Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies

The persistence of depressive morbidity is frequent in bipolar disorder, and the pharmacological management of this symptomatology often lacks effectiveness. This systematic review aimed to summarize the results of the naturalistic observational studies on the pharmacological treatment of bipolar depression published through April 2022. The certainty of evidence was evaluated according to the GRADE approach. In sum, 16 studies on anticonvulsants, 20 on atypical antipsychotics, 2 on lithium, 28 on antidepressants, and 9 on other compounds were found. Lamotrigine, quetiapine, aripiprazole, and ketamine were the most investigated compounds. Overall, the results support the recommendations regarding the effectiveness of lamotrigine and quetiapine. In contrast to the current recommendations, aripiprazole was shown to be effective and generally well tolerated. Additionally, SSRIs were shown to be effective, but, since they were associated with a possibly higher switch risk, they should be used as an adjunctive therapy to mood stabilizers. Lithium was only studied in two trials but was shown to be effective, although the serum concentrations levels were not associated with clinical response. Finally, ketamine showed divergent response rates with a low certainty of evidence and, so far, unclear long-term effects. Heterogeneity in diagnosis, sample sizes, study designs, reporting of bias, and side effects limited the possibility of a head-to-head comparison

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons

Ca2+-activated ion channels shape membrane excitability in response to elevations in intracellular Ca2+. The most extensively studied Ca2+-sensitive ion channels are Ca2+-activated K+ channels, whereas the physiological importance of Ca2+-activated Cl- channels has been poorly studied. Here we show that a Ca2+-activated Cl- currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells. Electrophysiological recording of mouse sympathetic neurons in an in vitro preparation of the superior cervical ganglion (SCG) identifies neurons with two different firing patterns in response to long depolarizing current pulses (1 s). Neurons classified as phasic (Ph) made up 67% of the cell population whilst the remainders were tonic (T). When a high frequency train of spikes was induced by intracellular current injection, SCG sympathetic neurons reached an afterpotential mainly dependent on the ratio of activation of two Ca2+-dependent currents: the K+ [IK(Ca)] and CaCC. When the IK(Ca) was larger, an afterhyperpolarization was the predominant afterpotential but when the CaCC was larger, an afterdepolarization (ADP) was predominant. These afterpotentials can be observed after a single action potential (AP). Ph and T neurons had similar ADPs and hence, the CaCC does not seem to determine the firing pattern (Ph or T) of these neurons. However, inhibition of Ca2+-activated Cl- channels with anthracene-9′-carboxylic acid (9AC) selectively inhibits the ADP, reducing the firing frequency and the instantaneous frequency without affecting the characteristics of single- or first-spike firing of both Ph and T neurons. Furthermore, we found that the CaCC underlying the ADP was significantly larger in SCG neurons from males than from females. Furthermore, the CaCC ANO1/TMEM16A was more strongly expressed in male than in female SCGs. Blocking ADPs with 9AC did not modify synaptic transmission in either Ph or T neurons. We conclude that the CaCC responsible for ADPs increases repetitive firing in both Ph and T neurons, and it is more relevant in male mouse sympathetic ganglion neurons.This work was supported by grants PB92-0347 and PM95-0107 (from the Dirección General de Investigación Científica y Técnica, Spain) to Roberto Gallego and the Instituto de Cultura Juan Gil-Albert (Diputación de Alicante, Spain) to FdC. Our current work was supported by grants SAF2016-77575-R and RD16/0015/0019 (both from Ministerio de Economía, Innovación y Competitividad-MINEICO, Spain) to FdC and Generalitat Valenciana, PROMETEOII/2015/016 to AN. CIBERDEM is an initiative of the Instituto de Salud Carlos III

The Physical Drivers and Observational Tracers of CO-to-H2 Conversion Factor Variations in Nearby Barred Galaxy Centers

The CO-to-H$_2$ conversion factor (\alpha_\rm{CO}) is central to measuring the amount and properties of molecular gas. It is known to vary with environmental conditions, and previous studies have revealed lower \alpha_\rm{CO} in the centers of some barred galaxies on kpc scales. To unveil the physical drivers of such variations, we obtained ALMA Band 3, 6, and 7 observations toward the inner 2 kpc of NGC 3627 and NGC 4321 tracing $^{12}$CO, $^{13}$CO, and C$^{18}$O lines on 100 pc scales. Our multi-line modeling and Bayesian likelihood analysis of these datasets reveal variations of molecular gas density, temperature, optical depth, and velocity dispersion, which are among the key drivers of \alpha_\rm{CO}. The central 300 pc nuclei in both galaxies show strong enhancement of temperature T_\rm{k}>100 K and density n_\rm{H_2}>10^3 cm$^{-3}$. Assuming a CO-to-H$_2$ abundance of $3\times10^{-4}$, we derive 4-15 times lower \alpha_\rm{CO} than the Galactic value across our maps, which agrees well with previous kpc-scale measurements. Combining the results with our previous work on NGC 3351, we find a strong correlation of \alpha_\rm{CO} with low-J $^{12}$CO optical depths (\tau_\rm{CO}), as well as an anti-correlation with T_\rm{k}. The \tau_\rm{CO} correlation explains most of the \alpha_\rm{CO} variation in the three galaxy centers, whereas changes in T_\rm{k} influence \alpha_\rm{CO} to second order. Overall, the observed line width and $^{12}$CO/$^{13}$CO 2-1 line ratio correlate with \tau_\rm{CO} variation in these centers, and thus they are useful observational indicators for \alpha_\rm{CO} variation. We also test current simulation-based \alpha_\rm{CO} prescriptions and find a systematic overprediction, which likely originates from the mismatch of gas conditions between our data and the simulations.Comment: Accepted for publication in ApJ; 30 pages of main text + 3 appendice

