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Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA).
Methods
A 2018–2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample.
Results
In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (s.e.) of 0.66 (0.04) in the test sample. A strong gradient in probability (s.e.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors.
Conclusions
Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.
Fewer than half of patients with major depressive disorder (MDD) respond to psychotherapy. Pre-emptively informing patients of their likelihood of responding could be useful as part of a patient-centered treatment decision-support plan.
Methods
This prospective observational study examined a national sample of 807 patients beginning psychotherapy for MDD at the Veterans Health Administration. Patients completed a self-report survey at baseline and 3-months follow-up (data collected 2018–2020). We developed a machine learning (ML) model to predict psychotherapy response at 3 months using baseline survey, administrative, and geospatial variables in a 70% training sample. Model performance was then evaluated in the 30% test sample.
Results
32.0% of patients responded to treatment after 3 months. The best ML model had an AUC (SE) of 0.652 (0.038) in the test sample. Among the one-third of patients ranked by the model as most likely to respond, 50.0% in the test sample responded to psychotherapy. In comparison, among the remaining two-thirds of patients, <25% responded to psychotherapy. The model selected 43 predictors, of which nearly all were self-report variables.
Conclusions
Patients with MDD could pre-emptively be informed of their likelihood of responding to psychotherapy using a prediction tool based on self-report data. This tool could meaningfully help patients and providers in shared decision-making, although parallel information about the likelihood of responding to alternative treatments would be needed to inform decision-making across multiple treatments.
Introduced species can have strong ecological, social and economic effects on their non-native environment. Introductions of megafaunal species are rare and may contribute to rewilding efforts, but they may also have pronounced socio-ecological effects because of their scale of influence. A recent introduction of the hippopotamus Hippopotamus amphibius into Colombia is a novel introduction of a megaherbivore onto a new continent, and raises questions about the future dynamics of the socio-ecological system into which it has been introduced. Here we synthesize current knowledge about the Colombian hippopotamus population, review the literature on the species to predict potential ecological and socio-economic effects of this introduction, and make recommendations for future study. Hippopotamuses can have high population growth rates (7–11%) and, on the current trajectory, we predict there could be 400–800 individuals in Colombia by 2050. The hippopotamus is an ecosystem engineer that can have profound effects on terrestrial and aquatic environments and could therefore affect the native biodiversity of the Magdalena River basin. Hippopotamuses are also aggressive and may pose a threat to the many inhabitants of the region who rely upon the Magdalena River for their livelihoods, although the species could provide economic benefits through tourism. Further research is needed to quantify the current and future size and distribution of this hippopotamus population and to predict the likely ecological, social and economic effects. This knowledge must be balanced with consideration of social and cultural concerns to develop appropriate management strategies for this novel introduction.
Near-concurrent surges and multi-decadal surface-elevation changes on the Malaspina Glacier system Alaska, USA, and Yukon, Canada, were investigated using digital elevation models and laser altimetry from airborne and space-borne sensors. Surface-elevation changes on Seward Lobe in two time periods support a hypothesis of moraine folding by a mechanism of sequential surges alternating from southeast to south-southwest. The near-concurrent surges of Agassiz, Lower Seward and Marvine glaciers support a hypothesis of englacial water storage being a critical factor of surging. Acceleration of area-average surface lowering on the piedmont glaciers occurred, from 1.5 ± 0.1 m a−1 between 1972 and 1999 to 2.3 ± 0.3 m a−1 between 1999 and 2002. On the western half of Upper Seward Glacier, above 1600 m, acceleration of surface lowering occurred from 2000 to 2003 relative to that from 1976 to 2000, indicating an effect from the surge of Lower Seward Glacier. From 2003 to 2006, the rate of surface lowering on Upper Seward Glacier has moderated back to the pre-2000 rate, indicating a recovery of surface elevation following the surge. From 1972 to 2002, the Malaspina Glacier system lost 156 ± 19 km3 (ice equivalent) on an area of 3661 km2.
Using airborne and spaceborne high-resolution digital elevation models and laser altimetry, we present estimates of interannual and multi-decadal surface elevation changes on the Bering Glacier system, Alaska, USA, and Yukon, Canada, from 1972 to 2006. We find: (1) the rate of lowering during 1972–95 was 0.9 ± 0.1 m a−1; (2) this rate accelerated to 3.0 ± 0.7 m a−1 during 1995–2000; and (3) during 2000–03 the lowering rate was 1.5 ± 0.4 m a−1. From 1972 to 2003, 70% of the area of the system experienced a volume loss of 191 ± 17 km3, which was an area-average surface elevation lowering of 1.7 ± 0.2 m a−1. From November 2004 to November 2006, surface elevations across Bering Glacier, from McIntosh Peak on the south to Waxell Ridge on the north, rose as much as 53 m. Up-glacier on Bagley Ice Valley about 10 km east of Juniper Island nunatak, surface elevations lowered as much as 28 m from October 2003 to October 2006. NASA Terra/MODIS observations from May to September 2006 indicated muddy outburst floods from the Bering terminus into Vitus Lake. This suggests basal–englacial hydrologic storage changes were a contributing factor in the surface elevation changes in the fall of 2006.
Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.
Humans have been managing terrestrial carbon (C) since time immemorial as a way to obtain energy stored in vegetation, food, and fiber from domesticated crops and animals, as well as wood products from forests. This manipulation of terrestrial C, inadvertent at first, has been more deliberate since 1800 and led to a net release of C to the atmosphere of about 200 Pg C since then. The net annual carbon dioxide (CO2) flux to the atmosphere from vegetation and soils, currently estimated at 1.2 Pg C·y−1 mainly due to land-use changes in tropical environments, is a major factor contributing to rising atmospheric CO2.
