Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.

OBJECTIVE: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. METHODS: We conducted an umbrella review to capture all meta-analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small-study effects and excess significance bias was assessed. RESULTS: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value <0.05) effect. Seventy-two of the associations exhibited large or very large between-study heterogeneity, while 13 associations had evidence for small-study effects. Excess significance bias was found in 18 associations. Only five factors (childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level) showed robust evidence. CONCLUSION: Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders. The evidence on peripheral biomarkers for schizophrenia spectrum disorders remains limited.

Homocysteine as a peripheral biomarker in bipolar disorder: A meta-analysis.

BACKGROUND: Bipolar disorder (BD) is a psychiatric disorder with an uncertain aetiology. Recently, special attention has been given to homocysteine (Hcy), as it has been suggested that alterations in 1-carbon metabolism might be implicated in diverse psychiatric disorders. However, there is uncertainty regarding possible alterations in peripheral Hcy levels in BD. METHODS: This study comprises a meta-analysis comparing serum and plasma Hcy levels in persons with BD and healthy controls. We conducted a systematic search for all eligible English and non-English peer-reviewed articles. RESULTS: Nine cross-sectional studies were included in the meta-analyses, providing data on 1547 participants. Random-effects meta-analysis showed that serum and plasma levels of Hcy were increased in subjects with BD in either mania or euthymia when compared to healthy controls, with a large effect size in the mania group (g=0.98, 95% CI: 0.8-1.17, P<0.001, n=495) and a small effect in the euthymia group (g=0.3, 95% CI: 0.11-0.48, P=0.002, n=1052). CONCLUSIONS: Our meta-analysis provides evidence that Hcy levels are elevated in persons with BD during mania and euthymia. Peripheral Hcy could be considered as a potential biomarker in BD, both of trait (since it is increased in euthymia), and also of state (since its increase is more accentuated in mania). Longitudinal studies are needed to clarify the relationship between bipolar disorder and Hcy, as well as the usefulness of peripheral Hcy as both a trait and state biomarker in BD.

Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.

OBJECTIVE: To conduct a systematic review and meta-analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HCs). METHOD: The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random-effects models. RESULT: Eighty-two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon-gamma levels were lower in MDD (Hedge's g = -0.477, P = 0.043). Levels of IL-1ß, IL-2, IL-4, IL-8, the soluble IL-6 receptor (sIL-6R), IL-5, CCL-3, IL-17, and transforming growth factor-beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I2 : 51.6-97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index). CONCLUSION: Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.

Bias in emerging biomarkers for bipolar disorder.

BACKGROUND: To date no comprehensive evaluation has appraised the likelihood of bias or the strength of the evidence of peripheral biomarkers for bipolar disorder (BD). Here we performed an umbrella review of meta-analyses of peripheral non-genetic biomarkers for BD. METHOD: The Pubmed/Medline, EMBASE and PsycInfo electronic databases were searched up to May 2015. Two independent authors conducted searches, examined references for eligibility, and extracted data. Meta-analyses in any language examining peripheral non-genetic biomarkers in participants with BD (across different mood states) compared to unaffected controls were included. RESULTS: Six references, which examined 13 biomarkers across 20 meta-analyses (5474 BD cases and 4823 healthy controls) met inclusion criteria. Evidence for excess of significance bias (i.e. bias favoring publication of 'positive' nominally significant results) was observed in 11 meta-analyses. Heterogeneity was high for (I 2 ⩾ 50%) 16 meta-analyses. Only two biomarkers met criteria for suggestive evidence namely the soluble IL-2 receptor and morning cortisol. The median power of included studies, using the effect size of the largest dataset as the plausible true effect size of each meta-analysis, was 15.3%. CONCLUSIONS: Our findings suggest that there is an excess of statistically significant results in the literature of peripheral biomarkers for BD. Selective publication of 'positive' results and selective reporting of outcomes are possible mechanisms.

