Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders,bipolar disorder and major depressive disorder: a systematic review and meta‐analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = ?3.6, p = 0.0003, r² = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.     

Sedentary behavior and physical activity levels in people with schizophrenia,bipolar disorder and major depressive disorder: a global systematic review and meta‐analysis

People with severe mental illness (schizophrenia, bipolar disorder or major depressive disorder) die up to 15 years prematurely due to chronic somatic comorbidities. Sedentary behavior and low physical activity are independent yet modifiable risk factors for cardiovascular disease and premature mortality in these people. A comprehensive meta‐analysis exploring these risk factors is lacking in this vulnerable population. We conducted a meta‐analysis investigating sedentary behavior and physical activity levels and their correlates in people with severe mental illness. Major electronic databases were searched from inception up to April 2017 for articles measuring sedentary behavior and/or physical activity with a self‐report questionnaire or an objective measure (e.g., accelerometer). Random effects meta‐analyses and meta‐regression analyses were conducted. Sixty‐nine studies were included (N=35,682; 39.5% male; mean age 43.0 years). People with severe mental illness spent on average 476.0 min per day (95% CI: 407.3‐545.4) being sedentary during waking hours, and were significantly more sedentary than age‐ and gender‐matched healthy controls (p=0.003). Their mean amount of moderate or vigorous physical activity was 38.4 min per day (95% CI: 32.0‐44.8), being significantly lower than that of healthy controls (p=0.002 for moderate activity, p<0.001 for vigorous activity). People with severe mental illness were significantly less likely than matched healthy controls to meet physical activity guidelines (odds ratio = 1.5; 95% CI: 1.1‐2.0, p<0.001, I²=95.8). Lower physical activity levels and non‐compliance with physical activity guidelines were associated with male gender, being single, unemployment, fewer years of education, higher body mass index, longer illness duration, antidepressant and antipsychotic medication use, lower cardiorespiratory fitness and a diagnosis of schizophrenia. People with bipolar disorder were the most physically active, yet spent most time being sedentary. Geographical differences were detected, and inpatients were more active than outpatients and those living in the community. Given the established health benefits of physical activity and its low levels in people with severe mental illness, future interventions specifically targeting the prevention of physical inactivity and sedentary behavior are warranted in this population.     

Prevalence,incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls

People with severe mental illness (SMI) – schizophrenia, bipolar disorder and major depressive disorder – appear at risk for cardiovascular disease (CVD), but a comprehensive meta‐analysis is lacking. We conducted a large‐scale meta‐analysis assessing the prevalence and incidence of CVD; coronary heart disease; stroke, transient ischemic attack or cerebrovascular disease; congestive heart failure; peripheral vascular disease; and CVD‐related death in SMI patients (N=3,211,768) versus controls (N=113,383,368) (92 studies). The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4‐13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross‐sectional studies (odds ratio, OR=1.53, 95% CI: 1.27‐1.83; 11 studies), and higher odds of coronary heart disease (OR=1.51, 95% CI: 1.47‐1.55) and cerebrovascular disease (OR=1.42, 95% CI: 1.21‐1.66). People with major depressive disorder were at increased risk for coronary heart disease, while those with schizophrenia were at increased risk for coronary heart disease, cerebrovascular disease and congestive heart failure. Cumulative CVD incidence in SMI patients was 3.6% (95% CI: 2.7‐5.3) during a median follow‐up of 8.4 years (range 1.8‐30.0). Adjusting for a median of six confounders, SMI patients had significantly higher CVD incidence than controls in longitudinal studies (hazard ratio, HR=1.78, 95% CI: 1.60‐1.98; 31 studies). The incidence was also higher for coronary heart disease (HR=1.54, 95% CI: 1.30‐1.82), cerebrovascular disease (HR=1.64, 95% CI: 1.26‐2.14), congestive heart failure (HR=2.10, 95% CI: 1.64‐2.70), and CVD‐related death (HR=1.85, 95% CI: 1.53‐2.24). People with major depressive disorder, bipolar disorder and schizophrenia were all at increased risk of CVD‐related death versus controls. CVD incidence increased with antipsychotic use (p=0.008), higher body mass index (p=0.008) and higher baseline CVD prevalence (p=0.03) in patients vs. controls. Moreover, CVD prevalence (p=0.007), but not CVD incidence (p=0.21), increased in more recently conducted studies. This large‐scale meta‐analysis confirms that SMI patients have significantly increased risk of CVD and CVD‐related mortality, and that elevated body mass index, antipsychotic use, and CVD screening and management require urgent clinical attention.     