In 1977, Freeman Dyson hypothesized that the accumulation of CO2 in the atmosphere could be controlled via tree planting and estimated that approximately 4.5 Pg C · y−1 could be sequestered this way (Dyson 1977). The possibility of storing C in soils as a way to mitigate atmospheric CO2 increase and to restore lost soil organic matter and fertility emerged about two decades ago. Cole et al. (1997) estimated that about two-thirds of the historical losses of soil organic carbon (SOC) (approximately 40 Pg C) could be sequestered over 50 to 100 years through the implementation of nutrient management, cropping intensity, diversified crop rotation, and reduced tillage practices. In the Intergovernmental Panel on Climate Change (IPCC) second assessment report, Brown et al. (1996) estimated that about 38 Pg C could be sequestered on 345 × 106 hectares during 50 years via afforestation, reforestation, and agroforestry practices. Indeed, the Kyoto Protocol recognized afforestation and reforestation as mitigation practices implementable through the Clean Development Mechanism (CDM). Although the importance of soils as a C repository was recognized in the Kyoto Protocol, this technology was not included as a mitigation practice during the first commitment period (2008 to 2012) due to measurement uncertainties.
Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944–45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.
The recurrent affective disorders are discussed from the perspective of accumulating inherited and experiential effects on gene expression. Stress and episodes of affective illness are viewed as leaving biochemical and microstructural residues in the central nervous system (CNS) in relation to their patterning, severity, and recurrence. Comorbid factors such as substance abuse and developmental disturbances may also interact with these illness-related variables. In addition to the primary pathological processes, secondary adaptive changes can also be induced, which, in concert with pharmacological interventions, may be sufficient to counter episode occurrences and illness progression. We postulate that the balance of primary pathological and secondary adaptive changes at multiple levels of CNS regulation accounts for recurrence and cyclicity in the affective disorders. The importance of early, effective, long-term interventions in the recurrent affective disorders and the therapeutic potential of several new treatment modalities including repeated transcranial magnetic stimulation (rTMS) are discussed.
Electrophysiological kindling and behavioral sensitization to psychomotor stimulants and stress provide paradigms for understanding how repeated acute events can leave neurobiological residues in gene expression, accounting for the observed long-lasting alterations in behavioral responsivity. Kindling helps conceptualize how repeated electrical stimulation of the brain can progressively evoke increased behavioral and convulsive responsivity, leading to spontaneous seizures in the absence of exogenous stimulation following sufficient stimulations. As kindling unfolds, a complex spatiotemporal cascade of events occurs and includes the induction of immediate early genes (e.g., c-fos) and late effector genes (including peptides and growth factors) possibly associated with the observed changes in brain microstructure (e.g., synapse formation, axonal and dendritic sprouting, apoptosis). Behavioral sensitization to psychomotor stimulants and stress has also been shown to induce related but different cascades of effects on immediate early and late effector gene expression. These may be associated with the observed long-lasting alterations in behavioral responsivity based on prior experience. If these types of alterations are put into a developmental context, this would provide a paradigm for understanding how early life events could exert profound and behaviorally relevant biochemical and microstructural effects on the central nervous system of the developing organism. The conceptual overview offered by the sensitization and kindling models suggests that environmentally triggered neurobiological processes do not form a single or static residue but, instead, engage processes related to developmental neurobiology and learning and memory and whose substrate is constantly evolving over an organism's lifetime.
Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing.
Methods
During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments.
Results
We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity.
Conclusion
These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.
Psychosocial stress plays an important role at multiple junctures in
the onset and course of bipolar disorder. Childhood adversity may be a
risk factor for vulnerability to early onset illness, and an array of
stressors may be relevant not only to the onset, recurrence, and
progression of affective episodes, but the highly prevalent substance
abuse comorbidities as well. A substantial group of controlled studies
indicate that various cognitive behavioral psychotherapies and
psychoeducational approaches may yield better outcomes in bipolar disorder
than treatment as usual. Yet these approaches do not appear to be
frequently or systematically employed in clinical practice, and this may
contribute to the considerable residual morbidity and mortality associated
with conventional treatment. Possible practical approaches to reducing
this deficit (in an illness that is already underdiagnosed and
undertreated even with routine medications) are offered. Without the
mobilization of new clinical and public health approaches to earlier and
more effective treatment and supportive interventions, bipolar illness
will continue to have grave implications for many patients' long-term
well being.This article was based on work
in the Intramural Program of the NIMH and work in the former Stanley
Foundation Bipolar Network. The principal investigators of the Network
included L. Altshuler, M. Frye, T. Suppes, S. McElroy, P. Keck, Jr., W.
Nolen, R. Kupka, J. Walden, and H. Grunze. We also acknowledge the special
contributions of D. Luckenbaugh and S. Perez in data analysis and C. Gavin
and H. Brightman in manuscript preparation.
Few studies have examined the relative risks of switching into hypomania
or mania associated with second-generation antidepressant drugs in
bipolar depression.
Aims
To examine the relative acute effects of bupropion, sertraline and
venlafaxine as adjuncts to mood stabilisers.
Method
In a 10-week trial, participants receiving out-patient treatment for
bipolar disorder (stratified for rapid cycling) were randomly treated
with a flexible dose of one of the antidepressants, or their respective
matching placebos, as adjuncts to mood stabilisers.
Results
A total of 174 adults with bipolar disorder I, II or not otherwise
specified, currently in the depressed phase, were included. All three
antidepressants were associated with a similar range of acute response
(49–53%) and remission (34–41%). There was a significantly increased risk
of switches into hypomania or mania in participants treated with
venlafaxine compared with bupropion or sertraline.
Conclusions
More caution appears indicated in the use of venlafaxine rather than
bupropion or sertraline in the adjunctive treatment of bipolar
depression, especially if there is a prior history of rapid cycling.