43 and ZNRF3, which control Frizzled surface levels in an R-spondin-sensitive manner. We propose that PLR-1 downregulates Wnt receptor surface levels via lysine ubiquitylation of Frizzled to coordinate spatial and temporal responses to Wnts during neuronal development.

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine. OBJECTIVE AND METHODS: Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context. RESULTS: A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported. CONCLUSION: Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

Depressive symptom trajectories in late adolescence and early adulthood: A systematic review.

OBJECTIVE: In adolescents and young adults, depressive symptoms are highly prevalent and dynamic. For clinicians, it is difficult to determine whether a young person reporting depressive symptoms is at risk of developing ongoing mood difficulties or whether symptoms form part of a transient maturational process. Trajectory analyses of longitudinally assessed symptoms in large cohorts have the potential to untangle clinical heterogeneity by determining subgroups or classes of symptom course and their risk factors, by interrogating the impact of known or suspected risk factors on trajectory slope and intercept and by tracing the interrelation between depressive symptoms and other clinical outcomes over time. METHOD: We conducted a systematic review of trajectory studies conducted in cohorts including people aged between 15 and 25 years. RESULTS: We retrieved 47 relevant articles. These studies suggest that young people fall into common mood trajectory classes and that class membership and symptom course are mediated by biological and environmental risk factors. Furthermore, studies provide evidence that high and persistent depressive symptoms are associated with a range of concurrent health and behavioral outcomes. CONCLUSION: Findings could assist in the formulation of novel concepts of depressive disorders in young people and inform preventive strategies and predictive models for clinical practice.

A substantial peer-worker workforce in a psychiatric service will improve patient outcomes - the case against.

OBJECTIVES: The aim of this work was to examine, via narrative review, the evidence supporting the drive for more peer workers to gauge the likely impact on patient outcomes. CONCLUSIONS: Despite considerable research into the effectiveness of peer workers in clinical psychiatry, there is insufficient evidence to support the proposition that a substantial peer workforce would improve the outcomes of people living with mental illness.