Fuelling the nuclear ring of NGC 1097

Galactic bars can drive cold gas inflows towards the centres of galaxies. The gas transport happens primarily through the so-called bar ``dust lanes'', which connect the galactic disc at kpc scales to the nuclear rings at hundreds of pc scales much like two gigantic galactic rivers. Once in the ring, the gas can fuel star formation activity, galactic outflows, and central supermassive black holes. Measuring the mass inflow rates is therefore important to understanding the mass/energy budget and evolution of galactic nuclei. In this work, we use CO datacubes from the PHANGS-ALMA survey and a simple geometrical method to measure the bar-driven mass inflow rate onto the nuclear ring of the barred galaxy NGC~1097. The method assumes that the gas velocity in the bar lanes is parallel to the lanes in the frame co-rotating with the bar, and allows one to derive the inflow rates from sufficiently sensitive and resolved position-position-velocity diagrams if the bar pattern speed and galaxy orientations are known. We find an inflow rate of $\dot{M}=(3.0 \pm 2.1)\, \rm M_\odot\, yr^{-1}$ averaged over a time span of 40 Myr, which varies by a factor of a few over timescales of $\sim$10 Myr. Most of the inflow appears to be consumed by star formation in the ring which is currently occurring at a rate of ${\rm SFR}\simeq~1.8$-$2 \rm M_\odot\, yr^{-1}$, suggesting that the inflow is causally controlling the star formation rate in the ring as a function of time.Comment: Accepted in MNRA

Serendipitous Nebular-phase JWST Imaging of SN Ia 2021aefx: Testing the Confinement of 56-Co Decay Energy

We present new 0.3-21 micron photometry of SN 2021aefx in the spiral galaxy NGC 1566 at +357 days after B-band maximum, including the first detection of any SN Ia at >15 micron. These observations follow earlier JWST observations of SN 2021aefx at +255 days after the time of maximum brightness, allowing us to probe the temporal evolution of the emission properties. We measure the fraction of flux emerging at different wavelengths and its temporal evolution. Additionally, the integrated 0.3-14 micron decay rate of $\Delta m_{0.3-14} = 1.35 \pm 0.05$ mag/100 days is higher than the decline rate from the radioactive decay of $^{56}$Co of $\sim 1.2$mag/100 days. The most plausible explanation for this discrepancy is that flux is shifting to >14 micron, and future JWST observations of SNe Ia will be able to directly test this hypothesis. However, models predicting non-radiative energy loss cannot be excluded with the present data.Comment: Accepted for publication in ApJL; 11 pages, 4 figures, 2 tables in two-column AASTEX63 forma

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers

PHANGS-JWST First Results: A combined HST and JWST analysis of the nuclear star cluster in NGC 628

We combine archival HST and new JWST imaging data, covering the ultraviolet to mid-infrared regime, to morphologically analyze the nuclear star cluster (NSC) of NGC 628, a grand-design spiral galaxy. The cluster is located in a 200 pc x 400 pc cavity, lacking both dust and gas. We find roughly constant values for the effective radius (r_eff ~ 5 pc) and ellipticity ({\epsilon} ~ 0.05), while the S\'ersic index (n) and position angle (PA) drop from n ~ 3 to ~ 2 and PA ~ 130{\deg} to 90{\deg}, respectively. In the mid-infrared, r_eff ~ 12pc, {\epsilon} ~ 0.4, and n ~ 1-1.5, with the same PA ~ 90{\deg}. The NSC has a stellar mass of log10 (M_nsc / M_Sun) = 7.06 +- 0.31, as derived through B-V, confirmed when using multi-wavelength data, and in agreement with the literature value. Fitting the spectral energy distribution, excluding the mid-infrared data, yields a main stellar population's age of (8 +- 3) Gyr with a metallicity of Z = 0.012 +- 0.006. There is no indication of any significant star formation over the last few Gyr. Whether gas and dust were dynamically kept out or evacuated from the central cavity remains unclear. The best-fit suggests an excess of flux in the mid-infrared bands, with further indications that the center of the mid-infrared structure is displaced with respect to the optical center of the NSC. We discuss five potential scenarios, none of them fully explaining both the observed photometry and structure.Comment: 26 pages, 10 figures, 6 tables. Accepted for publication by ApJ

PHANGS-JWST First Results: Spurring on Star Formation: JWST Reveals Localized Star Formation in a Spiral Arm Spur of NGC 628

We combine JWST observations with Atacama Large Millimeter/submillimeter Array CO and Very Large Telescope MUSE Hα data to examine off-spiral arm star formation in the face-on, grand-design spiral galaxy NGC 628. We focus on the northern spiral arm, around a galactocentric radius of 3-4 kpc, and study two spurs. These form an interesting contrast, as one is CO-rich and one CO-poor, and they have a maximum azimuthal offset in MIRI 21 μm and MUSE Hα of around 40° (CO-rich) and 55° (CO-poor) from the spiral arm. The star formation rate is higher in the regions of the spurs near spiral arms, but the star formation efficiency appears relatively constant. Given the spiral pattern speed and rotation curve of this galaxy and assuming material exiting the arms undergoes purely circular motion, these offsets would be reached in 100-150 Myr, significantly longer than the 21 μm and Hα star formation timescales (both < 10 Myr). The invariance of the star formation efficiency in the spurs versus the spiral arms indicates massive star formation is not only triggered in spiral arms, and cannot simply occur in the arms and then drift away from the wave pattern. These early JWST results show that in situ star formation likely occurs in the spurs, and that the observed young stars are not simply the “leftovers” of stellar birth in the spiral arms. The excellent physical resolution and sensitivity that JWST can attain in nearby galaxies will well resolve individual star-forming regions and help us to better understand the earliest phases of star formation

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p &lt; 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D