Leptin in bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) is a psychiatric disorder associated with increased rates of obesity and inflammation. Leptin is an adipokine that is mainly produced by the white adipose tissue in response to insulin. It stimulates the immune system, increasing the production of pro-inflammatory cytokines. There is currently uncertainty regarding possible alterations in peripheral leptin levels across the mood states in BD. METHODS: This study comprises a between-group meta-analysis comparing serum and plasma leptin levels in people with BD in mania, depression or euthymia and healthy controls. We conducted a systematic search for all possibly eligible-English and non-English peer-reviewed articles. We calculated the effect size (ES) utilizing Hedges' adjusted g using random effects. RESULTS: Eleven studies were included in the meta-analyses, providing data on 1118 participants. Serum and plasma leptin levels were not altered in subjects with BD when compared to healthy controls in mania (g=-0.99, 95% CI -2.43 to 0.43, P=0.171), in depression (g=0.17, 95% CI -0.45 to 0.79, P=0.584), or in euthymia (g=0.03, 95% CI -0.39 to 0.46, P=0.882). However, we did observe a stronger association between leptin levels and both age and BMI in patients with BD in euthymia compared to healthy controls, such that the greater the age of the individuals, the greater the difference in leptin levels between BD and controls; and the higher the BMI, the greater the difference in leptin levels between BD and controls. CONCLUSIONS: Our meta-analysis provides evidence that leptin levels are not altered in BD across the mood spectrum compared to healthy controls. The disproportionate increase of leptin levels with increase in BMI in BD speaks in favour of a potential inflammatory role of white adipose tissue in BD and a disproportionate increase of leptin levels with increase in age.

MEK (MAPKK) inhibitors. Part 2: structure-activity relationships of 4-anilino-3-cyano-6,7-dialkoxyquinolines.

A series of 4-anilino-3-cyano-6,7-dialkoxyquinolines with different substituents attached to the 4-anilino group has been prepared that are potent MEK (MAP kinase kinase) inhibitors. The best activity is obtained when a phenyl or a thienyl group is attached to the para-position of the aniline through a hydrophobic linker, such as an oxygen, a sulfur, or a methylene group. The most active compounds show low nanomolar IC(50)'s against MEK (MAP kinase kinase), and have potent growth inhibitory activity in LoVo cells (human colon tumor line).

Analogues of platelet activating factor. 8. Antagonists of PAF containing an aromatic ring linked to a pyridinium ring.

A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards.

Analogues of platelet activating factor. 7. Bis-aryl amide and bis-aryl urea receptor antagonists of PAF.

A series of bis-aryl amide (13-57 and 66-81) and bis-aryl urea (58 and 85) antagonists of platelet-activating factor (PAF) was prepared that contain, separating the two aromatic rings, linear amide linkages of the form -(CH2)nCONH- (n = 0-2), -OCH2CONH-, and -(CH2)nNHCO- (n = 0-1), branched amide linkages of the form -(CH2)nN(COR)- (n = 1-3, R = CH3 or n-C3H7), and -N(COCH3)CH2-, and urea linkages of the form -NHCONH- and -CH2N(CONHCH3)-. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in the mouse, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Best activity was observed for compounds having linkages of the type -CH2CONH-, -CH2N(COR)-, and -CH2NHCO-. Many of these compounds inhibit PAF-induced platelet aggregation with IC50's under 1 microM.

Studies of the effect of a platelet-activating factor antagonist, CL 184,005, in animal models of gram-negative bacterial sepsis.

The effect of CL 184,005, a potent and specific platelet-activating factor antagonist, has been examined in a variety of animal models relevant to gram-negative bacterial sepsis. Pretreatment of mice with CL 184,005 protected them from the lethal effects of platelet-activating factor. When rats or primates rendered hypotensive with endotoxin were treated with CL 184,005, blood pressure was normalized. Pretreatment of rats with CL 184,005 protected them from the gastrointestinal lesions induced by endotoxin. Pretreatment of rats and mice with CL 184,005 protected them from the lethal effects of endotoxin. Plasma tumor necrosis factor levels in endotoxin-treated mice were lower when the mice were pretreated with CL 184,005. These observations suggest that CL 184,005 may be potentially useful in the treatment of gram-negative bacterial sepsis, and the agent is undergoing clinical evaluation.

Analogues of platelet activating factor. 6. Mono- and bis-aryl phosphate antagonists of platelet activating factor.

A series of aryl phosphoglyceride (3, 19-61) and bis-aryl phosphate (67-135) antagonists of platelet activating factor (PAF) were prepared. A group of four bifunctional phosphorus reagents (5a-c and 7) were developed that allowed the preparation of these aryl phosphates in which the position of aromatic substitution can be varied. These compounds were examined for their ability to inhibit PAF-induced platelet aggregation of rabbit platelets. Selected compounds were also evaluated for their ability to displace [3H]PAF from its receptor on rabbit platelets. These in vitro data were compared to similar data obtained for a number of known PAF antagonists. The compounds were evaluated in vivo, in both the mouse and rabbit, for their ability to prevent death induced by a lethal challenge of PAF. The relationships between the biological activity and the nature, lipophilicity, and position of substituents of the aromatic rings were studied. Compound 105 (CL 184005) has been selected to undergo further development as a potential therapeutic agent for the treatment of septic shock in man.

A computerized multichannel platelet aggregometer system.

Commercially available instrumentation for conducting platelet aggregation studies in clinical and research laboratories consists of one-, two-, or four-channel aggregometers used in conjunction with strip chart recorders. These instruments have limited utility in large-scale drug screening and evaluation of the mode of action of drugs or in the clinical diagnosis of platelet disorders. A new instrument, a computerized multichannel aggregometer system (CMPAS) has been developed to collect, display, and analyze platelet aggregation data. The system is comprised of a 24-channel Born-type aggregometer, interfaced to a Rockwell AIM-65 microcomputer through an analogue-to-digital converter and an Epson dot-matrix printer. Each channel is individually calibrated, and aggregation data can be collected on up to 24 different platelet-rich plasma samples simultaneously. Conversational programs written in BASIC prompt the user for the addition of agonists and inhibitors. The tracings for each channel are displayed simultaneously, and a program automatically analyzes the data to generate the following parameters: baseline optical density, maximum aggregation response, positive and negative slopes, time to peak aggregation, and percentage response. Computerized multichannel aggregometer system data outputs are comparable to data generated by a standard Chronolog aggregometer unit. The advantages of the system include multichannel capability, simultaneous display of all channels allowing relative comparisons between control and experimental groups, and time savings and improved efficiency in conducting and analyzing aggregation experiments.

Analogues of platelet activating factor. 5. Multiple oxygen substitution of the alkoxy chain.

Racemic analogues of platelet activating factor (PAF) in which the alkoxy chain (R = -O(CH2)15CH3) has been replaced with a chain containing multiple ether linkages near the end (17, R = -O(CH2)8O(CH2)2O(CH2)2OCH3) or at the beginning (18, R = -O(CH2)2O(CH2)2O(CH2)9CH3) of the chain have been prepared. Both compounds exhibit reduced hypotensive and platelet aggregation responses compared to racemic C16-PAF (1a). This reduction in the biological activities is more apparent when the new oxygen atoms are located near the end of the chain. This substitution of additional oxygen atoms into the alkoxy chain does not result in any dramatic gains in selectivity of the biological responses.

Analogues of platelet activating factor. 4. Some modifications of the phosphocholine moiety.

Racemic analogues of platelet activating factor (PAF) in which the methylene bridge separating the phosphate and trimethylammonium moieties is altered in length (7a-f) have been prepared. Increasing the length of this bridge results in a progressive decrease in the hypotensive and platelet aggregation responses. Analogues in which the phosphocholine group is substituted with a methyl group (7h and 7i) or a phenyl group (5j) or in which the methylene bridge is replaced with a meta-substituted benzyl group (5k) have been prepared. With respect to both the blood pressure and platelet aggregation responses, 7i and 5k showed little if any changes in potency compared to racemic C16-PAF (1a). While 7h is more potent than 1a with respect to both the hypotensive and platelet aggregation properties, 5j is less potent. Replacement of the phosphate moiety of C18-PAF (1b) with a phosphonate group (7g) leads to decreased activity in both assays. Analogue 11, in which the phosphocholine group has been replaced with a 4-(trimethylammonio)butoxy group, exhibited no detectable hypotensive or platelet aggregating activity. None of the analogues exhibited a separation of the blood pressure and platelet aggregation activities.

Analogues of platelet activating factor (PAF). 2. Some modifications of the glycerine backbone.

Racemic analogues of platelet activating factor (PAF) that contain a methylene group between the C2 and C3 carbon atoms (39) or between the C1 and C2 carbon atoms (40) have been synthesized. These compounds show reduced platelet aggregation and hypotensive activity as measured against racemic C16 PAF. Compounds in which the C1 carbon atom of PAF is substituted with one or two methyl groups (41 and 42, respectively) or the C3 carbon is substituted with a single methyl group (43) have been synthesized. Platelet aggregation and hypotensive responses produced by these compounds are significantly less than those obtained with racemic C16 PAF. None of the above compounds exhibit a separation of the platelet aggregation and hypotensive activities.

Analogues of platelet activating factor. 3. Replacement of the phosphate moiety with a sulfonylbismethylene group.

An analogue of platelet activating factor (PAF) in which the phosphate moiety has been replaced with a sulfonylbismethylene group has been prepared. A key step in the synthetic sequence is the preparation of 4-[[3-(dimethylamino)propyl]thio]-1-(hexadecyloxy)-2-butanol via a one-pot reaction involving a sequential Michael addition and reduction. In comparison to racemic C16-PAF, 8 showed no platelet aggregating activity and substantially reduced hypotensive activity.

Automated platelet aggregation analysis using a digitizer.

A method of rapidly entering, reducing, and interpreting data collected in platelet aggregation studies has been developed. The standard aggregometer output is a chart recording of light transmittance (or optical density) as a function of time following the addition of an aggregating agent to a cuvette containing platelet-rich plasma or washed, suspended platelets. Two problems associated with aggregation studies are the proper calibration of the aggregometer and recorder to insure that comparisons of data can be made from experiment to experiment and the need to find a convenient way to analyze and summarize the data generated. In this method, the chart recorder is calibrated using reference cuvettes containing water or a suspension of latex beads of a known optical density. Since the analysis and interpretation of aggregation curves can be a time-consuming task, a standard digitizer has been interfaced to a computer, allowing the X,Y coordinates of the data, and, thus, the time-aggregation history of the sample, to be entered into the computer. The cursor of the digitizer is traced over the aggregation curve and the X,Y coordinates are transferred either at operator-selectable points or at fixed time intervals. A computer program (AGGPAD) calculates and stores several variables (e.g., sample baseline density, the magnitude of the aggregation, time to peak aggregation, maximum aggregation rate, and maximum deaggregation rate) that can be easily retrieved. The system reduces analysis time by a factor of five and allows for automated data storage and retrieval. The method is applicable to any computer and hardware costs are below $1000.00.

Analogues of platelet activating factor (PAF). 1. Some modifications of the alkoxy chain.

Analogues of platelet activating factor (PAF) in which the ether oxygen has been removed (6) and in which the alkoxy chain at C1 has been replaced with a o-, p-, or m-alkylphenoxy group (30, 31, and 35, respectively) have been prepared. Compound 6 shows reduced platelet aggregation and hypotensive activity in comparison with C16 and C18 PAF. The results obtained for compounds 30, 31, and 35 indicate that the hypotensive and platelet aggregating responses are sensitive to structural modification of the ether chain. The ortho analogue 30 shows no platelet aggregating activity and only a weak hypotensive response. The para analogue 31 exhibits a moderate decrease in activity in both assays. The meta analogue 35 is the most active of the three.