Effects of antipsychotics,antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia,depression and bipolar disorder

People with severe mental illness have a considerably shorter lifespan than the general population. This excess mortality is mainly due to physical illness. Next to mental illness‐related factors, unhealthy lifestyle, and disparities in health care access and utilization, psychotropic medications can contribute to the risk of physical morbidity and mortality. We systematically reviewed the effects of antipsychotics, antidepressants and mood stabilizers on physical health outcomes in people with schizophrenia, depression and bipolar disorder. Updating and expanding our prior systematic review published in this journal, we searched MEDLINE (November 2009 ‐ November 2014), combining the MeSH terms of major physical disease categories (and/or relevant diseases within these categories) with schizophrenia, major depressive disorder and bipolar disorder, and the three major psychotropic classes which received regulatory approval for these disorders, i.e., antipsychotics, antidepressants and mood stabilizers. We gave precedence to results from (systematic) reviews and meta‐analyses wherever possible. Antipsychotics, and to a more restricted degree antidepressants and mood stabilizers, are associated with an increased risk for several physical diseases, including obesity, dyslipidemia, diabetes mellitus, thyroid disorders, hyponatremia; cardiovascular, respiratory tract, gastrointestinal, haematological, musculoskeletal and renal diseases, as well as movement and seizure disorders. Higher dosages, polypharmacy, and treatment of vulnerable (e.g., old or young) individuals are associated with greater absolute (elderly) and relative (youth) risk for most of these physical diseases. To what degree medication‐specific and patient‐specific risk factors interact, and how adverse outcomes can be minimized, allowing patients to derive maximum benefits from these medications, requires adequate clinical attention and further research.     

Mortality in people with schizophrenia: a systematic review and meta‐analysis of relative risk and aggravating or attenuating factors

People with schizophrenia die 15‐20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random‐effects meta‐analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all‐cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific‐cause mortality. Publication bias, subgroup and meta‐regression analyses, and quality assessment (Newcastle‐Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population. Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio‐cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All‐cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001‐0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all‐cause and suicide‐related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide‐related mortality risk in incident schizophrenia samples. All‐cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all‐cause mortality (RR=1.62, 95% CI: 1.47‐1.80, n=3). Antipsychotics were protective against all‐cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59‐0.84, n=11), with largest effects for second‐generation long‐acting injectable anti­psychotics (SGA‐LAIs) (RR=0.39, 95% CI: 0.27‐0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34‐0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39‐0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44‐0.63, n=4). Antipsychotics were also protective against natural cause‐related mortality, yet first‐generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural‐cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long‐term maintenance antipsychotic treatment and appropriate/earlier use of SGA‐LAIs and clozapine could reduce this mortality gap.     

Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review,meta‐analysis and meta‐regression analysis

Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta‐analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co‐primary outcomes were total symptom reduction and study‐defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=–0.53, 95% CI: ?0.87 to ?0.19, p=0.002). However, superiority was only apparent in open‐label and low‐quality trials (both p<0.001), but not in double‐blind and high‐quality ones (p=0.120 and 0.226, respectively). Study‐defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non‐significant in double‐blind and high‐quality studies (both p=0.990). Findings were replicated in clozapine and non‐clozapine augmentation studies. No differences emerged regarding all‐cause/specific‐cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=–0.38, 95% CI: ?0.63 to ?0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=–0.41, 95% CI: ?0.79 to ?0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double‐blind/high‐quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.     

The financial situation before and after first-time psychiatric in-patient diagnosis of schizophrenia spectrum,bipolar, and major depressive disorder

Schizophrenia spectrum, bipolar, and major depressive disorders are severe mental illnesses (SMIs) that not only entail great suffering for those affected but also major societal costs. In this study, I use administrative register data to provide a detailed picture of the financial situation of people with SMI in Sweden during a period of $\pm$10 years around first-time psychiatric in-patient diagnosis of schizophrenia spectrum, bipolar, and major depressive disorders. Receiving a diagnosis was associated with a considerable drop in earnings, which was largely compensated for by social transfers: mainly sickness and disability insurance. However, there were also large and increasing pre-diagnosis earnings gaps, relative to matched comparison groups, especially among those with schizophrenia spectrum disorders. These gaps were to a lesser extent compensated for by social transfers. Consequently, there were permanent and increasing – due to lost earnings growth – income differentials. Hence, findings in previous studies are confirmed: even in an advanced welfare state, people with SMI – especially those with schizophrenia – have an extremely weak position on the labour market and an equally difficult financial situation.     

Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil

Linkage and association studies in five independently ascertained samples have suggested that polymorphisms of the regulator of G-protein signaling 4 (RGS4) may confer risk for schizophrenia (SCZ). Suggestive evidence for association with bipolar disorder (BD) has also been presented. However, the associated alleles and haplotypes have differed among the samples. Data from other independent samples may clarify the putative associations. Hence, we investigated an independent, ethnically diverse Brazilian population comprising patients with SCZ (n=271) or BD1 (n=306), who were contrasted with 576 community-based controls. Parents of 49 SCZ cases and 44 BD cases were available for transmission disequilibrium tests (TDTs). Four RGS4 single-nucleotide polymorphisms (SNPs) 1, 4, 7 and 18 putatively associated with SCZ were investigated. In the SCZ samples, significant case-control differences were not observed for individual SNPs or haplotypes, though the TDT suggested transmission distortion similar to that observed in the initial report. For the BD sample, case-control comparisons revealed no significant differences for individual SNPs, but an omnibus test suggested differences in the overall distribution of haplotypes bearing all four SNPs (SNP-EM Omnibus likelihood ratio test; P=0.003). The TDT revealed over-transmission of allele A at SNP7 (P=0.016), as well as haplotypes incorporating this allele. However, global tests incorporating all haplotypes yielded only suggestive trends for association (P=0.19). In conclusion, association with SCZ was not detected in the present analyses. The failure to detect an association may be related to inadequate power or to confounds related to ethnic admixture. Suggestive associations with BD detected here require further investigation in a larger sample.     

Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder

Recent data from several reports indicate that free radicals are involved in aetiopathogenesis of many human pathologies including neuropsychiatric disorders such as schizophrenia, bipolar disorder etc. In the present study, we aimed at determining and evaluating levels of malondialdehyde (MDA), a product of lipid peroxidation, and antioxidant enzyme superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels in patients diagnosed with schizophrenia (n = 25) and bipolar disorder (n = 23). The control group was composed of 20 healthy subjects. There was a significant increase in MDA levels of patients with schizophrenia and bipolar disorder compared with controls. SOD and GSH-Px activity levels were significantly higher in the schizophrenic group compared with controls. SOD activity levels in bipolar the group were significantly higher than controls whereas there were no significant changes in GSH-Px activity levels in the bipolar group and controls. Significant differences between lipid peroxidation product and antioxidant enzyme (SOD and GSH-Px) activity levels in schizophrenic and bipolar disorder patients compared with controls leads us to believe that these differences are related to the heterogenities in aetiologies of these disorders.     

The promise of cognitive behavior therapy for treatment of severe mental disorders: a review of recent developments

Cognitive behavior therapy (CBT), as exemplified by the model of psychotherapy developed and refined over the past 40 years by A.T. Beck and colleagues, is one of the treatments of first choice for ambulatory depressive and anxiety disorders. Over the past several decades, there have been vigorous efforts to adapt CBT for treatment of more severe mental disorders, including schizophrenia and the more chronic and/or treatment refractory mood disorders. These efforts have primarily studied CBT as an adjunctive therapy, i.e., in combination with pharmacotherapy. Given the several limitations of state‐of‐the‐art pharmacotherapies for these severe mental disorders, demonstration of clinically meaningful additive effects for CBT would have important implications for improving public health. This paper reviews the key developments in this important area of therapeutics, providing a summary of the current state of the art and suggesting directions for future research.     

Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia

We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.     

Eveningness and poor sleep quality contribute to depressive residual symptoms and behavioral inhibition in patients with bipolar disorder

ABSTRACT

Eveningness and sleep disturbances are considered as markers of Bipolar Disorder (BD) and influence mood and emotional or behavioral states. This study investigates the associations between circadian markers and sleep quality on residual depressive symptoms and inhibition/activation dimensions during the euthymic phase. A sample of 89 euthymic adult individuals with BD was assessed for circadian preference and typology using the Composite Scale of Morningness (CSM) and the Circadian Type Inventory (CTI) and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). The Montgomery and Asberg Depression Rating Scale (MADRS) and the Multidimensional Assessment of Thymic States (MAThyS) were used to measure residual depressive symptoms and the inhibition/activation dimensions. We examined any associations between these parameters using correlations and path analyses. We identified significant associations between eveningness and poorer sleep quality that correlated to higher depressive residual symptoms and a global inhibition. The use of path analyses led us to conclude that poor sleep quality mediated the relationship between eveningness and either residual mood symptoms or behavioral inhibition (motivation, sensory perception, interpersonal interaction, and cognition). These factors should be considered in the clinical evaluation of individuals with BD, with a specific attention during the euthymic phase, in order to achieve the best functional outcome possible.     

Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized,double-blind,placebo-controlled study

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness–Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.     

