The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression.

BACKGROUND: The Psychopharmacology Algorithm Project at the Harvard South Shore Program (PAPHSS) published algorithms for bipolar depression in 1999 and 2010. Developments over the past 9 years suggest that another update is needed. METHODS: The 2010 algorithm and associated references were reevaluated. A literature search was conducted on PubMed for recent studies and review articles to see what changes in the recommendations were justified. Exceptions to the main algorithm for special patient populations, including those with attention-deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), substance use disorders, anxiety disorders, and women of childbearing potential, and those with common medical comorbidities were considered. RESULTS: Electroconvulsive therapy (ECT) is still the first-line option for patients in need of urgent treatment. Five medications are recommended for early usage in acute bipolar depression, singly or in combinations when monotherapy fails, the order to be determined by considerations such as side effect vulnerability and patient preference. The five are lamotrigine, lurasidone, lithium, quetiapine, and cariprazine. After trials of these, possible options include antidepressants (bupropion and selective serotonin reuptake inhibitors are preferred) or valproate (very small evidence-base). In bipolar II depression, the support for antidepressants is a little stronger but depression with mixed features and rapid cycling would usually lead to further postponement of antidepressants. Olanzapine+fluoxetine, though Food and Drug Administration (FDA) approved for bipolar depression, is not considered until beyond this point, due to metabolic side effects. The algorithm concludes with a table of other possible treatments that have some evidence. CONCLUSIONS: This revision incorporates the latest FDA-approved treatments (lurasidone and cariprazine) and important new studies and organizes the evidence systematically.

Casein kinase II-mediated phosphorylation of lipin 1ß phosphatidate phosphatase at Ser-285 and Ser-287 regulates its interaction with 14-3-3ß protein.

The mammalian lipin 1 phosphatidate phosphatase is a key regulatory enzyme in lipid metabolism. By catalyzing phosphatidate dephosphorylation, which produces diacylglycerol, the enzyme plays a major role in the synthesis of triacylglycerol and membrane phospholipids. The importance of lipin 1 to lipid metabolism is exemplified by cellular defects and lipid-based diseases associated with its loss or overexpression. Phosphorylation of lipin 1 governs whether it is associated with the cytoplasm apart from its substrate or with the endoplasmic reticulum membrane where its enzyme reaction occurs. Lipin 1ß is phosphorylated on multiple sites, but less than 10% of them are ascribed to a specific protein kinase. Here, we demonstrate that lipin 1ß is a bona fide substrate for casein kinase II (CKII), a protein kinase that is essential to viability and cell cycle progression. Phosphoamino acid analysis and phosphopeptide mapping revealed that lipin 1ß is phosphorylated by CKII on multiple serine and threonine residues, with the former being major sites. Mutational analysis of lipin 1ß and its peptides indicated that Ser-285 and Ser-287 are both phosphorylated by CKII. Substitutions of Ser-285 and Ser-287 with nonphosphorylatable alanine attenuated the interaction of lipin 1ß with 14-3-3ß protein, a regulatory hub that facilitates the cytoplasmic localization of phosphorylated lipin 1. These findings advance our understanding of how phosphorylation of lipin 1ß phosphatidate phosphatase regulates its interaction with 14-3-3ß protein and intracellular localization and uncover a mechanism by which CKII regulates cellular physiology.

Validating Nonlinear Registration to Improve Subtraction Images for Lesion Detection and Quantification in Multiple Sclerosis.

BACKGROUND AND PURPOSE: To propose and validate nonlinear registration techniques for generating subtraction images because of their ability to reduce artifacts and improve lesion detection and lesion volume quantification. METHODS: Postcontrast T1 -weighted spin echo and T2 -weighted dual echo images were acquired for 20 patients with relapsing-remitting multiple sclerosis (RRMS) on a monthly basis for a year (14 women, average age 33.6 ± 6.9). The T2 -weighted images from the first scan were used as a baseline for each patient. The images from the last scan were registered to the baseline image. Four different registration algorithms used for evaluation included; linear, halfway linear, nonlinear, and nonlinear halfway. Subtraction images were generated after brain extraction, intensity normalization, and Gaussian blurring. Lesion activity changes along with identified artifacts were scored on all four techniques by two independent observers. Additionally, quantitative analysis of the algorithms was performed by estimating the volume changes of simulated lesions and real lesions. For real lesion volume change analysis, five subjects were selected randomly. Subtraction images were generated between all the 11 time points and the baseline image using linear and nonlinear registration for the five subjects. RESULTS: Lesion activity detection resulted in similar performance among the four registration techniques. Lesion volume measurements on subtraction images using nonlinear registration were closer to lesion volume on T2 -weighted images. A statistically significant difference was observed among the four registration techniques while evaluating yin-yang artifacts. Pairwise comparisons showed that nonlinear registration results in the least amount of yin-yang artifacts, which are significantly different. CONCLUSIONS: Nonlinear registration for generation of subtraction images has been demonstrated to be a promising new technique as it shows improvement in lesion activity change detection. This approach decreases the number of artifacts in subtraction images. With improved lesion volume estimates and reduced artifacts, nonlinear registration may lead to discarding less subject data and an improvement in the statistical power of subtraction imaging studies.

WITHDRAWN: Clinical pathways inference from decision rules by hybrid stream mining and fuzzy unordered rule induction strategy.

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A longitudinal investigation into the progression of dynamic postural stability performance in adolescents.

