Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression

Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study

Non-Canonical Pathways in the Pathophysiology and Therapeutics of Bipolar Disorder

Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway

Ejection of Matter and Energy from NGC 4258

It has been claimed that the megamaser observations of the nucleus of NGC 4258 show that a massive black hole is present in its center (Miyoshi et al. 1995, Greenhill et al. 1995). We show that the evidence of ejection of gas, radio plasma, and X-ray emitting QSOs from this nucleus all show that the ejection is coming from the center in a curving flow within a cone with angle ~40 degrees, centered at P.A. 100 degrees. This is close to the direction in which the velocities from the megamaser have been measured, so that the evidence taken as a whole suggests that the masering gas also is being ejected in the same direction at velocities +/- 900 km/sec and not rotating about a massive black hole. Thus it does not provide evidence for a black hole in the center. Subject headings: galaxies: nuclei: individual (NGC 4258) -- black holes -- masersComment: 7 pages, 1 Figure, LaTex using epsf.tex, submitted to Ap.J.Letter

On the Dynamical and Physical State of the `Diffuse Ionized Medium' in Nearby Spiral Galaxies

We have analyzed deep narrow-band H$\alpha$ images and high-resolution long-slit spectra for a sample of the nearest and brightest late-type galaxies to study the morphology, physical state, and kinematics of the `Diffuse Ionized Medium' (`DIM'). We find that the DIM covers most of the star-forming disk, and is morphologically related to the presence of the giant HII regions. In addition, the DIM and the giant HII regions differ systematically in their physical and dynamical state. The DIM is characterized by enhanced emission in the low-ionization forbidden lines ([OI], [NII], and [SII]), and even the high-ionization [OIII]$\lambda$5007 line is moderately strong in the DIM. We verify the inference made by Lehnert & Heckman that the DIM contributes significantly to the global emission-line ratios measured in late-type galaxies. We also find that the DIM is more disturbed kinematically than the gas in the giant HII regions. The intrinsic FWHMs of the H$\alpha$ and [NII]$\lambda$6584 lines range from 30 to 100 km s$^{-1}$ in the DIM compared to 20-50 km s$^{-1}$ in HII regions. The high-ionization gas in the DIM is even more kinematically disturbed than the low-ionization gas: the [OIII]$\lambda$5007 lines have intrinsic FWHMs of 70-150 km s$^{-1}$. The differing kinematics implies that `the DIM' is not a single monolithic phase of the ISM. Instead, it may consist of a `quiescent DIM' with a low ionization-state and small scale-height (few hundred pc) and a `disturbed DIM' with a high ionization state and moderate scale-height (0.5 to 1 kpc). We argue that the quiescent DIM is most likely photoionized by radiation leaking out of giant HII regions, while the disturbed DIM is most likely heated by the mechanical energy supplied by supernovae and stellar winds.Comment: 37 pages(including 7 tables) and 12 figures. To appear in the Dec 10, 1997 issue of The Astrophysical Journa

Radio Continuum Jet in NGC 7479

The barred galaxy NGC 7479 hosts a remarkable jet-like radio continuum feature: bright, 12-kpc long in projection, and hosting an aligned magnetic field. The degree of polarization is 6%-8% along the jet, and remarkably constant, which is consistent with helical field models. The radio brightness of the jet suggests strong interaction with the ISM and hence a location near the disk plane. We observed NGC 7479 at four wavelengths with the VLA and Effelsberg radio telescopes. The equipartition strength is 35-40 micro-G for the total and >10 micro-G for the ordered magnetic field in the jet. The jet acts as a bright, polarized background. Faraday rotation between 3.5 and 6 cm and depolarization between 6 and 22 cm can be explained by magneto-ionic gas in front of the jet, with thermal electron densities of ~0.06 cm**(-3) in the bar and ~0.03 cm**(-3) outside the bar. The regular magnetic field along the bar points toward the nucleus on both sides. The regular field in the disk reveals multiple reversals, probably consisting of field loops stretched by a shearing gas flow in the bar. The projection of the jet bending in the sky plane is in the sense opposite to that of the underlying stellar and gaseous spiral structure. The bending in 3-D is most easily explained as a precessing jet, with an age less than 10**6 years. Our observations are consistent with very recent triggering, possibly by a minor merger. NGC 7479 provides a unique opportunity to study interaction-triggered 15-kpc scale radio jets within a spiral galaxy.Comment: 18 pages, 21 figures, accepted for publication in the Astrophysical Journa

Clusters of Extragalactic Ultra Compact HII Regions

We report on the detection of optically thick free-free radio sources in the galaxies M33, NGC 253, and NGC 6946 using data in the literature. We interpret these sources as being young, embedded star birth regions, which are likely to be clusters of ultracompact HII regions. All 35 of the sources presented in this article have positive radio spectral indices alpha>0 suggesting an optically thick thermal bremsstrahlung emission arising in the HII region surrounding hot stars. Energy requirements indicate a range of a several to >500 O7V star equivalents powering each HII region. Assuming a Salpeter IMF, this corresponds to integrated stellar masses of 0.1--60,000 Msun. For roughly half of the sources in our sample, there is no obvious optical counterpart, giving further support for their deeply embedded nature. Their luminosities and radio spectral energy distributions are consistent with HII regions having electron densities from 1500 cm^-3 to 15000 cm^-3 and radii of 1 - 7 pc. We suggest that the less luminous of these sources are extragalactic ultracompact HII region complexes, those of intermediate luminosity are similar to W49 in the Galaxy, while the brightest will be counterparts to 30 Doradus. These objects constitute the lower mass range of extragalactic ``ultradense HII regions'' which we argue are the youngest stages of massive star cluster formation yet observed. This sample is beginning to fill in the continuum of objects between small associations of ultracompact HII regions and the massive extragalactic clusters that may evolve into globular clusters.Comment: 37 pages, uses AASTeX; scheduled to appear in ApJ v. 559 October 2001. Full postscript version available from http://www.astro.wisc.edu/~chip/Papers/Johnson_Kobulnicky_etal_ApJ559.ps.g

Polarized Narrow-Line Emission from the Nucleus of NGC 4258

The detection of polarized continuum and line emission from the nucleus of NGC 4258 by Wilkes et al. (1995) provides an intriguing application of the unified model of Seyfert nuclei to a galaxy in which there is known to be an edge-on, rotating disk of molecular gas surrounding the nucleus. Unlike most Seyfert nuclei, however, NGC 4258 has strongly polarized narrow emission lines. To further investigate the origin of the polarized emission, we have obtained spectropolarimetric observations of the NGC 4258 nucleus at the Keck-II telescope. The narrow-line polarizations range from 1.0% for [S II] 6716 to 13.9% for the [O II] 7319,7331 blend, and the position angle of polarization is oriented nearly parallel to the projected plane of the masing disk. A correlation between critical density and degree of polarization is detected for the forbidden lines, indicating that the polarized emission arises from relatively dense (n_e > 10^4 cm^-3) gas. An archival Hubble Space Telescope narrow-band [O III] image shows that the narrow-line region has a compact, nearly unresolved core, implying a FWHM size of <2.5 pc. We discuss the possibility that the polarized emission might arise from the accretion disk itself and become polarized by scattering within the disk atmosphere. A more likely scenario is an obscuring torus or strongly warped disk surrounding the inner portion of a narrow-line region which is strongly stratified in density. The compact size of the narrow-line region implies that the obscuring structure must be smaller than ~2.5 pc in diameter.Comment: To appear in the Astronomical Journal. 13 pages, including 1 table and 4 figures. Uses emulateapj.st

Chandra Observations and the Nature of the Anomalous Arms of NGC 4258 (M 106)

This paper presents high resolution X-ray observations with Chandra of NGC 4258 and infers the nature of the so called ``anomalous arms'' in this galaxy. The anomalous arms dominate the X-ray image; diffuse X-ray emission from the ``plateaux'' regions, seen in radio and H$\alpha$ imaging, is also found. X-ray spectra have been obtained at various locations along the anomalous arms and are well described by thermal (mekal) models with kT in the range 0.37 - 0.6 keV. The previously known kpc-scale radio jets are surrounded by cocoons of hot X-ray emitting gas for the first 350 pc of their length. The radio jets, seen in previous VLBA and VLA observations, propagate perpendicular to the compact nuclear gas disk (imaged in water vapor maser emission). The angle between the jets and the rotation axis of the galactic disk is 60$^{\circ}$. The jets shock the normal interstellar gas along the first 350 pc of their length, causing the hot, X-ray emitting cocoons noted above. At a height of z = 175 pc from the disk plane, the jets exit the normal gas disk and then propagate though the low density halo until they reach ``hot spots'' (at 870 pc and 1.7 kpc from the nucleus), which are seen in radio, optical line and X-ray emission. These jets must drive mass motions into the low density halo gas. This high velocity halo gas impacts on the dense galactic gas disk and shock heats it along and around a ``line of damage'', which is the projection of the jets onto the galactic gas disk as viewed down the galaxy disk rotation axis. However, because NGC 4258 is highly inclined ($i$ = 64$^{\circ}$), the ``line of damage'' projects on the sky in a different direction to the jets themselves. We calculate the expected p.a. of the ``line of damage'' on the sky and find that it coincides with the anomalous arms to within 2$^{\circ}$. (Abstract truncated).Comment: 12 pages plus 9 figures, to be published in the Astrophysical Journal, v560, nr 1, pt 1 (Oct 10, 2001 issue

Ultraviolet Signposts of Resonant Dynamics in the Starburst-Ringed Sab Galaxy, M94 (NGC 4736)

M94 (NGC 4736) is investigated using images from the Ultraviolet Imaging Telescope (FUV-band), Hubble Space Telescope (NUV-band), Kitt Peak 0.9-m telescope (H-alpha, R, and I bands), and Palomar 5-m telescope (B-band), along with spectra from the International Ultraviolet Explorer and Lick 1-m telescopes. The wide-field UIT image shows FUV emission from (a) an elongated nucleus, (b) a diffuse inner disk, where H-alpha is observed in absorption, (c) a bright inner ring of H II regions at the perimeter of the inner disk (R = 48 arcsec. = 1.1 kpc), and (d) two 500-pc size knots of hot stars exterior to the ring on diametrically opposite sides of the nucleus (R= 130 arcsec. = 2.9 kpc). The HST/FOC image resolves the NUV emission from the nuclear region into a bright core and a faint 20 arcsec. long ``mini-bar'' at a position angle of 30 deg. Optical and IUE spectroscopy of the nucleus and diffuse inner disk indicates an approximately 10^7 or 10^8 yr-old stellar population from low-level starbirth activity blended with some LINER activity. Analysis of the H-alpha, FUV, NUV, B, R, and I-band emission along with other observed tracers of stars and gas in M94 indicates that most of the star formation is being orchestrated via ring-bar dynamics involving the nuclear mini-bar, inner ring, oval disk, and outer ring. The inner starburst ring and bi-symmetric knots at intermediate radius, in particular, argue for bar-mediated resonances as the primary drivers of evolution in M94 at the present epoch. Similar processes may be governing the evolution of the ``core-dominated'' galaxies that have been observed at high redshift. The gravitationally-lensed ``Pretzel Galaxy'' (0024+1654) at a redshift of approximately 1.5 provides an important precedent in this regard.Comment: revised figure 1 (corrected coordinate labels on declination axis); 19 pages of text + 19 figures (jpg files); accepted for publication in A

Atomic Hydrogen produced in M33 Photodissociation Regions

We derive total (atomic + molecular) hydrogen densities in giant molecular clouds (GMCs) in the nearby spiral galaxy M33 using a method that views the atomic hydrogen near regions of recent star formation as the product of photodissociation. Far-UV photons emanating from a nearby OB association produce a layer of atomic hydrogen on the surfaces of nearby GMCs. Our approach provides an estimate of the total hydrogen density in these GMCs from observations of the excess far-UV emission that reaches the GMC from the OB association, and the excess 21-cm radio HI emission produced after these far-UV photons convert H2 into HI on the GMC surface. The method provides an alternative approach to the use of CO emission as a tracer of H2 in GMCs, and is especially sensitive to a range of density well below the critical density for CO(1-0) emission. We describe our "PDR method" in more detail and apply it using GALEX far-UV and VLA 21-cm radio data to obtain volume densities in a selection of GMCs in the nearby spiral galaxy M33. We have also examined the sensitivity of the method to the linear resolution of the observations used; the results obtained at 20 pc are similar to those for the larger set of data at 80 pc resolution. The cloud densities we derive range from 1 to 500 cm-3, with no clear dependence on galactocentric radius; these results are generally similar to those obtained earlier in M81, M83, and M101 using the same method.Comment: Accepted for publication in MNRAS. 25 figures, 16 tables, including online-only material