首发重性抑郁症患者肠道菌群组成及与胃肠道症状的相关性

【背景】重性抑郁症(majordepressivedisorder,MDD)是一种常见的重大精神疾病,MDD患者多伴有胃肠道症状,但很少有研究关注MDD患者胃肠道症状发生的机制。【目的】探索首发未治疗MDD患者肠道菌群的特征及其与炎症标志物和胃肠道症状的相关性,为MDD的治疗提供理论依据。【方法】募集符合入组和排除标准的91例首发未服药MDD患者和105名健康对照者(healthy controls, HCs)。采用16S rRNA基因测序技术和生物信息学分析评估粪便菌群组成。采用酶联免疫吸附试验(enzymelinkedimmunosorbentassay,ELISA)检测外周血高敏C反应蛋白(high-sensitivity C-reactive protein, hs-CRP)、白细胞介素-1β (interleukin-1β, IL-1β)、白细胞介素-6(interleukin-6,IL-6)、白细胞介素-10(interleukin-10,IL-10)和肿瘤坏死因子-α(tumornecrosis factor-α, TNF-α);采用胃肠症状评定量表(gastrointe...     

Early warning biomarkers in major depressive disorder: a strategic approach to a testing question

Purpose: Identification of biomarkers in major depressive disorder (MDD) has proceeded in an extemporised manner. No single biomarker has been identified with utility in screening, diagnosis, prognosis, or monitoring, and screening tests have different characteristics than the other functions. Using chaos, bifurcation, and perturbation (CBP) theories, the aim is to identify biomarkers to aid clinicians in screening for MDD.

Materials and methods: MDD is a complex disorder; consequently, a reductionist approach to characterize the complex system changes found in MDD will be inchoate and unreliable. A holistic approach is used to identify biomarkers reflecting the tipping points seen before the catastrophic bifurcation that results in MDD.

Results: Applying CBP theories revealed skew, resistance to change, flickering, increased variance and autocorrelation as patterns of biomarkers. Integrals and differentials of extracellular and intracellular biomarkers were identified, specifically focussed on hypothalamo-pituitary axis (HPA) dysfunction, metabolic dysfunction, inflammation and mitochondrial oxidative stress, and tryptophan metabolism.

Conclusions: Applying CBP theories to the dysfunctional complex biological systems in MDD led to development of integrals and differentials of biomarkers that can be used in screening for MDD and planning future biomarker research, targeting intracellular and extracellular inflammation, HPA axis dysfunction, and tryptophan metabolism.     

Management of persons with co-occurring severe mental illness and substance use disorder: program implications

Adults with severe mental illness have extraordinarily high rates of co-occurring substance use disorders, typically around 50% or more, which adversely affect their current adjustment, course, and outcome. Separate and parallel mental health and substance abuse treatment systems do not offer interventions that are accessible, integrated, and tailored for the presence of co-occurrence. Recent integrated interventions for this population have the specific goal of ameliorating substance use disorder and the general goal of improving adjustment and quality of life. The authors overview the current research and offer guidelines related to mission and philosophy, leadership, comprehensive reorganization, training, specific programs, and quality improvement.     

Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=?1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.     

Long‐term effectiveness of oral second‐generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta‐analysis of direct head‐to‐head comparisons

Second‐generation antipsychotics (SGAs) are recommended for maintenance treatment in schizophrenia. However, comparative long‐term effectiveness among SGAs is unclear. Here we provide a systematic review and meta‐analysis of randomized trials lasting ≥?6 months comparing SGAs head‐to‐head in schizophrenia and related disorders. The primary outcome was all‐cause discontinuation. Secondary outcomes included efficacy and tolerability, i.e., psychopathology, inefficacy‐related and intolerability‐related discontinuation, relapse, hospitalization, remission, functioning, quality of life, and adverse events. Pooled risk ratio and standardized mean difference were calculated using random‐effects models. Across 59 studies (N=45,787), lasting 47.4±32.1 weeks (range 24‐186), no consistent superiority of any SGA emerged across efficacy and tolerability outcomes. Regarding all‐cause discontinuation, clozapine, olanzapine and risperidone were significantly (p<0.05) superior to several other SGAs, while quetiapine was inferior to several other SGAs. As to psychopathology, clozapine and olanzapine were superior to several other SGAs, while quetiapine and ziprasidone were inferior to several other SGAs. Data for other efficacy outcomes were sparse. Regarding intolerability‐related discontinuation, risperidone was superior and clozapine was inferior to several other SGAs. Concerning weight gain, olanzapine was worse than all other compared non‐clozapine SGAs, and risperidone was significantly worse than several other SGAs. As to prolactin increase, risperidone and amisulpride were significantly worse than several other SGAs. Regarding parkinsonism, olanzapine was superior to risperidone, without significant differences pertaining to akathisia. Concerning sedation and somnolence, clozapine and quetiapine were significantly worse than some other SGAs. In summary, different long‐term SGA efficacy and tolerability patterns emerged. The long‐term risk‐benefit profiles of specific SGAs need to be tailored to individual patients to optimize maintenance treatment outcomes.     

The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta‐analysis of direct comparisons

Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: −0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant.