Treatment-resistant depression: definition,prevalence, detection,management, and investigational interventions

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.     

A NEW METHOD OF POLARIZATION MICROSCOPIC ANALYSIS : I. Scanning with a Birefringence Detection System

A new method of polarized light analysis is described in which a highly sensitive electronic detector specific for birefringence is used to identify the crystalline axes of an object and then measure its phase retardation due to birefringence. The microscopic system employed in the method consists of an electronic birefringence detection system (BDS), a microscope with strain-free lenses, and a driven stage for passing the specimen at appropriate velocities across the image of an aperture placed at the field stop and imaged in the specimen plane by the condenser. The detector registers retardations directly as voltage at a constant deflection sensitivity of ca. 1.1 v per angstrom unit over a range of 120 angstrom units. The basal rms noise level is 0.002 A for a spot 36 µ in diameter formed by a 95 x, N. A. 1.25 objective pair, and increases in proportion to the reciprocal of the diameter of the scanning spot. The increase in noise with high resolution scanning can be offset by increasing the instrumental time constant, which is adjustable in decades between 0.004 and 0.4 seconds. A number of difficult problems in high extinction polarization microscopy are avoided by the use of modulated light and a rapid electronic detector. For example: (a) The measured distribution of birefringence is unaffected by the usual diffraction anomaly; therefore polarization rectifiers are not required. (b) The detector is selective for birefringence, so that there is no problem in separating contrast due to different optical properties (e.g. dichroism, light scattering). (c) The speed and sensitivity are both increased by between one and two orders of magnitude over that attainable by visual or photographic methods, thereby rendering a vast number of weakly birefringent, light-scattering, and motile objects readily analyzable for the first time with polarized light.     

Differentiation of species in Gonioloboceras

The type specimen ofGonioloboceras goniolobum (Meek), rediscovered by Spath in the British Museum, is the foundation for a more accurate comparative study of this and other species ofGonioloboceras.Gonioloboceras described asG. goniolobum byElias in 1938 is differentiated asGonioloboceras schmidti, new species. Suture sets (new term) for several growth stages inG. goniolobum (Meek),G. welleriSmith,G. schmidtiElias, G.eliasiMiller &Owen, andG. asiaticumLibrovitch are assembled and used for differentiation of the species.The Kazakhstan goniatite faunule containingG. asiaticum is considered of very late Pennsylvanian age.     

Spontaneous Activity in Crustacean Neurons

Single units which discharged with regular spontaneous rhythms without intentional stimulation were observed in the ventral nerve cord by intracellular recording close to the sixth abdominal ganglion. These units were divided into two groups: group A units in which interspike intervals varied less than 10 msec.; group B units in which interspike intervals varied within a range of 10 to 30 msec. Group A units maintained "constant" interspike intervals and could not be discharged by sensory inputs, while the majority of group B units could be discharged by appropriate sensory nerve stimulation. Both group A and B units discharged to direct stimulation when the stimulating and recording electrodes were placed in the same ganglionic intersegment, and directly evoked single spikes reset the spontaneous rhythm. In group B units, presynaptic volleys reset the spontaneous rhythm of some units; but in others, synaptically evoked spikes were interpolated within the spontaneous rhythm without resetting. The phenomenon of enhancement could also be demonstrated in spontaneously active units as a result of repetitive stimulation. It is concluded that endogenous pacemaker activity is responsible for much of the regular spontaneous firing observed in crayfish central neurons, and that interaction of evoked responses with such pacemaker sites can produce a variety of effects dependent upon the anatomical relationships between pacemaker and synaptic regions.     

Radiolabelling Studies of Lipids in the Marine Cryptomonad Chroomonas salina in Relation to Fatty Acid Desaturation

Cells of Chroomonas salina were exposed to [¹⁴C]acetate, [^l4C]16:0,[¹⁴C]18:0, [¹⁴C]18:1(n-9), [¹⁴C]18:2(n–6) or [¹⁴C]18:3(n–3)for 1 h and then incubated for 24 h in non-radioactive medium.At the end of the pulse period, non-glycolipid polar lipidscontained the highest proportions of radioactivity incorporatedfrom [¹⁴C]acetate and [¹⁴C]18:3(n–3) whereas with [¹⁴C]16:0,[¹⁴C]18:1 and [¹⁴C]18:2(n–6), triacylglycerols were mosthighly labelled. ¹⁴C-18:0 was recovered mainly as non-esterifiedfatty acid. Monogalactosyldiacylglycerol initially contained17% of label incorporated from [¹⁴C]acetate but less than 3%of that from [¹⁴C]fatty acids. With all substrates, excluding[¹⁴C]18:0, a gradual transfer of label from polar lipids totriacylglycerols was observed during the chase period. Saturatesand monoenes synthesised from [¹⁴C]acetate were mostly transferedfrom phospholipids and glycolipids to neutral lipid withoutfurther desaturation. Most of the incorporated ¹⁴C-fatty acidsremained unchanged and only with [¹⁴C]18:3(n–3) was substantialamounts of label recovered in penta- and hexaenoic fatty acids.The results indicate that, under the conditions of the study,lipid synthesis in the algae was heavily dominated by triacylglycerolformation and that the mechanisms of fatty acid desaturationin this species may differ from those in higher plants. (Received December 10, 1991; Accepted March 6, 1992)     

Light, temperature and nutrients as factors in photosynthetic adjustment to an elevated concentration of carbon dioxide

The short-term stimulation of the net rate of carbon dioxide exchange of leaves by elevated concentrations of CO₂ usually observed in C₃ plants sometimes does not persist. Experiments were conducted to test whether the patterns of response to the environment during growth were consistent with the hypotheses that photosynthetic adjustment to elevated CO₂ concentration is due to (1) feedback inhibition or (2) nutrient stress. Soybean [Glycine max (L.) Merr. cv. Williams] and sugar beet (Best vulgaris L. cv. Mono Hye-4) were grown from seed at 350 and 700 μl^? CO₂, at 20 and 25°C, at a photon flux density of 0.5 and 1.0 mmol m^?2 S^?1 and with three nutrient regimes until the third trifoliolate leaf of soybean or the sixth leaf of sugar beet had finished expanding. Net rates of CO₂ exchange of the most recently expanded leaves were then measured at both 350 and 700 μl 1^?1 CO₂. Plants grown at the elevated CO₂ concentration had net rates of leaf CO₂ exchange which were reduced by 33% in sugar beet and 23% in soybean when measured at 350 μl 1^?1 CO₂ and when averaged over all treatments. Negative photosynthetic adjustment to elevated CO₂ concentration was not greater at 20 than at 25°C, was not greater at a photon flux density of 1.0 than at 0.5 mmol m^?2 S^?1 and was not greater with limiting nutrients. Furthermore, in soybean, negative photosynthetic adjustment could be induced by a single night at elevated CO₂ concentration, with net rates of CO₂ exchange the next day equal to those of leaves of plants grown from seed at the elevated concentration of CO₂. These patterns do not support either the feedback-inhibition or the nutrient-stress hypothesis of photosynthetic adjustment to elevated concentrations of CO₂.     

COMPARISON OF PLANT DNA CONTENTS DETERMINED BY FEULGEN MICROSPECTROPHOTOMETRY AND LASER FLOW CYTOMETRY

An improved procedure is reported for determining DNA amounts of plant nuclei. Nuclei stained with propidium iodide, isolated from chopped plant leaves, were passed through an Ortho Cytofluorograph with a Lexel model 95 argon laser (514 nm) and the fluorescence measured, integrated, and recorded using an Ortho 2140 Data Acquisition computer. All nuclear samples were mixed with nuclei of Sultan barley (2C DNA content = 11.12 pg [picogram]) as an internal standard. DNA contents of ten plant species, ranging from 2C = 1.7 pg to 36.1 pg measured by flow cytometry, correlated strongly (r = 0.99, slope = + 1.00) with DNA contents determined from Feulgen-stained nuclei of the same species using microspectrophotometry. The flow cytometric procedures were sufficiently sensitive to detect differences in DNA content between inbred lines of corn and their F1 hybrids. Our results obtained with improved procedures, specifically using propidium iodide as a fluorochrome and plant nuclei instead of chicken erythrocytes as an internal standard, demonstrate that laser flow cytometry can be a precise, rapid, and reliable method for determining nuclear DNA content of plants.