Adolescent female athletes have a higher incidence of certain non-contact lower limb injuries compared to their male counterparts. Decreased postural stability is an established risk factor for lower limb injuries; however developmental-related sex differences in postural stability during adolescence have not been investigated. The objectives of this study were to longitudinally examine changes over time, and potential sex differences in dynamic postural stability performance in adolescents. One hundred and eighty four adolescent athletes participated (mean age=13±0.34 years). Participants were assessed, using the Star Excursion Balance Test (SEBT) at baseline (T1) and at 6 (T2), 12 (T3), 18 (T4) and 24 (T5) months. At each time-point, participants performed 3 trials of the anterior, posterior-medial and posterior-lateral directions of the SEBT on each limb. Reach distance for each direction was averaged across the 3 trials normalised to leg length. General linear mixed model analyses were carried out on each of the dependant variables (reach directions) with sex and time as the categorical independent variables. There was a significant sex×time interaction for the posterior-lateral reach distance scores. There were no significant sex×time interactions for any of the other reach directions. Males increased performance on the posterior-lateral reach direction from T1 to T5, while females only increased performance until T3. Young males and females demonstrate diverging postural stability profiles during adolescence.

Lithium nephrotoxicity.

Reports of toxic effects on the kidney of lithium treatment emerged very soon after lithium therapy was introduced. Lithium-induced nephrogenic diabetes insipidus is usually self-limiting or not clinically dangerous. Some reports of irreversible chronic kidney disease and renal failure were difficult to attribute to lithium treatment since chronic kidney disease and renal failure exist in the population at large. In recent years, large-scale epidemiological studies have convincingly shown that lithium treatment elevates the risk of chronic kidney disease and renal failure. Most patients do not experience renal side effects. The most common side effect of polyuria only weakly predicts increasing creatinine or reduced kidney function. Among those patients who do experience decrease in creatinine clearance, some may require continuation of lithium treatment even as their creatinine increases. Other patients may be able to switch to a different mood stabilizer medication, but kidney function may continue to deteriorate even after lithium cessation. Most, but not all, evidence today recommends using a lower lithium plasma level target for long-term maintenance and thereby reducing risks of severe nephrotoxicity.

Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.

Evaluation of a dual-wavelength size exclusion HPLC method with improved sensitivity to detect protein aggregates and its use to better characterize degradation pathways of an IgG1 monoclonal antibody.

The evaluation of a dual wavelength size exclusion high performance liquid chromatography (DW-SE-HPLC) method with improved sensitivity to detect aggregates in a high concentration IgG1 monoclonal antibody formulation is presented. This technique utilizes ultraviolet detection at two different wavelengths to monitor the levels of monomer, aggregate, and fragments and was shown to have improved sensitivity for the detection aggregates and fragments compared to light scattering (LS) detection. After assay optimization including the use of column conditioning, the limit of quantitation for aggregates was determined to be 0.04% with essentially complete recovery of aggregates from the column (>99.5%). The DW-SE-HPLC method was used to evaluate the level of protein aggregates generated by different environmental conditions such as exposure to elevated temperatures/acidic pH or intense light. The detection and characterization of protein aggregates by DW-SE-HPLC was compared with an orthogonal biophysical technique (sedimentation velocity analytical ultracentrifugation, SV-AUC). A good overall correlation was observed for levels of monomer, aggregates (dimer and multimers), and fragments as measured by the two analytical techniques (e.g., 6.0% vs. 5.3% and 14% vs. 11% for dimeric aggregates generated by elevated temperature/acidic pH and light exposure, respectively). The stability profile of a high concentration IgG1 monoclonal antibody formulation was investigated under stressed storage conditions (40 degrees C over 3 months) using the DW-SE-HPLC method including the loss of monomeric species with the concomitant accumulation of both aggregates and fragments. The nature and composition of the aggregates (primarily noncovalent dimers) and fragments (primarily loss of Fab from an intact IgG1) formed during storage were further characterized by a combination of LS measurements and mass spectroscopy analysis of deglycosylated IgG1 samples isolated by preparative SE-HPLC. The combination of DW-SE-HPLC, SV-AUC, LS, and mass spectroscopy results provided a detailed overall understanding the monomer, aggregate, fragment degradation pathway(s) for a high concentration IgG1 monoclonal antibody formulation during storage.

Characterization of the photodegradation of a human IgG1 monoclonal antibody formulated as a high-concentration liquid dosage form.

The photodegradation of a human IgG1 monoclonal antibody has been examined in a high concentration (100 mg/mL) liquid formulation. It was observed that a yellowish color is generated when the formulation is exposed to intense and prolonged light exposure, and this discoloration occurs along with a loss in bioactivity. Extensive analytical characterization was performed to determine light induced degradation pathways that occur during exposure to intense light of ICH photodegradation conditions. It has been shown that the monoclonal antibody undergoes a combination of physical and chemical reactions under these conditions, including covalent aggregate formation, fragmentation at the hinge region, oxidation of Trp, His, and Met residues, and deamidation of Asn residues. Oxidation of Trp 94 and deamidation of Asn 93, located in the light chain CDR region, correlates with loss of bioactivity under these conditions. A series of formulation experiments were performed to elucidate the impact of the extent of light exposure, oxygen, protein concentration, and solution pH on the photostability of the formulation. Results demonstrated that photodegradation of the IgG, after intensive light exposure, can be prevented by proper secondary packaging. In addition, it is also shown that a high concentration, liquid dosage form of a human monoclonal antibody is stable upon exposure to the ambient light conditions encountered during routine manufacturing, long-term storage, and administration with proper design of formulation conditions, the primary container as well as the secondary package.